Publications
2026
-
Professional Stakeholders' Perspectives on Early Screening for Type 1 Diabetes in Children: A Systematic Review
Early screening for type 1 diabetes (T1D) is receiving increasing attention as presymptomatic screening initiatives and disease-modifying therapies continue to expand. However, the perspectives of professional stakeholders, who play a pivotal role in implementation, patient engagement, and health system preparedness, have not been systematically synthesised. We conducted a systematic review to examine professional views on paediatric early T1D screening. Following PRISMA guidelines, six... -
Testing the safety of nature-based microbial exposure in atopic dermatitis patients: a randomized, placebo-controlled, double-blinded pilot trial
The biodiversity hypothesis posits that contact with microbial biodiversity is beneficial for human health, and that the loss of such contact may contribute to immune-mediated diseases such as atopy. Based on this hypothesis, we aimed to investigate whether a lotion containing a highly diverse mixture of inactivated natural microbes is a safe and feasible method to administer nature-based microbial exposure to humans, and to assess its effects on healthy and atopic skin. Participants with atopic... -
Gut microbiome maturation in early childhood interacts with host genetics to predict type 1 diabetes risk
Prospective evidence linking early-life microbiome development and host genetics with type 1 diabetes (T1D) risk is limited. Here, we describe how gut microbiome maturation and host genetics influence T1D risk in the TEDDY study. We analysed 12,151 longitudinal metagenomes and host genetic data from 887 children at high genetic risk for T1D followed for up to 6 years. We identify three microbiome maturational patterns: Early Matured, Late Matured and Early Plateaued, driven primarily by... -
Coxsackievirus B Infections Are Associated With the Risk of Islet Autoimmunity in Children With Strong Genetic Susceptibility to Type 1 Diabetes-Results From the TRIGR Divia Study
CONCLUSIONS: This study supports previous evidence of the risk association of coxsackievirus B infections. These results support the role of certain virus infections as possible modulating factors in the pathogenesis of type 1 diabetes. -
Maternal Intake of Vitamins A, C, D, and E During Pregnancy and Risk of Type 1 Diabetes in the Child: The Norwegian Mother, Father, and Child Cohort Study
CONCLUSIONS: This prospective cohort study does not support the hypothesis that higher maternal intake of vitamins A, C, D, and E during pregnancy would decrease risk of type 1 diabetes in the child. Corroborated with previous evidence, our findings support a general pattern of null associations. -
Safety and Immunogenicity of a Vaccine Against Coxsackieviruses B (PRV-101)-Follow-up of the First-in-Human Phase 1 Trial
CONCLUSIONS: These results suggest that PRV-101 induces durable antibody responses lasting for at least 2 years. The findings support the continued development of PRV-101 for preventing both acute coxsackie B virus infections and chronic diseases like type 1 diabetes and celiac disease. -
Psychosocial implications, acceptability and ethics of screening for paediatric type 1 diabetes: a systematic review and mixed methods evidence synthesis
CONCLUSIONS/INTERPRETATION: This, the most comprehensive review of the literature to date, demonstrates that despite the emotional, cognitive and behavioural implications, thus far, screening and early detection of paediatric type 1 diabetes appears to be acceptable to parents/guardians who take part but critical evidence gaps remain. -
Exploring the psychosocial implications of general population screening for paediatric type 1 diabetes in Europe: Protocol for a mixed-methods study
CONCLUSIONS: The study will provide essential insights into how best a general population screening program for T1D can be integrated into existing European health systems. -
Early-life immunological and microbial differences between East African and North European children
CONCLUSIONS: These results highlight the early emergence of differences in the immune system and gut microbiota between children living in extremities of the microbial exposure gradient. These differences add to the existing knowledge of possible factors contributing to increasing prevalence of chronic inflammatory diseases in African societies shifting towards more Westernized lifestyle. -
Marine n-3 Long-Chain Polyunsaturated Fatty Acid Intake in Pregnancy and Risk of Early Life Infections in 3 Nordic Cohorts: A HEDIMED Consortium Study
CONCLUSIONS: This study does not provide consistent evidence that higher maternal n-3 LCPUFA pregnancy intake reduces the risk of infections in early childhood. -
Distinct Enterovirus Antigen Landscape in Children With Islet Autoimmunity
Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes. However, given the ubiquity of EV infections in children, disease susceptibility is likely driven by host-specific immune responses rather than viral exposure alone. To investigate the host antibody response to EVs, we used virome-wide serological profiling (VirScan) to compare the EV antigen landscapes in IA-positive case children versus IA-negative control children across two... -
Transient receptor potential ankyrin 1 promotes the expression of interferon-stimulated antiviral genes in human A549 lung epithelial cells
Transient receptor potential ankyrin 1 (TRPA1) is an ion channel known for its chemosensory function in neurons, causing pain and neurogenic inflammation. TRPA1 is activated by many noxious compounds including some inflammatory mediators. We and others have shown that TRPA1 is also expressed in epithelial cells, but its function in the epithelial barrier remains unclear. Here, we discovered in RNA-seq studies that inhibition of TRPA1 reduced the expression of a large number of antiviral and... -
Screening for Celiac Disease in Childhood: Cost-Effectiveness of Multiple Genetic and Serological Testing Approaches
CONCLUSIONS: The most cost-effective screening strategy for celiac disease was single-time untargeted serological testing at age 11. The optimal approach is affected by regional factors and may evolve with new evidence. Repeated screening may be preferable for high-risk groups and with high willingness to pay. -
Environmental Factors in Type 1 Diabetes
The contribution of environmental factors to the pathogenesis of type 1 diabetes is considered substantial, but their identification has turned out to be challenging. Large prospective studies are crucial for reliable identification of environmental risk and protective factors. However, only few large prospective birth cohort studies have been carried out. Enterovirus infections have shown quite consistent risk association with the initiation of islet autoimmunity (IA) across these studies.... -
Fate of five celiac disease-associated antibodies during normal diet in genetically at-risk children observed from birth in a natural history study
CONCLUSIONS: Potential CD trigger(s) other than only gluten probably function before AGA-IgG emerges, i.e., > or =3 months earlier than the transglutaminase-associated antibodies appear. In a remarkable proportion of the children, antibodies disappear spontaneously suggesting that regulatory immune phenomena under favorable circumstances are able to extinguish incipient CD in genetically at-risk children even without exclusion of gluten from the diet.
2025
-
Professional Stakeholders' Perspectives on Early Screening for Type 1 Diabetes in Children: A Systematic Review
Early screening for type 1 diabetes (T1D) is receiving increasing attention as presymptomatic screening initiatives and disease-modifying therapies continue to expand. However, the perspectives of professional stakeholders, who play a pivotal role in implementation, patient engagement, and health system preparedness, have not been systematically synthesised. We conducted a systematic review to examine professional views on paediatric early T1D screening. Following PRISMA guidelines, six... -
Psychosocial implications, acceptability and ethics of screening for paediatric type 1 diabetes: a systematic review and mixed methods evidence synthesis
CONCLUSIONS/INTERPRETATION: This, the most comprehensive review of the literature to date, demonstrates that despite the emotional, cognitive and behavioural implications, thus far, screening and early detection of paediatric type 1 diabetes appears to be acceptable to parents/guardians who take part but critical evidence gaps remain. -
Transient receptor potential ankyrin 1 promotes the expression of interferon-stimulated antiviral genes in human A549 lung epithelial cells
Transient receptor potential ankyrin 1 (TRPA1) is an ion channel known for its chemosensory function in neurons, causing pain and neurogenic inflammation. TRPA1 is activated by many noxious compounds including some inflammatory mediators. We and others have shown that TRPA1 is also expressed in epithelial cells, but its function in the epithelial barrier remains unclear. Here, we discovered in RNA-seq studies that inhibition of TRPA1 reduced the expression of a large number of antiviral and... -
Clustering patterns in Finnish type 1 diabetes patients: a nationwide register-based study
CONCLUSIONS: These results demonstrate evidence of spatiotemporal clustering of T1DM in Finnish children, supporting the hypothesis of environmental triggers in T1DM etiology. These findings highlight the need for further research to identify the specific environmental factors and mechanisms behind the clustering. -
Screening for Celiac Disease in Childhood: Cost-Effectiveness of Multiple Genetic and Serological Testing Approaches
CONCLUSIONS: The most cost-effective screening strategy for celiac disease was single-time untargeted serological testing at age 11. The optimal approach is affected by regional factors and may evolve with new evidence. Repeated screening may be preferable for high-risk groups and with high willingness to pay. -
Microbial associations and viruses on the risk of celiac disease (MAVRiC): a longitudinal post-hoc case-cohort study
Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten, yet these factors alone are not sufficient. Larger longitudinal studies are needed to determine the role of time-varying infections and gut microorganisms. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. By age 3-years, persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity... -
The Contribution of BMI to a Young Child's Risk of Islet Autoimmunity Is Dependent on HLA-DR4-DQ8 Without HLA-DR3-DQ2
CONCLUSIONS: The contribution of BMI to risk of IA during early childhood is dependent on the HLA-DR-DQ genotype more so than the first-appearing IA phenotype. -
Association of fever and infections with the subsequent risk of atopic diseases in children with genetic susceptibility for T1D: Results from the TEDDY cohort study
CONCLUSIONS: In a longitudinal cohort study, fever shows a clear impact on how infections associate with subsequent atopic diseases. Understanding the modifying role of fever on risk offers new possibilities to explore the mechanisms that mediate the effect of infections in the atopic process. -
Harmonising terminology for type 1 diabetes: the EDENT1FI lexicon initiative
No abstract -
Linking the edible plant microbiome and human gut microbiome
The edible plant microbiome, which includes microbes in raw-eaten plants, has been recently recognized as a vehicle delivering microbes to the gut. Fruits and vegetables can carry thousands to billions of microorganisms with diverse genetic capacities on each serving. Since the 'edible plant microbiome' concept was introduced in 2014, notable progress has been made in understanding its microbial diversity, factors influencing it, functional traits and biomarkers, and its interconnection with the... -
Machine learning-based identification of wastewater treatment plant-specific microbial indicators using 16S rRNA gene sequencing
Effluent released from municipal wastewater treatment plants reflects the microbial communities responsible for degrading and removing contaminants within the plants. Monitoring this effluent offers essential insights into its environmental impacts, the efficiency of treatment processes, and the presence of emerging contaminants. To support improved monitoring and source attribution, our study employed a machine-learning framework to identify microbial indicators capable of distinguishing... -
Air pollution-induced proteomic alterations increase the risk of child respiratory infections
Early life air pollution exposure may play a role in development of respiratory infections, but underlying mechanisms are still not understood. We utilized data from two independent prospective birth cohorts to investigate the influence of prenatal and postnatal ambient air pollution exposure of PM(2.5), PM(10) and NO(2) on maternal and child proteomic profiles and the risk of daily diary-registered common infections age 0-3 years in the Danish COPSAC(2010) (n = 613) and pneumonia, croup and... -
Temporal dynamics of the gut microbiome preceding celiac disease in genetically at-risk children
Longitudinal study of the microbial dysbiosis preceding celiac disease (CD) is needed, particularly in the first several years of life. Within the Environmental Determinants of Diabetes in the Young (TEDDY) multi-national prospective cohort study, a case-cohort study of 306 CD cases (i.e., seroconverting by 48 months of age), with controls matched 2:1 by site, gender, and time of birth, was assessed. Temporal microbiome case-control dynamics were modelled by 16S rRNA analysis of monthly... -
A case-cohort longitudinal study for the analysis of microbial associations and viruses on the risk of celiac disease (MAVRiC)
Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten before a child can develop the chronic autoimmune disorder. However, these factors alone are not sufficient. Even a child with persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity (CDA), does not necessarily develop celiac disease. Larger longitudinal studies are needed to determine the impact of time-varying infections and gut microorganisms on the subsequent and... -
Antibodies against <em>Clostridium butyricum</em> in the children of mothers at risk for gestational diabetes
Gestational diabetes mellitus (GDM) is linked to an imbalance in gut microbiota composition, which can be transferred to the mother's offspring. Clostridium butyricum, known for its health benefits in diabetes and allergy, lacks sufficient data regarding its effect on the immune system's development in the offspring of mothers with GDM. This study assessed antibody responses against C. butyricum T2F3 in children of mothers at risk for GDM, involving 88 children aged 1-6 years. Antibody responses... -
Virus detection in influent, activated sludge, and effluent from municipal wastewater treatment plants using composite and grab samples in Finland
Wastewater-based surveillance has been commonly used as a monitoring tool for public health. Also, viruses present in wastewater can pose a health risk. In this study, we screened enterovirus, rhinovirus, norovirus GI and GII, pan-adenovirus, and gastroenteritis-causing adenovirus F40/41 in different wastewater sample types using reverse transcription quantitative polymerase chain reaction and quantitative polymerase chain reaction. We analyzed composite influent samples (N = 22), grab influent... -
Unfolding the Mystery of Autoimmunity: The Environmental Determinants of Diabetes in the Young (TEDDY) Study
In 2025, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health celebrates 75 years of leadership in diabetes research. The NIDDK serves people of the U.S. affected by or at risk for many chronic diseases, including diabetes and other endocrine, metabolic, and digestive disorders, by funding innovative research to develop better treatment and prevention and a cure for these conditions. Autoimmunity that leads to type 1 diabetes or celiac... -
Joint analysis of the nPOD-Virus Group data: the association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue
CONCLUSIONS/INTERPRETATION: The nPOD-Virus Group conducted, to date, the largest and most comprehensive analysis of multiple indices of pancreatic enterovirus infections in type 1 diabetes; these were more prevalent in T1D-ICI and AAb^(++) donors than in other groups. Their preferential detection of these indices in donors with residual beta cells and autoimmunity implicates enterovirus infections across disease progression stages and supports a contribution to beta cell loss, directly or... -
Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes
CONCLUSIONS/INTERPRETATION: We report the most extensive analysis to date of VP1 and HLA-I in pancreases from donors with preclinical and diagnosed type 1 diabetes. We find an association of VP1 with residual beta cells after diagnosis and demonstrate VP1 positivity during the autoantibody-positive preclinical stage. For the first time, we show that VP1 positivity and HLA-I hyperexpression in islet cells are both present during the preclinical stage. While the study of tissues does not allow us... -
Detection of enterovirus RNA in pancreas and lymphoid tissues of organ donors with type 1 diabetes
CONCLUSIONS/INTERPRETATION: This was the largest coordinated effort to examine the presence of enterovirus RNA in the pancreas of organ donors with type 1 diabetes, using a multitude of assays. These findings are consistent with the notion that donors with type 1 diabetes and donors with islet autoantibodies may carry a low-grade enterovirus infection in the pancreas and lymphoid tissues. -
Comment on Manduchi et al. No Evidence for Persistent Enteroviral B Infection of Pancreatic Islets in Patients With Type 1 Diabetes and Prediabetes From RNA Sequencing Data. Diabetes 2024;73:1697-1704
No abstract -
Anti-viral action against type 1 diabetes autoimmunity: The GPPAD-AVAnT1A study protocol
Viral infections in the first year of life are associated with islet autoimmunity and type 1 diabetes risk. The Anti-Viral Action against Type 1 Diabetes Autoimmunity (AVAnT1A)- study is a clinical phase IV investigator initiated, randomised, controlled, multicentre, primary prevention trial conducted to determine whether vaccination against COVID-19 from 6 months of age reduces the cumulative incidence of islet autoantibodies or type 1 diabetes in children with elevated genetic risk.... -
Three-Year Follow-up After Antiviral Treatment in New-Onset Type 1 Diabetes: Results From the Diabetes Virus Detection and Intervention Trial
CONCLUSIONS: The decreased reduction in C-peptide levels after antiviral treatment is no longer present after 2 or 3 years. Further investigations are needed to explore options to use antiviral treatment in the prevention and treatment of T1D. -
EDENT1FI Master Protocol for screening of presymptomatic early-stage type 1 diabetes in children and adolescents
INTRODUCTION: The identification of type 1 diabetes at an early presymptomatic stage has clinical benefits. These include a reduced risk of diabetic ketoacidosis (DKA) at the clinical manifestation of the disease and a significant reduction in clinical symptoms. The European action for the Diagnosis of Early Non-clinical Type 1 diabetes For disease Interception (EDENT1FI) represents a pioneering effort to advance early detection of type 1 diabetes through public health screening. With the... -
Looking back at the TEDDY study: lessons and future directions
The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed. Recruitment and follow-up (from age 4 months to 15 years)... -
Early Appearance of Thyroid Autoimmunity in Children Followed From Birth for Type 1 Diabetes Risk
CONCLUSION: Thyroid autoantibodies may appear during the first years of life, especially in girls, and in children with a family history of AITD. Simultaneous appearance of both autoantibodies increases the risk for hypothyroidism or hyperthyroidism.
