Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Triggers and drivers of autoimmunity: lessons from coeliac disease

Nature Reviews Immunology volume 13, pages 294–302 (2013)Cite this article

Subjects

Abstract

Coeliac disease, an inflammatory disease of the small intestine, shares key features with autoimmune disorders, such as susceptibility genes, presence of autoantibodies and T cell-mediated destruction of specific cells. Strikingly, however, continuous exposure to the exogenous dietary antigen gluten and gluten-specific adaptive immunity are required to maintain immunopathology. These observations challenge the notion that autoimmunity requires adaptive immune activation towards self antigens. Using coeliac disease as an example, we propose that other exogenous factors might be identified as drivers of autoimmune processes, in particular when evidence for T cells with specificity for self antigens driving the disease is lacking.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Autoimmune phenomena and gluten-specific adaptive immunity are associated with coeliac disease and are dependent on gluten exposure.
Figure 2: Coeliac disease and autoimmune disorders share many common immune mechanisms.
Figure 3: Dietary antigen drives autoimmune processes in coeliac disease.

Similar content being viewed by others

References

  1. Dicke, W. Coeliac disease. Investigation of the harmful effects of certain types of cereal on patients with coeliac disease. Thesis, Univ. Utrecht (1950).

    Google Scholar 

  2. van Berge-Henegouwen, G. P. & Mulder, C. J. Pioneer in the gluten free diet: Willem-Karel Dicke 1905–1962, over 50 years of gluten free diet. Gut 34, 1473–1475 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Paulley, J. W. Observation on the aetiology of idiopathic steatorrhoea; jejunal and lymph-node biopsies. Br. Med. J. 2, 1318–1321 (1954).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Green, P. H. & Cellier, C. Celiac disease. N. Engl. J. Med. 357, 1731–1743 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Dieterich, W. et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Med. 3, 797–801 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Sollid, L. M. & Lie, B. A. Celiac disease genetics: current concepts and practical applications. Clin. Gastroenterol. Hepatol. 3, 843–851 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Trynka, G. et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nature Genet. 43, 1193–1201 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Smyth, D. J. et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N. Engl. J. Med. 359, 2767–2777 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhernakova, A. et al. Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet. 7, e1002004 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Trynka, G., Wijmenga, C. & van Heel, D. A. A genetic perspective on coeliac disease. Trends Mol. Med. 16, 537–550 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Cotsapas, C. et al. Pervasive sharing of genetic effects in autoimmune disease. PLoS Genet. 7, e1002254 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Voight, B. F. & Cotsapas, C. Human genetics offers an emerging picture of common pathways and mechanisms in autoimmunity. Curr. Opin. Immunol. 24, 552–557 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lyons, P. A. et al. Genetically distinct subsets within ANCA-associated vasculitis. N. Engl. J. Med. 367, 214–223 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. van Venrooij, W. J., van Beers, J. J. & Pruijn, G. J. Anti-CCP antibodies: the past, the present and the future. Nature Rev. Rheumatol. 7, 391–398 (2011).

    Article  CAS  Google Scholar 

  16. Marzari, R. et al. Molecular dissection of the tissue transglutaminase autoantibody response in celiac disease. J. Immunol. 166, 4170–4176 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Di Niro, R. et al. High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nature Med. 18, 441–445 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Bjorck, S., Brundin, C., Lorinc, E., Lynch, K. F. & Agardh, D. Screening detects a high proportion of celiac disease in young HLA-genotyped children. J. Pediatr. Gastroenterol. Nutr. 50, 49–53 (2010).

    Article  PubMed  Google Scholar 

  19. Klareskog, L., Ronnelid, J., Lundberg, K., Padyukov, L. & Alfredsson, L. Immunity to citrullinated proteins in rheumatoid arthritis. Annu. Rev. Immunol. 26, 651–675 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Sollid, L. M. Molecular basis of celiac disease. Annu. Rev. Immunol. 18, 53–81 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Turner, J. R. in Robbins and Cotran Pathologic Basis of Disease (eds Kumar, V., Abbas, A. K., Fausto, N. & Aster, J. C.) 763–831 (Elsevier, 2009).

    Google Scholar 

  22. Hüe, S. et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21, 367–377 (2004).

    Article  PubMed  Google Scholar 

  23. Meresse, B. et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21, 357–366 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Meresse, B. et al. Reprogramming of CTLs into natural killer-like cells in celiac disease. J. Exp. Med. 203, 1343–1355 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jabri, B. & Sollid, L. M. Tissue-mediated control of immunopathology in coeliac disease. Nature Rev. Immunol. 9, 858–870 (2009).

    Article  CAS  Google Scholar 

  26. Groh, V., Bruhl, A., El-Gabalawy, H., Nelson, J. L. & Spies, T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 100, 9452–9457 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ogasawara, K. et al. NKG2D blockade prevents autoimmune diabetes in NOD mice. Immunity 20, 757–767 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Asquith, D. L. & McInnes, I. B. Emerging cytokine targets in rheumatoid arthritis. Curr. Opin. Rheumatol. 19, 246–251 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Michalak-Stoma, A. et al. Cytokine network in psoriasis revisited. Eur. Cytokine Netw. 22, 160–168 (2011).

