Genomics and immunobiology behind celiac disease

Celiac disease autoantibody deposits in mice injected with celiac patient serum

The development of celiac disease requires a genetic component, namely human leukocyte antigen (HLA) DQ2 or DQ8 alleles. Of the celiac patients around 95% carry the DQ2 and almost all the rest the DQ8 allele. However, at the population level, approximately 40% of individuals possess these alleles, while only subset of these individuals acquire the disease during their lifetime making the determination of the HLA-type diagnostically useful for exclusion of celiac disease. In addition to HLA, other genetic variants associated with celiac disease have been identified in genome-wide association studies (GWAS) and with candidate-gene approaches. However, the precise contribution of these genetic variants is not currently well understood and studies addressing this aspect are ongoing. The genetic predispositions are not sufficient to explain the development of celiac disease. We have shown that the intestinal microbiota differs between different manifestations of celiac patients and that treated celiac patients with persistent symptoms have intestinal dysbiosis despite a strict gluten-free diet. Thus, in addition to gluten, there must be other environmental triggers, such as microbial infections or intestinal dysbiosis that contribute to disease progression.

We have also addressed the biological functions of the celiac disease-specific antibodies in the pathogenesis. Our results show that the antibodies modulate epithelial and endothelial cell biology for instance by enabling the passage of gliadin peptides across the epithelium and increasing vascular permeability. In addition, when injected into mice the celiac antibodies induce a condition mimicking early developing celiac disease. The studies focusing on the pathogenetic role of the celiac disease-specific antibodies will continue.

Our selected publications:

Kalliokoski S, Ortín Piqueras V, Frías R, Sulic AM, Määttä JAE, Kähkönen N, Viiri K, Huhtala H, Pasternack A, Laurila K, Sblattero D, Korponay-Szabó IR, Mäki M, Caja S, Kaukinen K, Lindfors K. Transglutaminase 2-specific coeliac disease autoantibodies induce morphological changes and signs of inflammation in the small-bowel mucosa of mice. Amino acids, 2016, in press DOI:10.1007/s00726-016-2306-0

Kalliokoski S, Caja S, Frias R, Laurila K, Koskinen O, Niemelä O, Mäki M, Kaukinen K, Korponay-Szabo IR, Lindfors K. Injection of celiac patient serum or immunoglobulins to mice reproduces a condition mimicking early developing celiac disease. J Mol Med 2015;93:51-62.

Wacklin P, Laurikka P, Lindfors K, Colli P, Salmi T, Lähdeaho ML, Saavalainen P, Mäki M, Mättö J, Kurppa K, Kaukinen K. Altered duodenal microbiota composition in celiav disease patients suffering from persistent symptoms on a long-term gluten-free diet. Am J Gastroenterol 2014;109:1933-41.

Nadalutti CA, Korponay-Szabo IR, Kaukinen K, Griffin M, Mäki M, Lindfors K. Celiac disease patient IgA antibodies induce endothelial adhesion and cell polarization deficts via extracellular transglutaminase 2. Cell Mol Life Sci 2014;71:1315-26.

Wacklin P, Kaukinen K, Tuovinen E, Lindfors K, Collin P, Partanen J, Mäki M, Mättö J. The duodenal microbiota composition of adult celiac disease patients is associated to the clinical manifestation of the disease. Inflamm Bowel Dis 2013;19:934-41.

Kalliokoski S, Sulic AM, Korponay-Szabó IR, Szondy Z, Frias R, Alea Perez M, Martucciello S, Roivainen A, Pelliniemi LJ, Esposito C, Griffin M, Sblattero D, Mäki M, Kaukinen K, Lindfors K, Caja S. Celiac disease–specific TG2-targeted autoantibodies inhibit angiogenesis in vitro and in vivo by modulating extracellular matrix. Plos One 2013;8:e65887.

Martucciello S, Lavric M, Toth B, Korponay-Szabo I, Nadaluttia C, Myrsky E, Rauhavirta T, Esposito C, Sulic AM, Sblattero D, Marzari R, Mäki M, Kaukinen K, Lindfors K, Caja S. RhoB is associated with the anti-angiogenic effects of celiac patient transglutaminase 2-targeted autoantibodies. J Mol Med 2012;90:817-26.

Rauhavirta T, Qiao SW, Jiang Z, Loponen J, Korponay-Szabo IR, Salovaara H, Garcia-Horsman A, Venäläinen J, Männistö PT, Collighan R, Mongeot A, Griffin M, Mäki M, Kaukinen K, Lindfors K. IgA-derived from coeliac disease patients enhances the passage of gliadin peptides across intestinal epithelium without breaking the epithelial barrier. Clin Exp Immunol 2011;164:127-136.

Dubois PCA, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, Zhernakova A, HeapGAR, Ádány R, Aromaa A, Bardilla MT, van den Berg LH, Bockett NA, de la Concha EG, Dema B, Fehrmann RSN, Fernández-Arquero M, Fiatal S, Grandote E, Green PM, Groen HJM, Gwilliam R, Houwen RHJ, Hunt SE, Kaukinen K, Séller D, Korponay-SzaboI, Kurppa K, MacMathuna P, Mäki M, Mazzilli MC, Owen T McCann, Mearin ML, Mein CA, Mirza MM, Mistry V, Mora B, Morley KI, Mulder CJ, Murray JA, Núñez C, Oosterom E, Ophoff RA, Polanco I, Peltonen L, Platteel M,Rybak A, Salomaa V, Schweizer JJ, Sperandeo MP, Tack GJ, Turner G, Veldink JH, Verbeek WHM, Weersma RK, Wolters VM, Urcelay E, Cukrowska B, Greco L, Neuhausen SL, McManus R, Barisani D, Deloukas P, Barreto JC, Saavalainen P, Wijmenga C, van Heel DA. Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 2010;42:295-302.

Koskinen LLE, Einarsdottir E, Dukes E, Heap G, Dubois P, Korponay-Szabo IR, Kaukinen K, Kurppa K, Ziberna F, Vatta S, Not T, Ventura A, Ádány R, Pocsai Z, Széles G, Mäki M, Kere J, Wijmenga C, van Heel D, Saavalainen P. Association study of IL18RAP in three European populations with coeliac disease. Hum Mol Gen 2009;18;1148-55.

Myrsky E, Caja S, Simon-Vecsei Z, Korponay-Szabo IR, Collighan R, Mongeot A, Griffin M, Mäki M, Kaukinen K, Lindfors K. Coeliac disease IgA modulates vascular permeability in vitro trough the activity of transglutaminase 2 and Rho A. Cell Mol Life Sci 2009;66:3375-85.

Lindfors K, Blomqvist T, Stenman S, Venälainen J, Mäki M, Kaukinen K. Live probiotic Bifidobacterium lactis bacvteria inhibits the toxic effects induced by wheat gliadin in epithelial cell culture. Clin Exp Immunol 2008;152:552-8.

Kaukinen K, Partanen J, Mäki M and Collin P. HLA DQ2 and DQ8 typing in the diagnosis of celiac disease. Am J Gastroenterol 2002;97:695-9.