2024
-
Psychosocial implications, acceptability and ethics of screening for paediatric type 1 diabetes: a systematic review and mixed methods evidence synthesis
CONCLUSIONS/INTERPRETATION: This, the most comprehensive review of the literature to date, demonstrates that despite the emotional, cognitive and behavioural implications, thus far, screening and early detection of paediatric type 1 diabetes appears to be acceptable to parents/guardians who take part but critical evidence gaps remain. -
Comment on Manduchi et al. No Evidence for Persistent Enteroviral B Infection of Pancreatic Islets in Patients With Type 1 Diabetes and Prediabetes From RNA Sequencing Data. Diabetes 2024;73:1697-1704
No abstract -
EDENT1FI Master Protocol for screening of presymptomatic early-stage type 1 diabetes in children and adolescents
INTRODUCTION: The identification of type 1 diabetes at an early presymptomatic stage has clinical benefits. These include a reduced risk of diabetic ketoacidosis (DKA) at the clinical manifestation of the disease and a significant reduction in clinical symptoms. The European action for the Diagnosis of Early Non-clinical Type 1 diabetes For disease Interception (EDENT1FI) represents a pioneering effort to advance early detection of type 1 diabetes through public health screening. With the... -
Looking back at the TEDDY study: lessons and future directions
The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed. Recruitment and follow-up (from age 4 months to 15 years)... -
Risk of celiac disease autoimmunity is modified by interactions between CD247 and environmental exposures
Season of birth, viral infections, HLA haplogenotypes and non-HLA variants are implicated in the development of celiac disease and celiac disease autoimmunity, suggesting a combined role of genes and environmental exposures. The aim of the study was to further decipher the biological pathways conveying the season of birth effect in celiac disease autoimmunity to gain novel insights into the early pathogenesis of celiac disease. Interactions between season of birth, genetics, and early-life... -
Detection of enterovirus RNA in pancreas and lymphoid tissues of organ donors with type 1 diabetes
CONCLUSIONS/INTERPRETATION: This was the largest coordinated effort to examine the presence of enterovirus RNA in pancreas of organ donors with type 1 diabetes, using a multitude of assays. These findings are consistent with the notion that both the subjects with type 1 diabetes and those with islet autoantibodies may carry a low-grade enterovirus infection in the pancreas and lymphoid tissues. -
Production, analysis, and safety assessment of a soil and plant-based natural material with microbiome- and immune-modulatory effects
It has been suggested that reduced contact with microbiota from the natural environment contributes to the rising incidence of immune-mediated inflammatory disorders (IMIDs) in western, highly urbanized societies. In line with this, we have previously shown that exposure to environmental microbiota in the form of a blend comprising of soil and plant-based material (biodiversity blend; BDB) enhances the diversity of human commensal microbiota and promotes immunoregulation that may be associated... -
Early-pregnancy BMI, maternal gestational weight gain, and asthma and allergic diseases in children
CONCLUSION: Association of early pregnancy BMI and maternal GWG, and asthma and allergic disease in children, is inconsistent. High maternal GWG may be associated with increased odds of atopic eczema. -
Using patterns of shared taxa to infer bacterial dispersal in human living environment in urban and rural areas
Contact with environmental microbial communities primes the human immune system. Factors determining the distribution of microorganisms, such as dispersal, are thus important for human health. Here, we used the relative number of bacteria shared between environmental and human samples as a measure of bacterial dispersal and studied these associations with living environment and lifestyles. We analyzed amplicon sequence variants (ASVs) of the V4 region of 16S rDNA gene from 347 samples of doormat... -
Skin exposure to soil microbiota elicits changes in cell-mediated immunity to pneumococcal vaccine
A resilient immune system is characterized by its capacity to respond appropriately to challenges, such as infections, and it is crucial in vaccine response. Here we report a paired randomized intervention-control trial in which we evaluated the effect of microbially rich soil on immune resilience and pneumococcal vaccine response. Twenty-five age and sex matched pairs of volunteers were randomized to intervention and control groups. The intervention group rubbed hands three times a day in... -
High Concentrations of Immunoglobulin G Against Cow Milk Proteins and Frequency of Cow Milk Consumption Are Associated With the Development of Islet Autoimmunity and Type 1 Diabetes-The Trial to Reduce Insulin-dependent Diabetes Mellitus (IDDM) in the Genetically at Risk (TRIGR) Study
CONCLUSIONS: Elevated cow milk antibody concentrations and high consumption of liquid milk after infancy are related to type 1 diabetes development in children with an increased genetic susceptibility to type 1 diabetes. Enhanced antibody concentrations to cow milk may provide a biomarker of immune system prone to develop islet autoimmunity. This trial was registered at clinicaltrials.gov as NCT00179777. -
Maternal gluten, cereal, and dietary fiber intake during pregnancy and lactation and the risk of islet autoimmunity and type 1 diabetes in the child
CONCLUSIONS: We observed no association between maternal intake of gluten, most consumed cereals, or dietary fiber during pregnancy or lactation and the risk of islet autoimmunity or type 1 diabetes in children from a high-risk population. -
Gut Inflammation Markers, Diet, and Risk of Islet Autoimmunity in Finnish Children - A Nested Case-Control Study
CONCLUSIONS: Higher HBD-2 in infancy may be associated with higher risk of islet autoimmunity. Dietary factors play a role in gut inflammatory status. -
Distinct cellular immune responses in children en route to type 1 diabetes with different first-appearing autoantibodies
Previous studies have revealed heterogeneity in the progression to clinical type 1 diabetes in children who develop islet-specific antibodies either to insulin (IAA) or glutamic acid decarboxylase (GADA) as the first autoantibodies. Here, we test the hypothesis that children who later develop clinical disease have different early immune responses, depending on the type of the first autoantibody to appear (GADA-first or IAA-first). We use mass cytometry for deep immune profiling of peripheral... -
Urban indoor gardening enhances immune regulation and diversifies skin microbiota - A placebo-controlled double-blinded intervention study
According to the hygiene and biodiversity hypotheses, frequent exposure to environmental microbiota, especially through soil contact, diversifies commensal microbiota, enhances immune modulation, and ultimately lowers the risk of immune-mediated diseases. Here we test the underlying assumption of the hygiene and biodiversity hypotheses by instructing volunteers to grow edible plants indoors during the winter season when natural exposure to environmental microbiota is low. The one-month... -
Novel antivirals for severe enterovirus infection in immunocompromised hosts; A case series
No abstract -
Coxsackievirus infection induces direct pancreatic β cell killing but poor antiviral CD8<sup>+</sup> T cell responses
Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β cell autoimmunity and type 1 diabetes. We investigated how CVB affects human β cells and anti-CVB T cell responses. β cells were efficiently infected by CVB in vitro, down-regulated human leukocyte antigen (HLA) class I, and presented few, selected HLA-bound viral peptides. Circulating CD8^(+) T cells from CVB-seropositive individuals recognized a fraction of these peptides; only another subfraction was targeted by... -
Intake of B vitamins and the risk of developing islet autoimmunity and type 1 diabetes in the TEDDY study
PURPOSE: The aim was to study the association between dietary intake of B vitamins in childhood and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D) by the age of 10 years. -
Safety, tolerability and immunogenicity of PRV-101, a multivalent vaccine targeting coxsackie B viruses (CVBs) associated with type 1 diabetes: a double-blind randomised placebo-controlled Phase I trial
CONCLUSIONS/INTERPRETATION: The results indicate that the tested multivalent CVB vaccine is well tolerated and immunogenic, supporting its further clinical development.
2023
-
Early-life immunological and microbial differences between East African and North European children
CONCLUSIONS: These results highlight the early emergence of differences in the immune system and gut microbiota between children living in extremities of the microbial exposure gradient. These differences add to the existing knowledge of possible factors contributing to increasing prevalence of chronic inflammatory diseases in African societies shifting towards more Westernized lifestyle. -
Distinct Enterovirus Antigen Landscape in Children With Islet Autoimmunity
Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes. However, given the ubiquity of EV infections in children, disease susceptibility is likely driven by host-specific immune responses rather than viral exposure alone. To investigate the host antibody response to EVs, we used virome-wide serological profiling (VirScan) to compare the EV antigen landscapes in IA-positive case children versus IA-negative control children across two... -
Joint analysis of the nPOD-Virus Group data: the association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue
CONCLUSIONS/INTERPRETATION: The nPOD-Virus Group conducted, to date, the largest and most comprehensive analysis of multiple indices of pancreatic enterovirus infections in type 1 diabetes; these were more prevalent in T1D-ICI and AAb^(++) donors than in other groups. Their preferential detection of these indices in donors with residual beta cells and autoimmunity implicates enterovirus infections across disease progression stages and supports a contribution to beta cell loss, directly or... -
Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes
CONCLUSIONS/INTERPRETATION: We report the most extensive analysis to date of VP1 and HLA-I in pancreases from donors with preclinical and diagnosed type 1 diabetes. We find an association of VP1 with residual beta cells after diagnosis and demonstrate VP1 positivity during the autoantibody-positive preclinical stage. For the first time, we show that VP1 positivity and HLA-I hyperexpression in islet cells are both present during the preclinical stage. While the study of tissues does not allow us... -
Anti-viral action against type 1 diabetes autoimmunity: The GPPAD-AVAnT1A study protocol
Viral infections in the first year of life are associated with islet autoimmunity and type 1 diabetes risk. The Anti-Viral Action against Type 1 Diabetes Autoimmunity (AVAnT1A)- study is a clinical phase IV investigator initiated, randomised, controlled, multicentre, primary prevention trial conducted to determine whether vaccination against COVID-19 from 6 months of age reduces the cumulative incidence of islet autoantibodies or type 1 diabetes in children with elevated genetic risk.... -
EDENT1FI Master Protocol for screening of presymptomatic early-stage type 1 diabetes in children and adolescents
INTRODUCTION: The identification of type 1 diabetes at an early presymptomatic stage has clinical benefits. These include a reduced risk of diabetic ketoacidosis (DKA) at the clinical manifestation of the disease and a significant reduction in clinical symptoms. The European action for the Diagnosis of Early Non-clinical Type 1 diabetes For disease Interception (EDENT1FI) represents a pioneering effort to advance early detection of type 1 diabetes through public health screening. With the... -
Editorial: The contribution of viruses and innate immune system in the pathogenesis of type 1 diabetes
No abstract -
CXADR polymorphism rs6517774 modifies islet autoimmunity characteristics and exhibits sex disparity
Enteroviral infections have been linked to the development of islet autoimmunity (IA) and type 1 diabetes (T1D), and the coxsackie and adenovirus receptor (CXADR) is one of the ligands used by adenoviruses and enteroviruses for cell internalization. Two CXADR single nucleotide polymorphisms (SNPs), rs6517774 and rs2824404, were previously associated with an increased susceptibility to IA in the international TEDDY study (The Environmental Determinants of Diabetes in the Young). This study aimed... -
Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection
Although the genetic basis and pathogenesis of type 1 diabetes have been studied extensively, how host responses to environmental factors might contribute to autoantibody development remains largely unknown. Here, we use longitudinal blood transcriptome sequencing data to characterize host responses in children within 12 months prior to the appearance of type 1 diabetes-linked islet autoantibodies, as well as matched control children. We report that children who present with insulin-specific... -
Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial
Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6-15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (n = 47) or placebo (n = 49) for 6 months, with the aim of preserving β cell function. The primary... -
Circulating metabolic signatures of rapid and slow progression to type 1 diabetes in islet autoantibody-positive children
CONCLUSION/INTERPRETATION: Our study suggests that a distinct metabolic profile is linked with the type 1 diabetes progression. The identification of specific metabolites and pathways that differentiate RP from SP may have implications for early intervention strategies to delay the development of type 1 diabetes. -
Serum APOC1 levels are decreased in young autoantibody positive children who rapidly progress to type 1 diabetes
Better understanding of the early events in the development of type 1 diabetes is needed to improve prediction and monitoring of the disease progression during the substantially heterogeneous presymptomatic period of the beta cell damaging process. To address this concern, we used mass spectrometry-based proteomics to analyse longitudinal pre-onset plasma sample series from children positive for multiple islet autoantibodies who had rapidly progressed to type 1 diabetes before 4 years of age (n... -
The edible plant microbiome: evidence for the occurrence of fruit and vegetable bacteria in the human gut
Diversity of the gut microbiota is crucial for human health. However, whether fruit and vegetable associated bacteria contribute to overall gut bacterial diversity is still unknown. We reconstructed metagenome-assembled genomes from 156 fruit and vegetable metagenomes to investigate the prevalence of associated bacteria in 2,426 publicly available gut metagenomes. The microbiomes of fresh fruits and vegetables and the human gut are represented by members in common such as Enterobacterales,... -
Comparison of the effect of autoclaved and non-autoclaved live soil exposure on the mouse immune system : Effect of soil exposure on immune system
CONCLUSIONS: . Our results indicate that exposure to the live and autoclaved soil powders is not toxic for mice. Exposure to live soil powder slightly skews the immune system towards type 1 direction which might be beneficial for inhibiting type 2-related inflammation. Further studies are warranted to quantify the impact of this exposure in experimental type 2 inflammation. -
Coxsackievirus infection induces direct pancreatic β-cell killing but poor anti-viral CD8+ T-cell responses
Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β-cell autoimmunity. We investigated how CVB impacts human β cells and anti-CVB T-cell responses. β cells were efficiently infected by CVB in vitro, downregulated HLA Class I and presented few, selected HLA-bound viral peptides. Circulating CD8^(+) T cells from CVB-seropositive individuals recognized only a fraction of these peptides, and only another sub-fraction was targeted by effector/memory T cells that expressed the... -
Human intestinal organoid models for celiac disease research
Celiac disease pathogenesis, in addition to immune cell component, encompasses pathogenic events also in the duodenal epithelium. In celiac disease patients, exposure to dietary gluten induces drastic changes in epithelial differentiation and elicit cellular response to inflammatory cytokines. The autoantigen in celiac disease, transglutaminase 2 (TG2) enzyme, has been also suggested to play its pathogenic gliadin deamidation event in the intestinal epithelium. Therefore in vitro epithelial... -
Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study
CONCLUSIONS: Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12-23 months prior to IAA. Norwalk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk. -
HLA Genotype and Probiotics Modify the Association Between Timing of Solid Food Introduction and Islet Autoimmunity in the TEDDY Study
CONCLUSIONS: Timing of solid food introduction, including rice, may be associated with IA in children with the HLA DR3/4 genotype not exposed to probiotics. The microbiome composition under these exposure combinations requires further study. -
SARS-CoV-2 - No Increased Islet Autoimmunity or Type 1 Diabetes in Teens
No abstract -
Vemurafenib Inhibits Acute and Chronic Enterovirus Infection by Affecting Cellular Kinase Phosphatidylinositol 4-Kinase Type IIIβ