    CAS  PubMed  Google Scholar 

  30. Rentzos, M. & Rombos, A. The role of IL-15 in central nervous system disorders. Acta Neurol. Scand. 125, 77–82 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Mention, J. J. et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125, 730–745 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Tang, F. et al. Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15. J. Exp. Med. 206, 707–719 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Groh, V. et al. Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nature Immunol. 2, 255–260 (2001).

    Article  CAS  Google Scholar 

  34. Roberts, A. I. et al. NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. J. Immunol. 167, 5527–5530 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Sulkanen, S. et al. Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease. Gastroenterology 115, 1322–1328 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Bardella, M. T. et al. Coeliac disease: a histological follow-up study. Histopathology 50, 465–471 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Molberg, O. et al. Gliadin specific, HLA DQ2-restricted T cells are commonly found in small intestinal biopsies from coeliac disease patients, but not from controls. Scand. J. Immunol. 46, 103–108 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Sollid, L. M., Qiao, S. W., Anderson, R. P., Gianfrani, C. & Koning, F. Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics 64, 455–460 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lundin, K. E. et al. Gliadin-specific, HLA-DQ(α1*0501, β1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J. Exp. Med. 178, 187–196 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Lundin, K. E., Scott, H., Fausa, O., Thorsby, E. & Sollid, L. M. T cells from the small intestinal mucosa of a DR4, DQ7/DR4, DQ8 celiac disease patient preferentially recognize gliadin when presented by DQ8. Hum. Immunol. 41, 285–291 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Molberg, O. et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nature Med. 4, 713–717 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. van de Wal, Y. et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J. Immunol. 161, 1585–1588 (1998).

    CAS  PubMed  Google Scholar 

  43. Tollefsen, S. et al. HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J. Clin. Invest. 116, 2226–2236 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Osman, A. A. et al. B cell epitopes of gliadin. Clin. Exp. Immunol. 121, 248–254 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shan, L. et al. Structural basis for gluten intolerance in celiac sprue. Science 297, 2275–2279 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Bodd, M. et al. HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal Immunol. 3, 594–601 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Abadie, V., Sollid, L. M., Barreiro, L. B. & Jabri, B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu. Rev. Immunol. 29, 493–525 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Sollid, L. M. Coeliac disease: dissecting a complex inflammatory disorder. Nature Rev. Immunol. 2, 647–655 (2002).

    Article  CAS  Google Scholar 

  49. Mäki, M. in Seventh International Symposium on Coeliac Disease (eds Feighery, C. & O'Farelly, C.) 246–252 (Oak Tree Press, 1992).

    Google Scholar 

  50. Sollid, L. M., Molberg, O., McAdam, S. & Lundin, K. E. Autoantibodies in coeliac disease: tissue transglutaminase—guilt by association? Gut 41, 851–852 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fleckenstein, B. et al. Molecular characterization of covalent complexes between tissue transglutaminase and gliadin peptides. J. Biol. Chem. 279, 17607–17616 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Prause, C. et al. Antibodies against deamidated gliadin as new and accurate biomarkers of childhood coeliac disease. J. Pediatr. Gastroenterol. Nutr. 49, 52–58 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Devendra, D. & Eisenbarth, G. S. Interferon alpha—a potential link in the pathogenesis of viral-induced type 1 diabetes and autoimmunity. Clin. Immunol. 111, 225–233 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Fujinami, R. S. & Oldstone, M. B. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 230, 1043–1045 (1985).

    Article  CAS  PubMed  Google Scholar 

  55. Wucherpfennig, K. W. & Strominger, J. L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lawson, C. M. Evidence for mimicry by viral antigens in animal models of autoimmune disease including myocarditis. Cell. Mol. Life Sci. 57, 552–560 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Pabst, O. & Mowat, A. M. Oral tolerance to food protein. Mucosal Immunol. 5, 232–239 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. DePaolo, R. W. et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471, 220–224 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Monteleone, G. et al. Role of interferon α in promoting T helper cell type 1 responses in the small intestine in coeliac disease. Gut 48, 425–429 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Raki, M. et al. Plasmacytoid dendritic cells are scarcely represented in the human gut mucosa and are not recruited to the celiac lesion. Mucosal Immunol. 23 Jan 2013 (doi:10.1038/mi.2012.136)

    Article  PubMed  CAS  Google Scholar 

  61. Medzhitov, R. & Janeway, C. A. Jr. Innate immune recognition and control of adaptive immune responses. Semin. Immunol. 10, 351–353 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Di Sabatino, A. et al. Evidence for the role of interferon-alfa production by dendritic cells in the Th1 response in celiac disease. Gastroenterology 133, 1175–1187 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Maiuri, L. et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 362, 30–37 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Barone, M. V. et al. Growth factor-like activity of gliadin, an alimentary protein: implications for coeliac disease. Gut 56, 480–488 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Terrazzano, G. et al. Gliadin regulates the NK–dendritic cell cross-talk by HLA-E surface stabilization. J. Immunol. 179, 372–381 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Junker, Y. et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J. Exp. Med. 209, 2395–2408 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Troncone, R. & Auricchio, S. Rotavirus and celiac disease: clues to the pathogenesis and perspectives on prevention. J. Pediatr. Gastroenterol. Nutr. 44, 527–528 (2007).