Enteroviruses are one of the most abundant viruses causing mild to serious acute infections in humans and also contributing to chronic diseases like type 1 diabetes. Presently, there are no approved antiviral drugs against enteroviruses. Here, we studied the potency of vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAF^(V600E) mutant-related melanoma, as an antiviral against enteroviruses. We showed that vemurafenib prevented enterovirus translation and replication at low... -
Assessment of Enterovirus Antibodies during Early Childhood Using a Multiplex Immunoassay
Enteroviruses are a group of positive single-stranded viruses that belong to the Picornaviridae family. They regularly infect humans and cause symptoms ranging from the common cold and hand-foot-and-mouth disease to life-threatening conditions, such as dilated cardiomyopathy and poliomyelitis. Enteroviruses have also been associated with chronic immune-mediated diseases, such as type 1 diabetes, celiac disease, and asthma. Studying these disease-pathogen connections is challenging due to the... -
Physical Activity and the Development of Islet Autoimmunity and Type 1 Diabetes in 5- to 15-Year-Old Children Followed in the TEDDY Study
CONCLUSIONS: More daily minutes spent in moderate to vigorous physical activity was associated with a reduced risk of progression to type 1 diabetes in children aged 5-15 years who had developed multiple IAs. -
Atopic sensitization in childhood depends on the type of green area around the home in infancy
No abstract -
HLA-DQ-conferred risk for type 1 diabetes does not alter neutralizing antibody response to a widely used enterovirus vaccine, the poliovirus vaccine
This study investigated whether children with HLA-DQ-conferred risk for type 1 diabetes (T1D) have an altered immune response to the widely-used enterovirus vaccine, namely poliovirus vaccine, and whether initiation of autoimmunity to pancreatic islets modulates this response. Neutralizing antibodies induced by the inactivated poliovirus vaccine against poliovirus type 1 (Salk) were analysed as a marker of protective immunity at the age of 18 months in a prospective birth cohort. No differences... -
Skin, gut, and sand metagenomic data on placebo-controlled sandbox biodiversity intervention study
The metagenomic data presented in this article are related to the published research of "A Placebo-controlled double-blinded test of the biodiversity hypothesis of immune-mediated diseases: Environmental microbial diversity elicits changes in cytokines and increase in T regulatory cells in young children" This database contains 16S ribosomal RNA (rRNA) metagenomics of sandbox sand and skin and gut microbiota of children in the intervention and placebo daycares. In intervention daycares, children... -
Interaction Between Dietary Iron Intake and Genetically Determined Iron Overload: Risk of Islet Autoimmunity and Progression to Type 1 Diabetes in the TEDDY Study
CONCLUSIONS: Iron intake may alter the risk of IA in children with high-risk HLA haplogenotypes. -
Respiratory infections and type 1 diabetes: Potential roles in pathogenesis
Among the environmental factors associated with type 1 diabetes (T1D), viral infections of the gut and pancreas has been investigated most intensely, identifying enterovirus infections as the prime candidate trigger of islet autoimmunity (IA) and T1D development. However, the association between respiratory tract infections (RTI) and IA/T1D is comparatively less known. While there are significant amounts of epidemiological evidence supporting the role of respiratory infections in T1D, there... -
Islet autoantibody screening in at-risk adolescents to predict type 1 diabetes until young adulthood: a prospective cohort study
BACKGROUND: Screening for islet autoantibodies in children and adolescents identifies individuals who will later develop type 1 diabetes, allowing patient and family education to prevent diabetic ketoacidosis at onset and to enable consideration of preventive therapies. We aimed to assess whether islet autoantibody screening is effective for predicting type 1 diabetes in adolescents aged 10-18 years with an increased risk of developing type 1 diabetes. -
Impact of Cultivation and Origin on the Fruit Microbiome of Apples and Blueberries and Implications for the Exposome
Vegetables and fruits are a crucial part of the planetary health diet, directly affecting human health and the gut microbiome. The objective of our study was to understand the variability of the fruit (apple and blueberry) microbiome in the frame of the exposome concept. The study covered two fruit-bearing woody species, apple and blueberry, two countries of origin (Austria and Finland), and two fruit production methods (naturally grown and horticultural). Microbial abundance, diversity, and... -
Association between asymptomatic infections and linear growth in 18-24-month-old Malawian children
Inadequate diet and frequent symptomatic infections are considered major causes of growth stunting in low-income countries, but interventions targeting these risk factors have achieved limited success. Asymptomatic infections can restrict growth, but little is known about their role in global stunting prevalence. We investigated factors related to length-for-age Z-score (LAZ) at 24 months by constructing an interconnected network of various infections, biomarkers of inflammation (as assessed by...
2022
-
Microbial associations and viruses on the risk of celiac disease (MAVRiC): a longitudinal post-hoc case-cohort study
Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten, yet these factors alone are not sufficient. Larger longitudinal studies are needed to determine the role of time-varying infections and gut microorganisms. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. By age 3-years, persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity... -
Mobile genetic elements from the maternal microbiome shape infant gut microbial assembly and metabolism
The perinatal period represents a critical window for cognitive and immune system development, promoted by maternal and infant gut microbiomes and their metabolites. Here, we tracked the co-development of microbiomes and metabolomes from late pregnancy to 1 year of age using longitudinal multi-omics data from a cohort of 70 mother-infant dyads. We discovered large-scale mother-to-infant interspecies transfer of mobile genetic elements, frequently involving genes associated with diet-related... -
Impact of Cultivation and Origin on the Fruit Microbiome of Apples and Blueberries and Implications for the Exposome
Vegetables and fruits are a crucial part of the planetary health diet, directly affecting human health and the gut microbiome. The objective of our study was to understand the variability of the fruit (apple and blueberry) microbiome in the frame of the exposome concept. The study covered two fruit-bearing woody species, apple and blueberry, two countries of origin (Austria and Finland), and two fruit production methods (naturally grown and horticultural). Microbial abundance, diversity, and... -
Serum 25-hydroxyvitamin D and fatty acids in relation to the risk of microbial infections in children: The TRIGR Divia study
CONCLUSIONS: In young children with increased susceptibility to type 1 diabetes, long-chain n-3 PUFAs may influence the risk of viral infections and immune response against the infections. However, this association may depend on the type of virus suggesting virus-specific effects. -
Coxsackievirus B infections are common in Cystic Fibrosis and experimental evidence supports protection by vaccination
Viral respiratory tract infections exacerbate airway disease and facilitate life-threatening bacterial colonization in cystic fibrosis (CF). Annual influenza vaccination is recommended and vaccines against other common respiratory viruses may further reduce pulmonary morbidity risk. Enteroviruses have been found in nasopharyngeal samples from CF patients experiencing pulmonary exacerbations. Using serology tests, we found that infections by a group of enteroviruses, Coxsackievirus Bs (CVBs), are... -
Predictors of the Initiation of Islet Autoimmunity and Progression to Multiple Autoantibodies and Clinical Diabetes: The TEDDY Study
CONCLUSIONS: Predictors of IAA-first versus GADA-first autoimmunity differ from each other and from the predictors of progression to diabetes. -
Rising Hemoglobin A1c in the Nondiabetic Range Predicts Progression of Type 1 Diabetes As Well As Oral Glucose Tolerance Tests
CONCLUSIONS: An increase of ≥10% in HbA1c from baseline is as informative as OGTT 2-hPG in predicting risk of stage 3 in youth with genetic risk and diabetes-associated autoantibodies. -
Association between asymptomatic infections and linear growth in 18-24-month-old Malawian children
Inadequate diet and frequent symptomatic infections are considered major causes of growth stunting in low-income countries, but interventions targeting these risk factors have achieved limited success. Asymptomatic infections can restrict growth, but little is known about their role in global stunting prevalence. We investigated factors related to length-for-age Z-score (LAZ) at 24 months by constructing an interconnected network of various infections, biomarkers of inflammation (as assessed by... -
Modulation of the food microbiome by apple fruit processing
During the early life, introduction to external exposures such as consumption of solid foods contribute to the development of the gut microbiota. Among solid foods, fruit and vegetables are normally consumed during early childhood making them key components of a healthy human diet. The role of the indigenous microbiota of fruits as a source for beneficial gut microbes, especially during food processing, is largely unknown. Therefore, we investigated the apple fruit microbiota before and after... -
Lack of Associations between Environmental Exposures and Environmental Enteric Dysfunction among 18-Month-Old Children in Rural Malawi
Environmental enteric dysfunction (EED) is common and contributes to linear growth faltering (stunting) and mortality among children in low-resource settings. A few studies on the environmental causes of EED have been conducted but the exact exposures that cause or predispose children to EED are context-specific and not clear. This study aimed to assess associations between selected environmental exposures and EED markers among 620 18-month-old children. This was a secondary analysis of data... -
A Placebo-controlled double-blinded test of the biodiversity hypothesis of immune-mediated diseases: Environmental microbial diversity elicits changes in cytokines and increase in T regulatory cells in young children
CONCLUSIONS: This is the first double-blinded placebo-controlled study to show that daily exposure to microbial biodiversity is associated with immune modulation in humans. The findings support the biodiversity hypothesis of immune-mediated diseases. We conclude that environmental microbiota may contribute to child health, and that adding microbiological diversity to everyday living environment may support immunoregulation. -
Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage
CONCLUSIONS/INTERPRETATION: Our data indicate that, in peripheral blood, antigen-presenting cells are the predominant source of enterovirus infection, and that infection is correlated with disease stage and genetic predisposition, thereby supporting a role for enterovirus infection prior to disease onset. -
Umbilical cord blood DNA methylation in children who later develop type 1 diabetes
CONCLUSIONS/INTERPRETATION: Based on our results, differences between children who progress to type 1 diabetes and those who remain healthy throughout childhood are not yet present in the perinatal DNA methylome. However, we cannot exclude the possibility that such differences would be found in a larger dataset. -
Exposomic determinants of immune-mediated diseases: Special focus on type 1 diabetes, celiac disease, asthma, and allergies: The HEDIMED project approach
The incidence of immune-mediated diseases (IMDs) is increasing rapidly in the developed countries constituting a huge medical, economic, and societal challenge. The exposome plays an important role since genetic factors cannot explain such a rapid change. In the Human Exposomic Determinants of Immune Mediated Diseases (HEDIMED) project, altogether 22 academic and industrial partners join their multidisciplinary forces to identify exposomic determinants that are driving the IMD epidemic. The... -
Associations Between Serum Fatty Acids and Immunological Markers in Children Developing Islet Autoimmunity-The TRIGR Nested Case-Control Study
CONCLUSIONS: In cases, SFAs were associated with several immunological markers (CXCL10, IL-6, IL-9, IL-17, and CM-CSF) previously linked to the type 1 diabetes disease process. Findings indicate that fatty acids could have immunomodulatory potential in the early phase of the disease development, although causality between fatty acids and the immunological pathways remains to be explored. -
Pancreas Whole Tissue Transcriptomics Highlights the Role of the Exocrine Pancreas in Patients With Recently Diagnosed Type 1 Diabetes
Although type 1 diabetes (T1D) is primarily a disease of the pancreatic beta-cells, understanding of the disease-associated alterations in the whole pancreas could be important for the improved treatment or the prevention of the disease. We have characterized the whole-pancreas gene expression of patients with recently diagnosed T1D from the Diabetes Virus Detection (DiViD) study and non-diabetic controls. Furthermore, another parallel dataset of the whole pancreas and an additional dataset from... -
Indoor green wall affects health-associated commensal skin microbiota and enhances immune regulation: a randomized trial among urban office workers
Urbanization reduces microbiological abundance and diversity, which has been associated with immune mediated diseases. Urban greening may be used as a prophylactic method to restore microbiological diversity in cities and among urbanites. This study evaluated the impact of air-circulating green walls on bacterial abundance and diversity on human skin, and on immune responses determined by blood cytokine measurements. Human subjects working in offices in two Finnish cities (Lahti and Tampere)... -
Sources of dietary gluten in the first 2 years of life and associations with celiac disease autoimmunity and celiac disease in Swedish genetically predisposed children: The Environmental Determinants of Diabetes in the Young (TEDDY) study
CONCLUSIONS: High daily intakes of bread at age 12 mo and of milk cereal drink during the second year of life are associated with increased risk of both CDA and CD in genetically at-risk children. -
Telomere length is not a main factor for the development of islet autoimmunity and type 1 diabetes in the TEDDY study
The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8676 children, 3-4 months of age, born with HLA-susceptibility genotypes for islet autoimmunity (IA) and type 1 diabetes (T1D). Whole-genome sequencing (WGS) was performed in 1119 children in a nested case-control study design. Telomere length was estimated from WGS data using five tools: Computel, Telseq, Telomerecat, qMotif and Motif_counter. The estimated median telomere length was 5.10 kb (IQR 4.52-5.68 kb) using... -
Childhood Height Growth Rate Association With the Risk of Islet Autoimmunity and Development of Type 1 Diabetes
CONCLUSION: Rapid height growth rate in childhood is associated with increased risk of islet autoimmunity and progression to T1D. Further work is needed to investigate the biological mechanism that may explain this association. -
Author Correction: A combined risk score enhances prediction of type 1 diabetes among susceptible children
No abstract -
Type 1 Diabetes in Children With Genetic Risk May Be Predicted Very Early With a Blood miRNA
No abstract -
Heterogeneity of DKA Incidence and Age-Specific Clinical Characteristics in Children Diagnosed With Type 1 Diabetes in the TEDDY Study
CONCLUSIONS: DKA at onset in TEDDY is uncommon, especially for FDRs. For those without familial risk, metabolic monitoring continues to provide a primary benefit of reduced DKA but requires regular follow-up. Clinical and laboratory features vary by age at onset, adding to the heterogeneity of type 1 diabetes. -
Persistent coxsackievirus B1 infection triggers extensive changes in the transcriptome of human pancreatic ductal cells
Enteroviruses, particularly the group B coxsackieviruses (CVBs), have been associated with the development of type 1 diabetes. Several CVB serotypes establish chronic infections in human cells in vivo and in vitro. However, the mechanisms leading to enterovirus persistency and, possibly, beta cell autoimmunity are not fully understood. We established a carrier-state-type persistent infection model in human pancreatic cell line PANC-1 using two distinct CVB1 strains and profiled the... -
Is staff consistency important to parents' satisfaction in a longitudinal study of children at risk for type 1 diabetes: the TEDDY study
CONCLUSIONS: Sociodemographic factors, parental characteristics, and study-related variables were all related to parent study satisfaction. Those that are potentially modifiable are of particular interest as possible targets of future efforts to improve parent study satisfaction. Three such factors were identified: parent accuracy about the child's type 1 diabetes risk, parent beliefs that something can be done to reduce the child's risk, and study staff consistency. However, staff consistency... -
Effect of inactivated nature-derived microbial composition on mouse immune system
CONCLUSIONS: These results provide insights on the effect of biodiversity on murine immune system in sterile environment. Subjecting mice to soil-based plant and microbe structures appears to elicit immune response that could be beneficial, for example, in type 2 inflammation-related diseases, that is, allergic diseases.
2021
-
Maternal Intake of Vitamins A, C, D, and E During Pregnancy and Risk of Type 1 Diabetes in the Child: The Norwegian Mother, Father, and Child Cohort Study
CONCLUSIONS: This prospective cohort study does not support the hypothesis that higher maternal intake of vitamins A, C, D, and E during pregnancy would decrease risk of type 1 diabetes in the child. Corroborated with previous evidence, our findings support a general pattern of null associations. -
Microbial associations and viruses on the risk of celiac disease (MAVRiC): a longitudinal post-hoc case-cohort study
Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten, yet these factors alone are not sufficient. Larger longitudinal studies are needed to determine the role of time-varying infections and gut microorganisms. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. By age 3-years, persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity... -
Air pollution-induced proteomic alterations increase the risk of child respiratory infections
Early life air pollution exposure may play a role in development of respiratory infections, but underlying mechanisms are still not understood. We utilized data from two independent prospective birth cohorts to investigate the influence of prenatal and postnatal ambient air pollution exposure of PM(2.5), PM(10) and NO(2) on maternal and child proteomic profiles and the risk of daily diary-registered common infections age 0-3 years in the Danish COPSAC(2010) (n = 613) and pneumonia, croup and... -
EDENT1FI Master Protocol for screening of presymptomatic early-stage type 1 diabetes in children and adolescents
INTRODUCTION: The identification of type 1 diabetes at an early presymptomatic stage has clinical benefits. These include a reduced risk of diabetic ketoacidosis (DKA) at the clinical manifestation of the disease and a significant reduction in clinical symptoms. The European action for the Diagnosis of Early Non-clinical Type 1 diabetes For disease Interception (EDENT1FI) represents a pioneering effort to advance early detection of type 1 diabetes through public health screening. With the... -
Persistent coxsackievirus B1 infection triggers extensive changes in the transcriptome of human pancreatic ductal cells
Enteroviruses, particularly the group B coxsackieviruses (CVBs), have been associated with the development of type 1 diabetes. Several CVB serotypes establish chronic infections in human cells in vivo and in vitro. However, the mechanisms leading to enterovirus persistency and, possibly, beta cell autoimmunity are not fully understood. We established a carrier-state-type persistent infection model in human pancreatic cell line PANC-1 using two distinct CVB1 strains and profiled the... -
Primary Site of Coxsackievirus B Replication in the Small Intestines: No Proof of Peyer's Patches Involvement
CONCLUSIONS: Virus was present in the epithelial cells but not in GCs of the PPs of the murine SIs. Our results do not support the hypothesis of EV replication in the PP especially in the GCs. -
Effect of inactivated nature-derived microbial composition on mouse immune system
CONCLUSIONS: These results provide insights on the effect of biodiversity on murine immune system in sterile environment. Subjecting mice to soil-based plant and microbe structures appears to elicit immune response that could be beneficial, for example, in type 2 inflammation-related diseases, that is, allergic diseases. -
Dynamic changes in immune gene co-expression networks predict development of type 1 diabetes
Significant progress has been made in elucidating genetic risk factors influencing Type 1 diabetes (T1D); however, features other than genetic variants that initiate and/or accelerate islet autoimmunity that lead to the development of clinical T1D remain largely unknown. We hypothesized that genetic and environmental risk factors can both contribute to T1D through dynamic alterations of molecular interactions in physiologic networks. To test this hypothesis, we utilized longitudinal blood... -
Coxsackievirus B Vaccines Prevent Infection-Accelerated Diabetes in NOD Mice and Have No Disease-Inducing Effect
Enteroviruses, including the Coxsackievirus Bs (CVB), have been implicated as causal agents in human type 1 diabetes. Immunization of at-risk individuals with a CVB vaccine provides an attractive strategy for elucidating the role of CVBs in the disease etiology. Previously, we have shown that an inactivated whole-virus vaccine covering all CVB serotypes (CVB1-6) is safe to administer and highly immunogenic in preclinical models, including nonhuman primates. Before initiating clinical trials with... -
Frailty modeling under a selective sampling protocol: an application to type 1 diabetes related autoantibodies
In studies following selective sampling protocols for secondary outcomes, conventional analyses regarding their appearance could provide misguided information. In the large type 1 diabetes prevention and prediction (DIPP) cohort study monitoring type 1 diabetes-associated autoantibodies, we propose to model their appearance via a multivariate frailty model, which incorporates a correlation component that is important for unbiased estimation of the baseline hazards under the selective sampling... -
Long-term biodiversity intervention shapes health-associated commensal microbiota among urban day-care children
CONCLUSIONS: This study shows that a 2-year biodiversity intervention shapes human commensal microbiota, including taxa that have been associated with immune regulation. Results indicate that intervention enriched commensal microbiota and suppressed the potentially pathogenic bacteria on the skin. We recommend future studies that expand intervention strategies to immune response and eventually the incidence of immune-mediated diseases. -
Characterisation of enterovirus RNA detected in the pancreas and other specimens of live patients with newly diagnosed type 1 diabetes in the DiViD study
CONCLUSIONS/INTERPRETATION: EV RNA can be frequently detected in various tissues of patients with type 1 diabetes. At least in some patients, the EV strain in the pancreatic islets may represent a slowly replicating persisting virus. -
Association of different enteroviruses with atopy and allergic diseases in early childhood
CONCLUSION: This study supports the evidence that EV exposure and development of allergic disease are inversely associated. Interestingly, the inverse association was not observed for bare atopic IgE sensitization, but for IgE sensitization coupled with clinical atopic disease. This suggests that environmental factors influencing IgE sensitization may differ from those influencing progression to clinical allergic disease. -
Immunological resilience and biodiversity for prevention of allergic diseases and asthma
Increase of allergic conditions has occurred at the same pace with the Great Acceleration, which stands for the rapid growth rate of human activities upon earth from 1950s. Changes of environment and lifestyle along with escalating urbanization are acknowledged as the main underlying causes. Secondary (tertiary) prevention for better disease control has advanced considerably with innovations for oral immunotherapy and effective treatment of inflammation with corticosteroids, calcineurin... -
Land Cover of Early-Life Environment Modulates the Risk of Type 1 Diabetes
CONCLUSIONS: The study suggests that exposure to an agricultural environment (comprising nonirrigated arable land, fruit trees and berry plantations, pastures, natural pastures, land principally occupied by agriculture with significant areas of natural vegetation, and agroforestry areas) early in life is inversely associated with the risk of type 1 diabetes. This association may be mediated by early exposure to environmental microbial diversity. -
Do Rural Second Homes Shape Commensal Microbiota of Urban Dwellers? A Pilot Study among Urban Elderly in Finland
According to the hygiene and biodiversity hypotheses, increased hygiene levels and reduced contact with biodiversity can partially explain the high prevalence of immune-mediated diseases in developed countries. A disturbed commensal microbiota, especially in the gut, has been linked to multiple immune-mediated diseases. Previous studies imply that gut microbiota composition is associated with the everyday living environment and can be modified by increasing direct physical exposure to biodiverse... -
Immunomodulatory Effects of Rhinovirus and Enterovirus Infections During the First Year of Life
Early childhood infections have been implicated in the development of immune-mediated diseases, such as allergies, asthma, and type 1 diabetes. We set out to investigate the immunomodulatory effects of early viral infections experienced before the age of one year on the peripheral regulatory T cell population (Treg) and circulating cytokines in a birth-cohort study of Estonian and Finnish infants. We show here a temporal association of virus infection with the expression of FOXP3 in regulatory T... -
An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood
CONCLUSIONS: The risk of developing islet autoimmunity declines exponentially with age, and the influence of major genetic factors on this risk is limited to the first few years of life. -
Enterovirus Infections Are Associated With the Development of Celiac Disease in a Birth Cohort Study
Enterovirus and adenovirus infections have been linked to the development of celiac disease. We evaluated this association in children who developed biopsy-proven celiac disease (N = 41) during prospective observation starting from birth, and in control children (N = 53) matched for the calendar time of birth, sex, and HLA-DQ genotype. Enterovirus and adenovirus infections were diagnosed by seroconversions in virus antibodies in longitudinally collected sera using EIA. Enterovirus infections... -
Serum fatty acids and risk of developing islet autoimmunity: A nested case-control study within the TRIGR birth cohort
CONCLUSIONS: We found direct associations of pentadecanoic acid, heptadecanoic acid, stearic acid, and conjugated linoleic acid with the risk of islet autoimmunity. Further studies are needed to understand the complex role of fatty acids in the development of type 1 diabetes. -
Infections and systemic inflammation are associated with lower plasma concentration of insulin-like growth factor I among Malawian children
CONCLUSIONS: The mean plasma IGF-I concentrations are similar in Malawi and Finland among 6-mo-old infants. Thereafter, mean concentrations rise markedly in Finland but not in Malawi. Systemic inflammation and clinically nonapparent infections are strongly associated with lower plasma IGF-I concentrations in Malawi through direct and indirect pathways. -
Associations between land cover categories, gaseous PAH levels in ambient air and endocrine signaling predicted from gut bacterial metagenome of the elderly
There is evidence that polycyclic aromatic hydrocarbons (PAHs) and human gut microbiota are associated with the modulation of endocrine signaling pathways. Independently, studies have found associations between air pollution, land cover and commensal microbiota. We are the first to estimate the interaction between land cover categories associated with air pollution or purification, PAH levels and endocrine signaling predicted from gut metagenome among urban and rural populations. The study... -
Faecal regenerating 1B protein concentration is not associated with child growth in rural Malawi
CONCLUSIONS: Faecal REG1B concentration is not associated with LAZ, WAZ, WLZ and MUACZ among 6-30-month-old infants and children in rural Malawi.
2020
-
Coxsackievirus B Infections Are Associated With the Risk of Islet Autoimmunity in Children With Strong Genetic Susceptibility to Type 1 Diabetes-Results From the TRIGR Divia Study
CONCLUSIONS: This study supports previous evidence of the risk association of coxsackievirus B infections. These results support the role of certain virus infections as possible modulating factors in the pathogenesis of type 1 diabetes. -
Distinct Enterovirus Antigen Landscape in Children With Islet Autoimmunity
Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes. However, given the ubiquity of EV infections in children, disease susceptibility is likely driven by host-specific immune responses rather than viral exposure alone. To investigate the host antibody response to EVs, we used virome-wide serological profiling (VirScan) to compare the EV antigen landscapes in IA-positive case children versus IA-negative control children across two... -
Microbial associations and viruses on the risk of celiac disease (MAVRiC): a longitudinal post-hoc case-cohort study
Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten, yet these factors alone are not sufficient. Larger longitudinal studies are needed to determine the role of time-varying infections and gut microorganisms. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. By age 3-years, persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity... -
Association of fever and infections with the subsequent risk of atopic diseases in children with genetic susceptibility for T1D: Results from the TEDDY cohort study
CONCLUSIONS: In a longitudinal cohort study, fever shows a clear impact on how infections associate with subsequent atopic diseases. Understanding the modifying role of fever on risk offers new possibilities to explore the mechanisms that mediate the effect of infections in the atopic process. -
Air pollution-induced proteomic alterations increase the risk of child respiratory infections
Early life air pollution exposure may play a role in development of respiratory infections, but underlying mechanisms are still not understood. We utilized data from two independent prospective birth cohorts to investigate the influence of prenatal and postnatal ambient air pollution exposure of PM(2.5), PM(10) and NO(2) on maternal and child proteomic profiles and the risk of daily diary-registered common infections age 0-3 years in the Danish COPSAC(2010) (n = 613) and pneumonia, croup and... -
Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes
CONCLUSIONS/INTERPRETATION: We report the most extensive analysis to date of VP1 and HLA-I in pancreases from donors with preclinical and diagnosed type 1 diabetes. We find an association of VP1 with residual beta cells after diagnosis and demonstrate VP1 positivity during the autoantibody-positive preclinical stage. For the first time, we show that VP1 positivity and HLA-I hyperexpression in islet cells are both present during the preclinical stage. While the study of tissues does not allow us... -
Early-pregnancy BMI, maternal gestational weight gain, and asthma and allergic diseases in children
CONCLUSION: Association of early pregnancy BMI and maternal GWG, and asthma and allergic disease in children, is inconsistent. High maternal GWG may be associated with increased odds of atopic eczema. -
Using patterns of shared taxa to infer bacterial dispersal in human living environment in urban and rural areas
Contact with environmental microbial communities primes the human immune system. Factors determining the distribution of microorganisms, such as dispersal, are thus important for human health. Here, we used the relative number of bacteria shared between environmental and human samples as a measure of bacterial dispersal and studied these associations with living environment and lifestyles. We analyzed amplicon sequence variants (ASVs) of the V4 region of 16S rDNA gene from 347 samples of doormat... -
Skin exposure to soil microbiota elicits changes in cell-mediated immunity to pneumococcal vaccine
A resilient immune system is characterized by its capacity to respond appropriately to challenges, such as infections, and it is crucial in vaccine response. Here we report a paired randomized intervention-control trial in which we evaluated the effect of microbially rich soil on immune resilience and pneumococcal vaccine response. Twenty-five age and sex matched pairs of volunteers were randomized to intervention and control groups. The intervention group rubbed hands three times a day in... -
Distinct cellular immune responses in children en route to type 1 diabetes with different first-appearing autoantibodies
Previous studies have revealed heterogeneity in the progression to clinical type 1 diabetes in children who develop islet-specific antibodies either to insulin (IAA) or glutamic acid decarboxylase (GADA) as the first autoantibodies. Here, we test the hypothesis that children who later develop clinical disease have different early immune responses, depending on the type of the first autoantibody to appear (GADA-first or IAA-first). We use mass cytometry for deep immune profiling of peripheral... -
Impact of Cultivation and Origin on the Fruit Microbiome of Apples and Blueberries and Implications for the Exposome
Vegetables and fruits are a crucial part of the planetary health diet, directly affecting human health and the gut microbiome. The objective of our study was to understand the variability of the fruit (apple and blueberry) microbiome in the frame of the exposome concept. The study covered two fruit-bearing woody species, apple and blueberry, two countries of origin (Austria and Finland), and two fruit production methods (naturally grown and horticultural). Microbial abundance, diversity, and... -
Exposomic determinants of immune-mediated diseases: Special focus on type 1 diabetes, celiac disease, asthma, and allergies: The HEDIMED project approach
The incidence of immune-mediated diseases (IMDs) is increasing rapidly in the developed countries constituting a huge medical, economic, and societal challenge. The exposome plays an important role since genetic factors cannot explain such a rapid change. In the Human Exposomic Determinants of Immune Mediated Diseases (HEDIMED) project, altogether 22 academic and industrial partners join their multidisciplinary forces to identify exposomic determinants that are driving the IMD epidemic. The... -
Immunomodulatory Effects of Rhinovirus and Enterovirus Infections During the First Year of Life
Early childhood infections have been implicated in the development of immune-mediated diseases, such as allergies, asthma, and type 1 diabetes. We set out to investigate the immunomodulatory effects of early viral infections experienced before the age of one year on the peripheral regulatory T cell population (Treg) and circulating cytokines in a birth-cohort study of Estonian and Finnish infants. We show here a temporal association of virus infection with the expression of FOXP3 in regulatory T... -
Enterovirus Infections Are Associated With the Development of Celiac Disease in a Birth Cohort Study
Enterovirus and adenovirus infections have been linked to the development of celiac disease. We evaluated this association in children who developed biopsy-proven celiac disease (N = 41) during prospective observation starting from birth, and in control children (N = 53) matched for the calendar time of birth, sex, and HLA-DQ genotype. Enterovirus and adenovirus infections were diagnosed by seroconversions in virus antibodies in longitudinally collected sera using EIA. Enterovirus infections... -
Detection of Viral -RNA and +RNA Strands in Enterovirus-Infected Cells and Tissues
The current methods to study the distribution and dynamics of viral RNA molecules inside infected cells are not ideal, as electron microscopy and immunohistochemistry can only detect mature virions, and quantitative real-time PCR does not reveal localized distribution of RNAs. We demonstrated here the branched DNA in situ hybridization (bDNA ISH) technology to study both the amount and location of the emerging -RNA and +RNA during acute and persistent enterovirus infections. According to our... -
Associations between land cover categories, gaseous PAH levels in ambient air and endocrine signaling predicted from gut bacterial metagenome of the elderly
There is evidence that polycyclic aromatic hydrocarbons (PAHs) and human gut microbiota are associated with the modulation of endocrine signaling pathways. Independently, studies have found associations between air pollution, land cover and commensal microbiota. We are the first to estimate the interaction between land cover categories associated with air pollution or purification, PAH levels and endocrine signaling predicted from gut metagenome among urban and rural populations. The study... -
Genetic Adaptation of Coxsackievirus B1 during Persistent Infection in Pancreatic Cells
Coxsackie B (CVB) viruses have been associated with type 1 diabetes. We have recently observed that CVB1 was linked to the initiation of the autoimmune process leading to type 1 diabetes in Finnish children. Viral persistency in the pancreas is currently considered as one possible mechanism. In the current study persistent infection was established in pancreatic ductal and beta cell lines (PANC-1 and 1.1B4) using four different CVB1 strains, including the prototype strain and three clinical... -
Faecal regenerating 1B protein concentration is not associated with child growth in rural Malawi
CONCLUSIONS: Faecal REG1B concentration is not associated with LAZ, WAZ, WLZ and MUACZ among 6-30-month-old infants and children in rural Malawi. -
Biodiversity intervention enhances immune regulation and health-associated commensal microbiota among daycare children
As the incidence of immune-mediated diseases has increased rapidly in developed societies, there is an unmet need for novel prophylactic practices to fight against these maladies. This study is the first human intervention trial in which urban environmental biodiversity was manipulated to examine its effects on the commensal microbiome and immunoregulation in children. We analyzed changes in the skin and gut microbiota and blood immune markers of children during a 28-day biodiversity... -
Correction: Saarinen, N.V.V., et al. Multiplexed High-Throughput Serological Assay for Human Enteroviruses. Microorganismis 2020, 8, 963
The authors wish to make the following corrections to this paper [...]. -
Early-life exposure to perfluorinated alkyl substances modulates lipid metabolism in progression to celiac disease
Celiac disease (CD) is a systemic immune-mediated disorder with increased frequency in the developed countries over the last decades implicating the potential causal role of various environmental triggers in addition to gluten. Herein, we apply determination of perfluorinated alkyl substances (PFAS) and combine the results with the determination of bile acids (BAs) and molecular lipids, with the aim to elucidate the impact of prenatal exposure on risk of progression to CD in a prospective series... -
Structural Insight into CVB3-VLP Non-Adjuvanted Vaccine
Coxsackievirus B (CVB) enteroviruses are common pathogens that can cause acute and chronic myocarditis, dilated cardiomyopathy, aseptic meningitis, and they are hypothesized to be a causal factor in type 1 diabetes. The licensed enterovirus vaccines and those currently in clinical development are traditional inactivated or live attenuated vaccines. Even though these vaccines work well in the prevention of enterovirus diseases, new vaccine technologies, like virus-like particles (VLPs), can offer... -
A combined risk score enhances prediction of type 1 diabetes among susceptible children
Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk¹. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common^(2,3) and is most severe in the very young^(4,5), in whom it can be life threatening and difficult to treat^(6-9). Autoantibody surveillance programs effectively... -
Differential Detection of Encapsidated versus Unencapsidated Enterovirus RNA in Samples Containing Pancreatic Enzymes-Relevance for Diabetes Studies
Using immunohistochemistry, enterovirus capsid proteins were demonstrated in pancreatic islets of patients with type 1 diabetes. Virus proteins are mainly located in beta cells, supporting the hypothesis that enterovirus infections may contribute to the pathogenesis of type 1 diabetes. In samples of pancreatic tissue, enterovirus RNA was also detected, but in extremely small quantities and in a smaller proportion of cases compared to the enteroviral protein. Difficulties in detecting viral RNA... -
Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study
CONCLUSIONS: The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D. -
Multiplexed High-Throughput Serological Assay for Human Enteroviruses
Immunological assays detecting antibodies against enteroviruses typically use a single enterovirus serotype as antigen. This limits the ability of such assays to detect antibodies against different enterovirus types and to detect possible type-specific variation in antibody responses. We set out to develop a multiplexed assay for simultaneous detection of antibodies against multiple enterovirus and rhinovirus types encompassing all human infecting species. Seven recombinant VP1 proteins from... -
A hexavalent Coxsackievirus B vaccine is highly immunogenic and has a strong protective capacity in mice and nonhuman primates
Coxsackievirus B (CVB) enteroviruses are common human pathogens known to cause severe diseases including myocarditis, chronic dilated cardiomyopathy, and aseptic meningitis. CVBs are also hypothesized to be a causal factor in type 1 diabetes. Vaccines against CVBs are not currently available, and here we describe the generation and preclinical testing of a novel hexavalent vaccine targeting the six known CVB serotypes. We show that the vaccine has an excellent safety profile in murine models and... -
Eradication of persistent coxsackievirus B infection from a pancreatic cell line with clinically used antiviral drugs
CONCLUSIONS: The identified drugs are feasible candidates for clinical trials among patients with persistent coxsackievirus B infections or chronic enterovirus-associated diseases. -
Enhancing and neutralizing anti-coxsackievirus activities in serum samples from patients prior to development of type 1 diabetes
CONCLUSIONS: Evaluating the anti-enterovirus neutralizing and enhancing activity of serum samples can be useful to investigate further the relationship between enteroviruses and the development of T1D. -
Association of Picornavirus Infections With Acute Otitis Media in a Prospective Birth Cohort Study
CONCLUSIONS: HEVs and HRVs may contribute to the development of AOM in a relatively large proportion of cases.
2019
-
Distinct Enterovirus Antigen Landscape in Children With Islet Autoimmunity
Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes. However, given the ubiquity of EV infections in children, disease susceptibility is likely driven by host-specific immune responses rather than viral exposure alone. To investigate the host antibody response to EVs, we used virome-wide serological profiling (VirScan) to compare the EV antigen landscapes in IA-positive case children versus IA-negative control children across two... -
Clustering patterns in Finnish type 1 diabetes patients: a nationwide register-based study
CONCLUSIONS: These results demonstrate evidence of spatiotemporal clustering of T1DM in Finnish children, supporting the hypothesis of environmental triggers in T1DM etiology. These findings highlight the need for further research to identify the specific environmental factors and mechanisms behind the clustering. -
Microbial associations and viruses on the risk of celiac disease (MAVRiC): a longitudinal post-hoc case-cohort study
Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten, yet these factors alone are not sufficient. Larger longitudinal studies are needed to determine the role of time-varying infections and gut microorganisms. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. By age 3-years, persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity... -
Joint analysis of the nPOD-Virus Group data: the association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue
CONCLUSIONS/INTERPRETATION: The nPOD-Virus Group conducted, to date, the largest and most comprehensive analysis of multiple indices of pancreatic enterovirus infections in type 1 diabetes; these were more prevalent in T1D-ICI and AAb^(++) donors than in other groups. Their preferential detection of these indices in donors with residual beta cells and autoimmunity implicates enterovirus infections across disease progression stages and supports a contribution to beta cell loss, directly or... -
Detection of enterovirus RNA in pancreas and lymphoid tissues of organ donors with type 1 diabetes
CONCLUSIONS/INTERPRETATION: This was the largest coordinated effort to examine the presence of enterovirus RNA in the pancreas of organ donors with type 1 diabetes, using a multitude of assays. These findings are consistent with the notion that donors with type 1 diabetes and donors with islet autoantibodies may carry a low-grade enterovirus infection in the pancreas and lymphoid tissues. -
Three-Year Follow-up After Antiviral Treatment in New-Onset Type 1 Diabetes: Results From the Diabetes Virus Detection and Intervention Trial
CONCLUSIONS: The decreased reduction in C-peptide levels after antiviral treatment is no longer present after 2 or 3 years. Further investigations are needed to explore options to use antiviral treatment in the prevention and treatment of T1D. -
Distinct cellular immune responses in children en route to type 1 diabetes with different first-appearing autoantibodies
Previous studies have revealed heterogeneity in the progression to clinical type 1 diabetes in children who develop islet-specific antibodies either to insulin (IAA) or glutamic acid decarboxylase (GADA) as the first autoantibodies. Here, we test the hypothesis that children who later develop clinical disease have different early immune responses, depending on the type of the first autoantibody to appear (GADA-first or IAA-first). We use mass cytometry for deep immune profiling of peripheral... -
Author Correction: A combined risk score enhances prediction of type 1 diabetes among susceptible children
No abstract -
A combined risk score enhances prediction of type 1 diabetes among susceptible children
Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk¹. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common^(2,3) and is most severe in the very young^(4,5), in whom it can be life threatening and difficult to treat^(6-9). Autoantibody surveillance programs effectively... -
Prospective virome analyses in young children at increased genetic risk for type 1 diabetes
Viruses are implicated in autoimmune destruction of pancreatic islet β cells, which results in insulin deficiency and type 1 diabetes (T1D)^(1-4). Certain enteroviruses can infect β cells in vitro⁵, have been detected in the pancreatic islets of patients with T1D⁶ and have shown an association with T1D in meta-analyses⁴. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid... -
Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study
CONCLUSIONS: Frequent exposure to enterovirus between 1 and 2 years of age was associated with increased risk of CDA. The increased risk conferred by the interaction between enteroviruses and higher gluten intake indicate a cumulative effect of these factors in the development of CDA. -
A preclinical assessment to repurpose drugs to target type 1 diabetes-associated type B coxsackieviruses
CONCLUSION: Hizentra, enviroxime, pleconaril, ribavirin, and favipiravir are effective against type B coxsackieviruses in vitro in their therapeutic serum concentrations. These antiviral drugs are therefore attractive candidates for type 1 diabetes prevention/treatment trials. They can also be used in other clinical conditions caused by type B coxsackieviruses. -
Metabolite-related dietary patterns and the development of islet autoimmunity
The role of diet in type 1 diabetes development is poorly understood. Metabolites, which reflect dietary response, may help elucidate this role. We explored metabolomics and lipidomics differences between 352 cases of islet autoimmunity (IA) and controls in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. We created dietary patterns reflecting pre-IA metabolite differences between groups and examined their association with IA. Secondary outcomes included IA cases... -
Combination of three virus-derived nanoparticles as a vaccine against enteric pathogens; enterovirus, norovirus and rotavirus
Enteric viruses cause diverse infections with substantial morbidity and mortality in children, rotavirus (RV) and norovirus (NoV) being the leading agents of severe pediatric gastroenteritis. Coxsackie B viruses (CVB) are common enteroviruses (EV), associated with increased incidence of severe neonatal CVB disease with potentially fatal consequences. To prevent majority of childhood gastroenteritis, we have developed a non-live NoV-RV combination vaccine consisting of NoV virus-like particles... -
The relationship between breastfeeding and reported respiratory and gastrointestinal infection rates in young children
CONCLUSIONS: This study demonstrates that breastfeeding can be protective against multiple respiratory and gastrointestinal acute illnesses in some children up to at least 6 months of age, with duration of exclusive breastfeeding being somewhat protective of otitis media even after breastfeeding has stopped. -
Formalin treatment increases the stability and immunogenicity of coxsackievirus B1 VLP vaccine
Type B Coxsackieviruses (CVBs) are a common cause of acute and chronic myocarditis, dilated cardiomyopathy and aseptic meningitis. However, no CVB-vaccines are available for human use. We have previously produced virus-like particles (VLPs) for CVB3 with a baculovirus-insect cell production system. Here we have explored the potential of a VLP-based vaccine targeting CVB1 and describe the production of CVB1-VLPs with a scalable VLP purification method. The developed purification method consisting... -
A comparative study of the effect of UV and formalin inactivation on the stability and immunogenicity of a Coxsackievirus B1 vaccine
Type B Coxsackieviruses (CVBs) belong to the enterovirus genus, and they cause both acute and chronic diseases in humans. CVB infections usually lead to flu-like symptoms but can also result in more serious diseases such as myocarditis, aseptic meningitis and life-threatening multi-organ infections in young infants. Thus, CVBs have long been considered as important targets of future vaccines. We have previously observed CVB1 capsid disintegration and virus concentration decrease with 12-day long... -
Circulating metabolites in progression to islet autoimmunity and type 1 diabetes
CONCLUSIONS/INTERPRETATION: Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease. -
Coxsackievirus B Persistence Modifies the Proteome and the Secretome of Pancreatic Ductal Cells
The group B Coxsackieviruses (CVB), belonging to the Enterovirus genus, can establish persistent infections in human cells. These persistent infections have been linked to chronic diseases including type 1 diabetes. Still, the outcomes of persistent CVB infections in human pancreas are largely unknown. We established persistent CVB infections in a human pancreatic ductal-like cell line PANC-1 using two distinct CVB1 strains and profiled infection-induced changes in cellular protein expression... -
Temporal variation in indoor transfer of dirt-associated environmental bacteria in agricultural and urban areas
An agricultural environment and exposure to diverse environmental microbiota has been suggested to confer protection against immune-mediated disorders. As an agricultural environment may have a protective role, it is crucial to determine whether the limiting factors in the transfer of environmental microbiota indoors are the same in the agricultural and urban environments. We explored how sampling month, garden diversity and animal ownership affected the indoor-transfer of environmental... -
Global phylogeography and ancient evolution of the widespread human gut virus crAssphage
Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global... -
Endocrine disruption and commensal bacteria alteration associated with gaseous and soil PAH contamination among daycare children
Polycyclic aromatic hydrocarbons (PAHs) are priority environmental pollutants that cause adverse health effects. PAHs belong to endocrine signaling disruptors to which children are sensitive to. Recent evidence suggests that PAH pollution alters the abundance of environmental bacteria that is associated with health outcomes. The alteration of environmental and commensal microbiota by PAH pollution has never been connected to endocrine signaling pathways. To estimate the risk of endocrine... -
Early childhood infections and the use of antibiotics and antipyretic-analgesics in Finland, Estonia and Russian Karelia
CONCLUSION: Infections and the use of antibiotics and antipyretic-analgesics in early childhood were most frequent in Finland, where socio-economic conditions are the most developed and microbial encounters are sparse. This may reflect on the hygiene hypothesis, a less effective immune system that allows normally harmless microbes to attack and cause clinical infections. -
Persistent Alterations in Plasma Lipid Profiles Before Introduction of Gluten in the Diet Associated With Progression to Celiac Disease
OBJECTIVES: Celiac disease (CD) is a chronic enteropathy characterized by an autoimmune reaction in the small intestine of genetically susceptible individuals. The underlying causes of autoimmune reaction and its effect on host metabolism remain largely unknown. Herein, we apply lipidomics to elucidate the early events preceding clinical CD in a cohort of Finnish children, followed up in the Type 1 Diabetes Prediction and Prevention study. -
Presence of Giardia lamblia in stools of six- to 18-month old asymptomatic Malawians is associated with children's growth failure
CONCLUSION: Asymptomatic G. lamblia infection was mainly associated with growth reduction in certain three-month periods. The result refers to the chronic nature of G. lamblia infection. -
Large enteroviral vaccination studies to prevent type 1 diabetes should be well founded and rely on scientific evidence. Reply to Skog O, Klingel K, Roivainen M et al [letter]
No abstract -
Predicting Islet Cell Autoimmunity and Type 1 Diabetes: An 8-Year TEDDY Study Progress Report
CONCLUSIONS: Prediction modeling statistics are valuable tools, when applied in a time-until-event setting, to evaluate the ability of risk factors to discriminate between those who will and those who will not get disease. Although significantly associated with IA and T1D, the TEDDY risk factors individually contribute little to prediction. However, in combination, these factors increased IA and T1D prediction substantially. -
Early-life exposure to common virus infections did not differ between coeliac disease patients and controls
CONCLUSION: This study did not find any marked overall differences in laboratory-confirmed common viral infections between the children who developed coeliac disease and the controls. However, rhinovirus infections were detected slightly more often in those patients who developed coeliac disease. -
High prevalence of selected viruses and parasites and their predictors in Malawian children
Enteric pathogens have been related to child undernutrition. Whereas there are lots of data on enteric bacterial microbiota and infections, much less is known about the incidence of prevalence of intestinal colonisation with viruses or important parasitic species. This study assessed the presence of selected viruses and parasites in stools of 469, 354, 468 Malawian children at 6, 12 and 18 months. We also assessed environmental predictors of the presence of viruses and parasites among 6-month... -
Rhinoviruses in infancy and risk of immunoglobulin E sensitization
Previous data about the role of viruses in the development of allergic immunoglobulin E (IgE) sensitization are contradictory. The aim of this study was to determine the possible associations between exposure to different viruses (rhinovirus, enterovirus, norovirus, and parechovirus) during the first year of life and IgE sensitization. Viruses were analyzed from stool samples collected monthly from infants participating in a prospective birth cohort study. From that study, 244 IgE sensitized...
2018
-
Machine learning-based identification of wastewater treatment plant-specific microbial indicators using 16S rRNA gene sequencing
Effluent released from municipal wastewater treatment plants reflects the microbial communities responsible for degrading and removing contaminants within the plants. Monitoring this effluent offers essential insights into its environmental impacts, the efficiency of treatment processes, and the presence of emerging contaminants. To support improved monitoring and source attribution, our study employed a machine-learning framework to identify microbial indicators capable of distinguishing... -
Detection of enterovirus RNA in pancreas and lymphoid tissues of organ donors with type 1 diabetes
CONCLUSIONS/INTERPRETATION: This was the largest coordinated effort to examine the presence of enterovirus RNA in the pancreas of organ donors with type 1 diabetes, using a multitude of assays. These findings are consistent with the notion that donors with type 1 diabetes and donors with islet autoantibodies may carry a low-grade enterovirus infection in the pancreas and lymphoid tissues. -
Immunological resilience and biodiversity for prevention of allergic diseases and asthma
Increase of allergic conditions has occurred at the same pace with the Great Acceleration, which stands for the rapid growth rate of human activities upon earth from 1950s. Changes of environment and lifestyle along with escalating urbanization are acknowledged as the main underlying causes. Secondary (tertiary) prevention for better disease control has advanced considerably with innovations for oral immunotherapy and effective treatment of inflammation with corticosteroids, calcineurin... -
Developing a vaccine for type 1 diabetes by targeting coxsackievirus B
INTRODUCTION: Virus infections have long been considered as a possible cause of type 1 diabetes (T1D). One virus group, enteroviruses (EVs), has been studied extensively, and clinical development of a vaccine against T1D-associated EV types has started. -
A longitudinal plasma lipidomics dataset from children who developed islet autoimmunity and type 1 diabetes
Early prediction and prevention of type 1 diabetes (T1D) are currently unmet medical needs. Previous metabolomics studies suggest that children who develop T1D are characterised by a distinct metabolic profile already detectable during infancy, prior to the onset of islet autoimmunity. However, the specificity of persistent metabolic disturbances in relation T1D development has not yet been established. Here, we report a longitudinal plasma lipidomics dataset from (1) 40 children who progressed... -
Temporal development of the gut microbiome in early childhood from the TEDDY study
The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial-immune crosstalk during this time thought to be involved in the pathobiology of later life diseases^(1-9) such as persistent islet autoimmunity and type 1 diabetes^(10-12). However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children... -
The Environmental Determinants of Diabetes in the Young (TEDDY) Study: 2018 Update
PURPOSE OF REVIEW: The environmental triggers of islet autoimmunity leading to type 1 diabetes (T1D) need to be elucidated to inform primary prevention. The Environmental Determinants of Diabetes in the Young (TEDDY) Study follows from birth 8676 children with T1D risk HLA-DR-DQ genotypes in the USA, Finland, Germany, and Sweden. Most study participants (89%) have no first-degree relative with T1D. The primary outcomes include the appearance of one or more persistent islet autoantibodies (islet... -
Early childhood CMV infection may decelerate the progression to clinical type 1 diabetes
CONCLUSION: Our results suggest that an early childhood CMV infection may decelerate the progression from islet autoimmunity to clinical T1D among at-risk children and may thus protect these children from progressing to T1D during childhood. -
Time-Resolved Autoantibody Profiling Facilitates Stratification of Preclinical Type 1 Diabetes in Children
Progression to clinical type 1 diabetes varies among children who develop β-cell autoantibodies. Differences in autoantibody patterns could relate to disease progression and etiology. Here we modeled complex longitudinal autoantibody profiles by using a novel wavelet-based algorithm. We identified clusters of similar profiles associated with various types of progression among 600 children from The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort study; these children... -
Enterovirus infection during pregnancy is inversely associated with atopic disease in the offspring
CONCLUSIONS AND CLINICAL RELEVANCE: Our results suggest that maternal EV infections during pregnancy are inversely associated with atopic disease in the offspring. Our finding provides further support to the previous studies suggesting an important role of the in utero environment in the development of atopic diseases. -
Molecular epidemiology of enteroviruses in young children at increased risk of type 1 diabetes
CONCLUSIONS: Compared to prevalence data from symptomatic patients requiring medical attention, this study provides a better view of EVs circulating in young children in the USA and in Europe. The observations may prove useful for the selection of strategies for designing EV vaccines in the future. The study also confirms our previous serological findings suggesting that EV infections are relatively rare in Finland. -
Reduction in White Blood Cell, Neutrophil, and Red Blood Cell Counts Related to Sex, HLA, and Islet Autoantibodies in Swedish TEDDY Children at Increased Risk for Type 1 Diabetes
Islet autoantibodies (IAs) precede the clinical onset of type 1 diabetes (T1D); however, the knowledge is limited about whether the prodrome affects complete blood counts (CBCs) in 4- to 12-year-old children with increased genetic risk for T1D. This study tested whether CBCs were altered in 4- to 12-year-old children without (n = 376) or with one or several IAs against insulin, GAD65, or IA-2 (n = 72). CBC was analyzed during longitudinal follow-up in 448 Swedish children enrolled in The... -
Dynamics of Plasma Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes - Type 1 Diabetes Prediction and Prevention Study (DIPP)
Type 1 diabetes (T1D) is one of the most prevalent autoimmune diseases among children in Western countries. Earlier metabolomics studies suggest that T1D is preceded by dysregulation of lipid metabolism. Here we used a lipidomics approach to analyze molecular lipids in a prospective series of 428 plasma samples from 40 children who progressed to T1D (PT1D), 40 children who developed at least a single islet autoantibody but did not progress to T1D during the follow-up (P1Ab) and 40 matched... -
Strain-Level Analysis of Mother-to-Child Bacterial Transmission during the First Few Months of Life
Bacterial community acquisition in the infant gut impacts immune education and disease susceptibility. We compared bacterial strains across and within families in a prospective birth cohort of 44 infants and their mothers, sampled longitudinally in the first months of each child's life. We identified mother-to-child bacterial transmission events and describe the incidence of family-specific antibiotic resistance genes. We observed two inheritance patterns across multiple species, where often the... -
Short-term direct contact with soil and plant materials leads to an immediate increase in diversity of skin microbiota
Immune-mediated diseases have increased during the last decades in urban environments. The hygiene hypothesis suggests that increased hygiene level and reduced contacts with natural biodiversity are related to the increase in immune-mediated diseases. We tested whether short-time contact with microbiologically diverse nature-based materials immediately change bacterial diversity on human skin. We tested direct skin contact, as two volunteers rubbed their hands with sixteen soil and plant based... -
Nature-derived microbiota exposure as a novel immunomodulatory approach
CONCLUSION: If these findings are reproduced in larger studies nature-derived microbial exposure strategies could be further developed for testing their efficacy in the treatment and prevention of immune-mediated diseases. -
Quality Control Analysis in Real-time (QC-ART): A Tool for Real-time Quality Control Assessment of Mass Spectrometry-based Proteomics Data
Liquid chromatography-mass spectrometry (LC-MS)-based proteomics studies of large sample cohorts can easily require from months to years to complete. Acquiring consistent, high-quality data in such large-scale studies is challenging because of normal variations in instrumentation performance over time, as well as artifacts introduced by the samples themselves, such as those because of collection, storage and processing. Existing quality control methods for proteomics data primarily focus on... -
Higher parental occupational social contact is associated with a reduced risk of incident pediatric type 1 diabetes: Mediation through molecular enteroviral indices
We aimed to examine the association between parental occupational social contact and hygiene factors on type 1 diabetes (T1D) risk and possible mediation of these effects through child enteroviral infection. We interviewed 333 incident T1D cases and 660 controls from 2008-2011 in Melbourne, Australia. Enteroviral indices (ribonucleic acid by reverse transcription polymerase chain reaction and Coxsackie B virus antibody levels) in peripheral blood were measured in nested case control samples.... -
Half-lives of PAHs and temporal microbiota changes in commonly used urban landscaping materials
CONCLUSIONS: In this study, PAH degradation depended on the organic matter content and bacterial community composition of landscaping materials. Contamination seems to alter bacterial community composition in landscaping materials depending on material type. This alteration includes changes in bacterial phyla associated with human health and immune system. This may open new possibilities for managing urban environments by careful selection of landscaping materials, to benefit health and... -
First trimester enterovirus IgM and beta cell autoantibodies in mothers to children affected by type 1 diabetes autoimmunity before 7 years of age
CONCLUSION: EV-IgM during the first trimester may be associated with beta cell autoantibodies in mothers to children who developed either beta cell autoantibodies or T1D before 7 years of age. -
Urbanization Reduces Transfer of Diverse Environmental Microbiota Indoors
Expanding urbanization is a major factor behind rapidly declining biodiversity. It has been proposed that in urbanized societies, the rarity of contact with diverse environmental microbiota negatively impacts immune function and ultimately increases the risk for allergies and other immune-mediated disorders. Surprisingly, the basic assumption that urbanization reduces exposure to environmental microbiota and its transfer indoors has rarely been examined. We investigated if the land use type... -
New Coxsackievirus 2A<sup>pro</sup> and 3C<sup>pro</sup> protease antibodies for virus detection and discovery of pathogenic mechanisms
Enteroviruses (EVs), such as the Coxsackie B-viruses (CVBs), are common human pathogens, which can cause severe diseases including meningitis, myocarditis and neonatal sepsis. EVs encode two proteases (2A^(pro) and 3C^(pro)), which perform the proteolytic cleavage of the CVB polyprotein and also cleave host cell proteins to facilitate viral replication. The 2A^(pro) cause direct damage to the infected heart and tools to investigate 2A^(pro) and 3C^(pro) expression may contribute new knowledge on... -
Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes
CONCLUSIONS/INTERPRETATION: CVB1 infections may contribute to the initiation of islet autoimmunity being particularly important in the insulin-driven autoimmune process. -
Early Infant Diet and Islet Autoimmunity in the TEDDY Study
CONCLUSIONS: The timing of gluten-containing cereals and IA should be studied further. -
A novel rat CVB1-VP1 monoclonal antibody 3A6 detects a broad range of enteroviruses
Enteroviruses (EVs) are common RNA viruses that cause diseases ranging from rash to paralytic poliomyelitis. For example, EV-A and EV-C viruses cause hand-foot and mouth disease and EV-B viruses cause encephalitis and myocarditis, which can result in severe morbidity and mortality. While new vaccines and treatments for EVs are under development, methods for studying and diagnosing EV infections are still limited and therefore new diagnostic tools are required. Our aim was to produce and... -
Quantitative CrAssphage real-time PCR assay derived from data of multiple geographically distant populations
After its computational inference from human stool metagenomes, the CrAssphage has proven to be the most prevalent phage in the human gut, with presumably very wide geographic distribution. The currently available molecular assays do not sufficiently reflect the CrAssphage sequence variability. Here, we report a novel real-time PCR assay whose primers and probes are derived from data of multiple CrAssphage strains obtained from gut viral metagenomes of European, Asian, and African subjects. This... -
A Coxsackievirus B vaccine protects against virus-induced diabetes in an experimental mouse model of type 1 diabetes
CONCLUSIONS/INTERPRETATION: CVB1 vaccine can efficiently protect against both CVB1 infection and CVB1-induced diabetes. This preclinical proof of concept study provides a base for further studies aimed at developing a vaccine for use in elucidating the role of enteroviruses in human type 1 diabetes. -
Enterovirus-associated changes in blood transcriptomic profiles of children with genetic susceptibility to type 1 diabetes
CONCLUSIONS/INTERPRETATION: We have, for the first time, identified enterovirus-associated transcriptomic profiles in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Our results provide a starting point for understanding the individual responses to enterovirus infections in blood and their potential connection to the development of type 1 diabetes. -
Correction to: Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study
The authors regret that the SNP in SH2B3 was incorrectly referred to as rs3184505 instead of rs3184504 on both mentions in this paper (Methods section and Table 1). -
Plasma 25-Hydroxyvitamin D Concentration and Risk of Islet Autoimmunity
We examined the association between plasma 25-hydroxyvitamin D [25(OH)D] concentration and islet autoimmunity (IA) and whether vitamin D gene polymorphisms modify the effect of 25(OH)D on IA risk. We followed 8,676 children at increased genetic risk of type 1 diabetes at six sites in the U.S. and Europe. We defined IA as positivity for at least one autoantibody (GADA, IAA, or IA-2A) on two or more visits. We conducted a risk set sampled nested case-control study of 376 IA case subjects and up to...
2017
-
Microbial associations and viruses on the risk of celiac disease (MAVRiC): a longitudinal post-hoc case-cohort study
Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten, yet these factors alone are not sufficient. Larger longitudinal studies are needed to determine the role of time-varying infections and gut microorganisms. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. By age 3-years, persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity... -
Machine learning-based identification of wastewater treatment plant-specific microbial indicators using 16S rRNA gene sequencing
Effluent released from municipal wastewater treatment plants reflects the microbial communities responsible for degrading and removing contaminants within the plants. Monitoring this effluent offers essential insights into its environmental impacts, the efficiency of treatment processes, and the presence of emerging contaminants. To support improved monitoring and source attribution, our study employed a machine-learning framework to identify microbial indicators capable of distinguishing... -
Joint analysis of the nPOD-Virus Group data: the association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue
CONCLUSIONS/INTERPRETATION: The nPOD-Virus Group conducted, to date, the largest and most comprehensive analysis of multiple indices of pancreatic enterovirus infections in type 1 diabetes; these were more prevalent in T1D-ICI and AAb^(++) donors than in other groups. Their preferential detection of these indices in donors with residual beta cells and autoimmunity implicates enterovirus infections across disease progression stages and supports a contribution to beta cell loss, directly or... -
Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes
CONCLUSIONS/INTERPRETATION: We report the most extensive analysis to date of VP1 and HLA-I in pancreases from donors with preclinical and diagnosed type 1 diabetes. We find an association of VP1 with residual beta cells after diagnosis and demonstrate VP1 positivity during the autoantibody-positive preclinical stage. For the first time, we show that VP1 positivity and HLA-I hyperexpression in islet cells are both present during the preclinical stage. While the study of tissues does not allow us... -
Using patterns of shared taxa to infer bacterial dispersal in human living environment in urban and rural areas
Contact with environmental microbial communities primes the human immune system. Factors determining the distribution of microorganisms, such as dispersal, are thus important for human health. Here, we used the relative number of bacteria shared between environmental and human samples as a measure of bacterial dispersal and studied these associations with living environment and lifestyles. We analyzed amplicon sequence variants (ASVs) of the V4 region of 16S rDNA gene from 347 samples of doormat... -
Skin exposure to soil microbiota elicits changes in cell-mediated immunity to pneumococcal vaccine
A resilient immune system is characterized by its capacity to respond appropriately to challenges, such as infections, and it is crucial in vaccine response. Here we report a paired randomized intervention-control trial in which we evaluated the effect of microbially rich soil on immune resilience and pneumococcal vaccine response. Twenty-five age and sex matched pairs of volunteers were randomized to intervention and control groups. The intervention group rubbed hands three times a day in... -
Maternal gluten, cereal, and dietary fiber intake during pregnancy and lactation and the risk of islet autoimmunity and type 1 diabetes in the child
CONCLUSIONS: We observed no association between maternal intake of gluten, most consumed cereals, or dietary fiber during pregnancy or lactation and the risk of islet autoimmunity or type 1 diabetes in children from a high-risk population. -
Childhood Height Growth Rate Association With the Risk of Islet Autoimmunity and Development of Type 1 Diabetes
CONCLUSION: Rapid height growth rate in childhood is associated with increased risk of islet autoimmunity and progression to T1D. Further work is needed to investigate the biological mechanism that may explain this association. -
Serum fatty acids and risk of developing islet autoimmunity: A nested case-control study within the TRIGR birth cohort
CONCLUSIONS: We found direct associations of pentadecanoic acid, heptadecanoic acid, stearic acid, and conjugated linoleic acid with the risk of islet autoimmunity. Further studies are needed to understand the complex role of fatty acids in the development of type 1 diabetes. -
Structural Insight into CVB3-VLP Non-Adjuvanted Vaccine
Coxsackievirus B (CVB) enteroviruses are common pathogens that can cause acute and chronic myocarditis, dilated cardiomyopathy, aseptic meningitis, and they are hypothesized to be a causal factor in type 1 diabetes. The licensed enterovirus vaccines and those currently in clinical development are traditional inactivated or live attenuated vaccines. Even though these vaccines work well in the prevention of enterovirus diseases, new vaccine technologies, like virus-like particles (VLPs), can offer... -
Early-life exposure to common virus infections did not differ between coeliac disease patients and controls
CONCLUSION: This study did not find any marked overall differences in laboratory-confirmed common viral infections between the children who developed coeliac disease and the controls. However, rhinovirus infections were detected slightly more often in those patients who developed coeliac disease. -
Rhinoviruses in infancy and risk of immunoglobulin E sensitization
Previous data about the role of viruses in the development of allergic immunoglobulin E (IgE) sensitization are contradictory. The aim of this study was to determine the possible associations between exposure to different viruses (rhinovirus, enterovirus, norovirus, and parechovirus) during the first year of life and IgE sensitization. Viruses were analyzed from stool samples collected monthly from infants participating in a prospective birth cohort study. From that study, 244 IgE sensitized... -
A Coxsackievirus B vaccine protects against virus-induced diabetes in an experimental mouse model of type 1 diabetes
CONCLUSIONS/INTERPRETATION: CVB1 vaccine can efficiently protect against both CVB1 infection and CVB1-induced diabetes. This preclinical proof of concept study provides a base for further studies aimed at developing a vaccine for use in elucidating the role of enteroviruses in human type 1 diabetes. -
The abundance of health-associated bacteria is altered in PAH polluted soils-Implications for health in urban areas?
Long-term exposure to polyaromatic hydrocarbons (PAHs) has been connected to chronic human health disorders. It is also well-known that i) PAH contamination alters soil bacterial communities, ii) human microbiome is associated with environmental microbiome, and iii) alteration in the abundance of members in several bacterial phyla is associated with adverse or beneficial human health effects. We hypothesized that soil pollution by PAHs altered soil bacterial communities that had known... -
Enterovirus-associated changes in blood transcriptomic profiles of children with genetic susceptibility to type 1 diabetes
CONCLUSIONS/INTERPRETATION: We have, for the first time, identified enterovirus-associated transcriptomic profiles in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Our results provide a starting point for understanding the individual responses to enterovirus infections in blood and their potential connection to the development of type 1 diabetes. -
Plasma 25-Hydroxyvitamin D Concentration and Risk of Islet Autoimmunity
We examined the association between plasma 25-hydroxyvitamin D [25(OH)D] concentration and islet autoimmunity (IA) and whether vitamin D gene polymorphisms modify the effect of 25(OH)D on IA risk. We followed 8,676 children at increased genetic risk of type 1 diabetes at six sites in the U.S. and Europe. We defined IA as positivity for at least one autoantibody (GADA, IAA, or IA-2A) on two or more visits. We conducted a risk set sampled nested case-control study of 376 IA case subjects and up to... -
Association Between Early-Life Antibiotic Use and the Risk of Islet or Celiac Disease Autoimmunity
CONCLUSIONS AND RELEVANCE: The use of the most prescribed antibiotics during the first 4 years of life, regardless of geographic region, was not associated with the development of autoimmunity for T1D or CD. These results suggest that a risk of islet or tissue transglutaminase autoimmunity need not influence the recommendations for clinical use of antibiotics in young children at risk for T1D or CD. -
Exocrine pancreas function decreases during the progression of the beta-cell damaging process in young prediabetic children
CONCLUSION: The results suggest that the defect in the exocrine function develops after the appearance of islet autoantibodies. Further studies are needed to assess whether reduced elastase levels predict rapid progression of islet autoimmunity to clinical disease. -
Pandemrix® vaccination is not associated with increased risk of islet autoimmunity or type 1 diabetes in the TEDDY study children
CONCLUSIONS/INTERPRETATION: Children with an increased genetic risk for type 1 diabetes who received the Pandemrix® vaccine during the A/H1N1 2009 pandemic had no increased risk of islet autoimmunity, multiple islet autoantibodies or type 1 diabetes. In Finland, the vaccine was associated with a reduced risk of islet autoimmunity and type 1 diabetes. -
Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies
β-cell autoantibodies against insulin (IAA), GAD65 (GADA) and IA-2 (IA-2A) precede onset of childhood type 1 diabetes (T1D). Incidence of the first appearing β-cell autoantibodies peaks at a young age and is patterned by T1D-associated genes, suggesting an early environmental influence. Here, we tested if gestational infections and interactions with child's human leukocyte antigen (HLA) and non-HLA genes affected the appearance of the first β-cell autoantibody. Singletons of mothers without... -
Live attenuated enterovirus vaccine (OPV) is not associated with islet autoimmunity in children with genetic susceptibility to type 1 diabetes: prospective cohort study
CONCLUSIONS/INTERPRETATION: Replication of attenuated poliovirus strains in gut mucosa is not associated with an increased risk of islet autoimmunity. -
Joint modeling of longitudinal autoantibody patterns and progression to type 1 diabetes: results from the TEDDY study
CONCLUSIONS: These findings indicate that T1D progression risk stratification based on autoantibody titers should focus on time points early after seroconversion. Joint modeling techniques allow for new insights into these associations. -
Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study
CONCLUSIONS/INTERPRETATION: Recent respiratory infections in young children correlate with an increased risk of islet autoimmunity in the TEDDY study. Further studies to identify the potential causative viruses with pathogen-specific assays should focus especially on the 9 month time window leading to autoantibody seroconversion. -
Avoidance of Cow's Milk-Based Formula for At-Risk Infants Does Not Reduce Development of Celiac Disease: A Randomized Controlled Trial
CONCLUSIONS: In a randomized controlled trial of 230 infants with genetic risk factors for celiac disease, we did not find evidence that weaning to a diet of extensively hydrolyzed formula compared with cow's milk-based formula would decrease the risk for celiac disease later in life. Increased titers of cow's milk antibody before anti-TG2A and celiac disease indicates that subjects with celiac disease might have increased intestinal permeability in early life. ClinicalTrials.gov Number:... -
Early childhood infections precede development of beta-cell autoimmunity and type 1 diabetes in children with HLA-conferred disease risk
CONCLUSIONS: Early childhood infections may play an important role in the pathogenesis of T1D. Current findings may reflect either differences in microbial exposures or early immunological aberrations making diabetes-prone children more susceptible to infections. -
Optimized production and purification of Coxsackievirus B1 vaccine and its preclinical evaluation in a mouse model
Coxsackie B viruses are among the most common enteroviruses, causing a wide range of diseases. Recent studies have also suggested that they may contribute to the development of type 1 diabetes. Vaccination would provide an effective way to prevent CVB infections, and the objective of this study was to develop an efficient vaccine production protocol for the generation of novel CVB vaccines. Various steps in the production of a formalin-inactivated Coxsackievirus B1 (CVB1) vaccine were optimized... -
Vipie: web pipeline for parallel characterization of viral populations from multiple NGS samples
CONCLUSIONS: The Vipie web application is a unique tool for multi-sample metagenomic analysis of viral data, producing searchable hits tables, interactive population maps, alpha diversity measures and clustered heatmaps that are grouped in applicable custom sample categories. Known references such as human genome and bacterial ribosomal genes are optionally removed from unmapped ('dark matter') reads. Secured results are accessible and shareable on modern browsers. Vipie is a freely available... -
Corrigendum: A Comparison of Rule-based Analysis with Regression Methods in Understanding the Risk Factors for Study Withdrawal in a Pediatric Study
No abstract -
Next-Generation Sequencing Combined with Specific PCR Assays To Determine the Bacterial 16S rRNA Gene Profiles of Middle Ear Fluid Collected from Children with Acute Otitis Media
The aim of the study was to analyze the bacteriome of acute otitis media with a novel modification of next-generation sequencing techniques. Outpatient children with acute otitis media were enrolled in the study, and middle ear fluids were collected during 90 episodes from 79 subjects aged 5 to 42 months (median age, 19 months). The bacteriome profiles of middle ear fluid samples were determined by a nested-PCR amplification of the 16S rRNA gene (V4 region), followed by mass sequencing. The... -
Correction: B-Cell Responses to Human Bocaviruses 1-4: New Insights from a Childhood Follow-Up Study
[This corrects the article DOI: 10.1371/journal.pone.0139096.].
2016
-
Microbial associations and viruses on the risk of celiac disease (MAVRiC): a longitudinal post-hoc case-cohort study
Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten, yet these factors alone are not sufficient. Larger longitudinal studies are needed to determine the role of time-varying infections and gut microorganisms. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. By age 3-years, persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity... -
Machine learning-based identification of wastewater treatment plant-specific microbial indicators using 16S rRNA gene sequencing
Effluent released from municipal wastewater treatment plants reflects the microbial communities responsible for degrading and removing contaminants within the plants. Monitoring this effluent offers essential insights into its environmental impacts, the efficiency of treatment processes, and the presence of emerging contaminants. To support improved monitoring and source attribution, our study employed a machine-learning framework to identify microbial indicators capable of distinguishing... -
Distinct cellular immune responses in children en route to type 1 diabetes with different first-appearing autoantibodies
Previous studies have revealed heterogeneity in the progression to clinical type 1 diabetes in children who develop islet-specific antibodies either to insulin (IAA) or glutamic acid decarboxylase (GADA) as the first autoantibodies. Here, we test the hypothesis that children who later develop clinical disease have different early immune responses, depending on the type of the first autoantibody to appear (GADA-first or IAA-first). We use mass cytometry for deep immune profiling of peripheral... -
Temporal variation in indoor transfer of dirt-associated environmental bacteria in agricultural and urban areas
An agricultural environment and exposure to diverse environmental microbiota has been suggested to confer protection against immune-mediated disorders. As an agricultural environment may have a protective role, it is crucial to determine whether the limiting factors in the transfer of environmental microbiota indoors are the same in the agricultural and urban environments. We explored how sampling month, garden diversity and animal ownership affected the indoor-transfer of environmental... -
Global phylogeography and ancient evolution of the widespread human gut virus crAssphage
Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global... -
Enterovirus-associated changes in blood transcriptomic profiles of children with genetic susceptibility to type 1 diabetes
CONCLUSIONS/INTERPRETATION: We have, for the first time, identified enterovirus-associated transcriptomic profiles in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Our results provide a starting point for understanding the individual responses to enterovirus infections in blood and their potential connection to the development of type 1 diabetes. -
Pandemrix® vaccination is not associated with increased risk of islet autoimmunity or type 1 diabetes in the TEDDY study children
CONCLUSIONS/INTERPRETATION: Children with an increased genetic risk for type 1 diabetes who received the Pandemrix® vaccine during the A/H1N1 2009 pandemic had no increased risk of islet autoimmunity, multiple islet autoantibodies or type 1 diabetes. In Finland, the vaccine was associated with a reduced risk of islet autoimmunity and type 1 diabetes. -
Early childhood infections precede development of beta-cell autoimmunity and type 1 diabetes in children with HLA-conferred disease risk
CONCLUSIONS: Early childhood infections may play an important role in the pathogenesis of T1D. Current findings may reflect either differences in microbial exposures or early immunological aberrations making diabetes-prone children more susceptible to infections. -
Circulating CXCR5+PD-1+ICOS+ Follicular T Helper Cells Are Increased Close to the Diagnosis of Type 1 Diabetes in Children With Multiple Autoantibodies
Although type 1 diabetes (T1D) is primarily perceived as a T cell-driven autoimmune disease, islet autoantibodies are the best currently available biomarker for autoimmunity and disease risk. These antibodies are produced by autoreactive B cells, the activation of which is largely dependent on the function of CD4^(+)CXCR5^(+) follicular T helper cells (Tfh). In this study, we have comprehensively characterized the Tfh- as well as B-cell compartments in a large cohort of children with newly... -
Coxsackie-adenovirus receptor expression is enhanced in pancreas from patients with type 1 diabetes
CONCLUSIONS: CAR is expressed in pancreatic islets of patients with T1D and the expression level of CAR is increased in explanted islets exposed to proinflammatory cytokines/chemokines produced by infected islets. T1D is associated with increased levels of certain chemokines/cytokines in the islets and this might be the mechanism behind the increased expression of CAR in TID islets. -
Imbalance of bacteriome profiles within the Finnish Diabetes Prediction and Prevention study: Parallel use of 16S profiling and virome sequencing in stool samples from children with islet autoimmunity and matched controls
CONCLUSIONS: The results confirm previous findings that an imbalance within the prevalent Bacteroides genus is associated with islet autoimmunity. The detected quantitative relation of the novel "orphan" bacteriophage CrAssphage with a prevalent species of the Bacteroides genus may exemplify possible modifiers of the bacteriome. -
Factors That Increase Risk of Celiac Disease Autoimmunity After a Gastrointestinal Infection in Early Life
CONCLUSIONS: Gastrointestinal infections increase the risk of celiac disease autoimmunity in children with genetic susceptibility to this autoimmune disorder. The risk is modified by HLA genotype, infant gluten consumption, breastfeeding, and rotavirus vaccination, indicating complex interactions among infections, genetic factors, and diet in the etiology of celiac disease in early childhood. -
Human enterovirus and rhinovirus infections are associated with otitis media in a prospective birth cohort study
CONCLUSIONS: HRV and HEV infections are frequent during the first months of life. The observed trend for increased risk of AOM in HRV and HEV positive children is in line with the results from hospital series suggesting that these viruses may play an independent role in the pathogenesis of AOM. -
Natural Development of Antibodies against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis Protein Antigens during the First 13 Years of Life
Conserved protein antigens have been investigated as vaccine candidates against respiratory pathogens. We evaluated the natural development of antibodies against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis proteins during childhood. Serum samples were collected from 50 healthy children from their first months to age 13 years (median sampling interval, 6 months). We also analyzed serum samples from 24 adults. Serum IgG antibodies against eight pneumococcal proteins... -
A Comparison of Rule-based Analysis with Regression Methods in Understanding the Risk Factors for Study Withdrawal in a Pediatric Study
Regression models are extensively used in many epidemiological studies to understand the linkage between specific outcomes of interest and their risk factors. However, regression models in general examine the average effects of the risk factors and ignore subgroups with different risk profiles. As a result, interventions are often geared towards the average member of the population, without consideration of the special health needs of different subgroups within the population. This paper... -
Exploring the risk factors for differences in the cumulative incidence of coeliac disease in two neighboring countries: the prospective DIABIMMUNE study
CONCLUSION: The 5-year cumulative incidence of childhood CD is significantly higher in Finland than in Estonia. Sequential infections early in life may increase the risk for developing CD. -
Viruses in type 1 diabetes
Environmental factors play an important role in the pathogenesis of type 1 diabetes and can determine if a genetically susceptible individual develops the disease. Increasing evidence suggest that among other exogenous agents certain virus infections can contribute to the beta-cell damaging process. Possible viral etiology of type 1 diabetes has been explored extensively but the final proof for causality is still lacking. Currently, the group of enteroviruses (EVs) is considered as the strongest... -
Moraxella catarrhalis Might Be More Common than Expected in Acute Otitis Media in Young Finnish Children
According to studies based on bacterial cultures of middle ear fluids, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis have been the most common pathogens in acute otitis media. However, bacterial culture can be affected by reduced viability or suboptimal growth of bacteria. PCR detects bacterial DNA from samples with greater sensitivity than culture. In the present study, we analyzed the middle ear pathogens with both conventional culture and semiquantitative... -
Complement gene variants in relation to autoantibodies to beta cell specific antigens and type 1 diabetes in the TEDDY Study
A total of 15 SNPs within complement genes and present on the ImmunoChip were analyzed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A total of 5474 subjects were followed from three months of age until islet autoimmunity (IA: n = 413) and the subsequent onset of type 1 diabetes (n = 115) for a median of 73 months (IQR 54-91). Three SNPs within ITGAM were nominally associated (p < 0.05) with IA: rs1143678 [Hazard ratio; HR 0.80; 95% CI 0.66-0.98; p = 0.032], rs1143683... -
Antibiotic resistance in pathogens causing acute otitis media in Finnish children
CONCLUSIONS: Antibiotic resistant bacterial strains causing AOM have increased in Finland. Nevertheless, most of the pathogens (72%) were sensitive to amoxicillin, which is still recommended as the first line antibiotic in the treatment of AOM. -
Relative sensitivity of immunohistochemistry, multiple reaction monitoring mass spectrometry, in situ hybridization and PCR to detect Coxsackievirus B1 in A549 cells
CONCLUSIONS: All methods were able to detect CVB1 in infected A549 cells. RT-PCR was most sensitive followed by LC/MRM/MS/MS and then IHC. The results from this in vitro survey suggest that all methods are suitable tools for EV detection but that their differential sensitivities need to be considered when interpreting the results from such studies. -
Development and maturation of norovirus antibodies in childhood
The burden of norovirus (NoV) gastroenteritis is substantial in young children. Maternal antibodies are thought to protect a child from NoV infection in early infancy but subsequent development of NoV-specific protective immunity in children is still largely unexplored. We have determined NoV-specific antibody seroconversion to GII.4 virus-like particles as an indicator of NoV infection in two children prospectively followed from birth to eight years of age. Blocking activity and affinity... -
Serum 25-Hydroxyvitamin D Concentrations in Children Progressing to Autoimmunity and Clinical Type 1 Diabetes
CONCLUSIONS: This study shows that serum 25(OH)D concentrations are not associated with the development of T1D in Finland. -
Participant Experiences in the Environmental Determinants of Diabetes in the Young Study: Common Reasons for Withdrawing
CONCLUSIONS: Results suggest that, for families of children genetically at risk for diabetes, procedures that can be painful/frightening should be used with caution. Study procedures must also be considered for the demands placed on participants. Study satisfaction should be regularly assessed as an indicator of risk for withdrawal. -
Association of Early Exposure of Probiotics and Islet Autoimmunity in the TEDDY Study
CONCLUSIONS AND RELEVANCE: Early probiotic supplementation may reduce the risk of islet autoimmunity in children at the highest genetic risk of T1DM. The result needs to be confirmed in further studies before any recommendation of probiotics use is made. -
Positivity for Zinc Transporter 8 Autoantibodies at Diagnosis Is Subsequently Associated With Reduced β-Cell Function and Higher Exogenous Insulin Requirement in Children and Adolescents With Type 1 Diabetes
CONCLUSIONS: Positivity for ZnT8A at diagnosis seems to reflect a more aggressive disease process before and after diagnosis. -
Effects of Gluten Intake on Risk of Celiac Disease: A Case-Control Study on a Swedish Birth Cohort
CONCLUSIONS: The amount of gluten consumed until 2 years of age increases the risk of celiac disease at least 2-fold in genetically susceptible children. These findings may be taken into account for future infant feeding recommendations.
2015
-
Distinct Enterovirus Antigen Landscape in Children With Islet Autoimmunity
Enteroviruses (EVs) have long been implicated in the development of islet autoimmunity (IA) and type 1 diabetes. However, given the ubiquity of EV infections in children, disease susceptibility is likely driven by host-specific immune responses rather than viral exposure alone. To investigate the host antibody response to EVs, we used virome-wide serological profiling (VirScan) to compare the EV antigen landscapes in IA-positive case children versus IA-negative control children across two... -
Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial
Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6-15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (n = 47) or placebo (n = 49) for 6 months, with the aim of preserving β cell function. The primary... -
Yard vegetation is associated with gut microbiota composition
Gut microbes play an essential role in the development and functioning of the human immune system. A disturbed gut microbiota composition is often associated with a number of health disorders including immune-mediated diseases. Differences in host characteristics such as ethnicity, living habit and diet have been used to explain differences in the gut microbiota composition in inter-continental comparison studies. As our previous studies imply that daily skin contact with organic gardening... -
Temporal variation in indoor transfer of dirt-associated environmental bacteria in agricultural and urban areas
An agricultural environment and exposure to diverse environmental microbiota has been suggested to confer protection against immune-mediated disorders. As an agricultural environment may have a protective role, it is crucial to determine whether the limiting factors in the transfer of environmental microbiota indoors are the same in the agricultural and urban environments. We explored how sampling month, garden diversity and animal ownership affected the indoor-transfer of environmental... -
Urbanization Reduces Transfer of Diverse Environmental Microbiota Indoors
Expanding urbanization is a major factor behind rapidly declining biodiversity. It has been proposed that in urbanized societies, the rarity of contact with diverse environmental microbiota negatively impacts immune function and ultimately increases the risk for allergies and other immune-mediated disorders. Surprisingly, the basic assumption that urbanization reduces exposure to environmental microbiota and its transfer indoors has rarely been examined. We investigated if the land use type... -
Factors That Increase Risk of Celiac Disease Autoimmunity After a Gastrointestinal Infection in Early Life
CONCLUSIONS: Gastrointestinal infections increase the risk of celiac disease autoimmunity in children with genetic susceptibility to this autoimmune disorder. The risk is modified by HLA genotype, infant gluten consumption, breastfeeding, and rotavirus vaccination, indicating complex interactions among infections, genetic factors, and diet in the etiology of celiac disease in early childhood. -
Development and maturation of norovirus antibodies in childhood
The burden of norovirus (NoV) gastroenteritis is substantial in young children. Maternal antibodies are thought to protect a child from NoV infection in early infancy but subsequent development of NoV-specific protective immunity in children is still largely unexplored. We have determined NoV-specific antibody seroconversion to GII.4 virus-like particles as an indicator of NoV infection in two children prospectively followed from birth to eight years of age. Blocking activity and affinity... -
Serum 25-Hydroxyvitamin D Concentrations in Children Progressing to Autoimmunity and Clinical Type 1 Diabetes
CONCLUSIONS: This study shows that serum 25(OH)D concentrations are not associated with the development of T1D in Finland. -
Participant Experiences in the Environmental Determinants of Diabetes in the Young Study: Common Reasons for Withdrawing
CONCLUSIONS: Results suggest that, for families of children genetically at risk for diabetes, procedures that can be painful/frightening should be used with caution. Study procedures must also be considered for the demands placed on participants. Study satisfaction should be regularly assessed as an indicator of risk for withdrawal. -
Positivity for Zinc Transporter 8 Autoantibodies at Diagnosis Is Subsequently Associated With Reduced β-Cell Function and Higher Exogenous Insulin Requirement in Children and Adolescents With Type 1 Diabetes
CONCLUSIONS: Positivity for ZnT8A at diagnosis seems to reflect a more aggressive disease process before and after diagnosis. -
Effects of Gluten Intake on Risk of Celiac Disease: A Case-Control Study on a Swedish Birth Cohort
CONCLUSIONS: The amount of gluten consumed until 2 years of age increases the risk of celiac disease at least 2-fold in genetically susceptible children. These findings may be taken into account for future infant feeding recommendations. -
B-Cell Responses to Human Bocaviruses 1-4: New Insights from a Childhood Follow-Up Study
Human bocaviruses (HBoVs) 1-4 are recently discovered, antigenically similar parvoviruses. We examined the hypothesis that the antigenic similarity of these viruses could give rise to clinically and diagnostically important immunological interactions. IgG and IgM EIAs as well as qPCR were used to study ~2000 sera collected from infancy to early adolescence at 3-6-month intervals from 109 children whose symptoms were recorded. We found that HBoV1-4-specific seroprevalences at age 6 years were... -
Influenza A virus antibodies show no association with pancreatic islet autoantibodies in children genetically predisposed to type 1 diabetes
CONCLUSIONS/INTERPRETATION: Our results suggest that influenza A infections are not associated with the development of islet autoimmunity in young children with increased genetic susceptibility to type 1 diabetes. -
Application of bioinformatics in probe design enables detection of enteroviruses on different taxonomic levels by advanced in situ hybridization technology
CONCLUSIONS: These novel in-house designed probe sets enable the detection of enteroviruses from formalin-fixed tissue samples. Optimization of probe sequences makes it possible to tailor the assay for the detection of enteroviruses on the serotype or species level. -
Multiple consecutive norovirus infections in the first 2 years of life
CONCLUSION: This study describes norovirus-specific serological responses in a child with four consecutive norovirus infection during the first 2 years of life. The response is type-specific and does not protect from a subsequent infection with a heterologous virus. -
Investigation of CTLA-4-318C/T gene polymorphism in cases with type 1 diabetes of Azerbaijan, Northwest Iran
This study analyzed the association of CTLA-4-318C/T gene polymorphism with susceptibility, clinical course and laboratory findings of Type 1 diabetes (T1D). One hundred and fifty-three T1D patients and 189 healthy controls entered this study. CTLA-4-318C/T genotyping was performed by tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) analysis. The allelic and genotypic frequencies of -318C/T gene polymorphism were similar in patients and controls.... -
Circulating IGF1 and IGFBP3 in relation to the development of β-cell autoimmunity in young children
CONCLUSIONS: Circulating IGF1 and IGFBP3 appear to have a role in early development of β-cell autoimmunity. The decreased IGF1 concentrations in children with the high-risk HLA genotype may contribute to the reduced growth previously described in such children. -
High-throughput multiplex quantitative polymerase chain reaction method for Giardia lamblia and Cryptosporidium species detection in stool samples
Giardia lamblia and Cryptosporidium species belong to a complex group of pathogens that cause diseases hampering development and socioeconomic improvements in the developing countries. Both pathogens are recognized as significant causes of diarrhea and nutritional disorders. However, further studies are needed to clarify the role of parasitic infections, especially asymptomatic infections in malnutrition and stunting. We developed a high-throughput multiplex quantitative polymerase chain... -
A method for reporting and classifying acute infectious diseases in a prospective study of young children: TEDDY
CONCLUSIONS: The data reduction and categorization process developed by TEDDY enables analysis of single infectious agents as well as larger arrays of infectious agents or clinical disease entities. The preliminary descriptive analyses of the incidence of infections among TEDDY participants younger than 4 years fits well with general knowledge of infectious disease epidemiology. This protocol can be used as a template in forthcoming time-dependent TEDDY analyses and in other epidemiological... -
Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes
CONCLUSIONS: This study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when... -
Clinical features of celiac disease: a prospective birth cohort
CONCLUSIONS: A majority of children detected with persistent tTGA in screenings are asymptomatic and have normal growth by age 4 years. tTGA levels correlate more strongly with severity of mucosal lesions in symptomatic as compared with asymptomatic children. -
Gut virome sequencing in children with early islet autoimmunity
CONCLUSIONS: The present data suggest no dramatic changes in the gut virome shortly before the emergence of islet autoimmunity and emphasize the need of verification of mass sequencing results when viral exposure is assessed in association studies. -
Predictors of Progression From the Appearance of Islet Autoantibodies to Early Childhood Diabetes: The Environmental Determinants of Diabetes in the Young (TEDDY)
CONCLUSIONS: In the TEDDY study, children who have progressed to diabetes usually expressed two or more autoantibodies. Higher IAA and IA-2A levels, but not GADA levels, increased the risk of diabetes in those children who were persistently autoantibody positive. -
The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes
Colonization of the fetal and infant gut microbiome results in dynamic changes in diversity, which can impact disease susceptibility. To examine the relationship between human gut microbiome dynamics throughout infancy and type 1 diabetes (T1D), we examined a cohort of 33 infants genetically predisposed to T1D. Modeling trajectories of microbial abundances through infancy revealed a subset of microbial relationships shared across most subjects. Although strain composition of a given species was... -
Serum proteomes distinguish children developing type 1 diabetes in a cohort with HLA-conferred susceptibility
We determined longitudinal serum proteomics profiles from children with HLA-conferred diabetes susceptibility to identify changes that could be detected before seroconversion and positivity for disease-associated autoantibodies. Comparisons were made between children who seroconverted and progressed to type 1 diabetes (progressors) and those who remained autoantibody negative, matched by age, sex, sample periodicity, and risk group. The samples represented the prediabetic period and ranged from... -
Age at gluten introduction and risk of celiac disease
CONCLUSIONS: In TEDDY, the time to first introduction to gluten introduction was not an independent risk factor for developing CD. -
Early childhood gut microbiomes show strong geographic differences among subjects at high risk for type 1 diabetes
CONCLUSIONS: The microbiome of high-risk infants is associated with geographical location. Future studies aiming to identify the microbiome disease phenotype need to carefully consider the geographical origin of subjects. -
Th1/Th17 plasticity is a marker of advanced β cell autoimmunity and impaired glucose tolerance in humans
Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late... -
Human parechovirus as a minor cause of acute otitis media in children
Human parechoviruses (HPeVs) cause mild upper respiratory infections, gastrointestinal symptoms, central nervous system infections and some studies have linked them with acute otitis media (AOM). The aim of the present study was to study further the role of HPeV infections in AOM by detecting these viruses directly from middle ear fluid (MEF), respiratory and stool samples collected from children during AOM episodes. A total of 91 MEF samples, 98 nasal swab (NS) samples and 92 stool samples were... -
Role of Type 1 Diabetes-Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study
The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GAD antibody, IA-2A, or micro insulin autoantibodies) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA single nucleotide...