    Article  PubMed  Google Scholar 

  68. Stene, L. C. et al. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am. J. Gastroenterol. 101, 2333–2340 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Hober, D. & Sauter, P. Pathogenesis of type 1 diabetes mellitus: interplay between enterovirus and host. Nature Rev. Endocrinol. 6, 279–289 (2010).

    Article  Google Scholar 

  70. Siegel, M. et al. Extracellular transglutaminase 2 is catalytically inactive, but is transiently activated upon tissue injury. PLoS ONE 3, e1861 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Jun, H. S. & Yoon, J. W. A new look at viruses in type 1 diabetes. Diabetes Metab. Res. Rev. 19, 8–31 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Rizza, P., Moretti, F. & Belardelli, F. Recent advances on the immunomodulatory effects of IFN-α: implications for cancer immunotherapy and autoimmunity. Autoimmunity 43, 204–209 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Carrero, J. A., Calderon, B. & Unanue, E. R. Type I interferon sensitizes lymphocytes to apoptosis and reduces resistance to Listeria infection. J. Exp. Med. 200, 535–540 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Woodward, J. J., Iavarone, A. T. & Portnoy, D. A. c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science 328, 1703–1705 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Manca, C. et al. Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-α/β. Proc. Natl Acad. Sci. USA 98, 5752–5757 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jones, J. W. et al. Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis. Proc. Natl Acad. Sci. USA 107, 9771–9776 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nature Rev. Immunol. 9, 313–323 (2009).

    Article  CAS  Google Scholar 

  78. Maynard, C. L., Elson, C. O., Hatton, R. D. & Weaver, C. T. Reciprocal interactions of the intestinal microbiota and immune system. Nature 489, 231–241 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Atkinson, M. A. & Chervonsky, A. Does the gut microbiota have a role in type 1 diabetes? Early evidence from humans and animal models of the disease. Diabetologia 55, 2868–2877 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mathis, D. & Benoist, C. Microbiota and autoimmune disease: the hosted self. Cell Host Microbe 10, 297–301 (2011).

    Article  CAS  PubMed  Google Scholar 

  82. Forsberg, G. et al. Presence of bacteria and innate immunity of intestinal epithelium in childhood celiac disease. Am. J. Gastroenterol. 99, 894–904 (2004).

    Article  PubMed  Google Scholar 

  83. Tjellstrom, B. et al. Gut microflora associated characteristics in children with celiac disease. Am. J. Gastroenterol. 100, 2784–2788 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Sanz, Y. et al. Differences in faecal bacterial communities in coeliac and healthy children as detected by PCR and denaturing gradient gel electrophoresis. FEMS Immunol. Med. Microbiol. 51, 562–568 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Di Cagno, R. et al. Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization. BMC Microbiol. 11, 219 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Nistal, E. et al. Differences of small intestinal bacteria populations in adults and children with/without celiac disease: effect of age, gluten diet, and disease. Inflamm. Bowel Dis. 18, 649–656 (2012).

    Article  PubMed  Google Scholar 

  87. De Palma, G. et al. Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children. BMC Microbiol. 10, 63 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Collado, M. C., Donat, E., Ribes-Koninckx, C., Calabuig, M. & Sanz, Y. Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J. Clin. Pathol. 62, 264–269 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Nadal, I., Donat, E., Ribes-Koninckx, C., Calabuig, M. & Sanz, Y. Imbalance in the composition of the duodenal microbiota of children with coeliac disease. J. Med. Microbiol. 56, 1669–1674 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Sanchez, E. et al. Reduced diversity and increased virulence-gene carriage in intestinal enterobacteria of coeliac children. BMC Gastroenterol. 8, 50 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Sanchez, E., Ribes-Koninckx, C., Calabuig, M. & Sanz, Y. Intestinal Staphylococcus spp. and virulent features associated with coeliac disease. J. Clin. Pathol. 65, 830–834 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Kagnoff, M. F. et al. Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease. Gut 28, 995–1001 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Benoist, C. & Mathis, D. Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? Nature Immunol. 2, 797–801 (2001).

    Article  CAS  Google Scholar 

  94. Wegner, N. et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 62, 2662–2672 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Saleh, M. & Elson, C. O. Experimental inflammatory bowel disease: insights into the host-microbiota dialog. Immunity 34, 293–302 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Khan, K. J. et al. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am. J. Gastroenterol. 106, 661–673 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Janowitz, H. D., Croen, E. C. & Sachar, D. B. The role of the fecal stream in Crohn's disease: an historical and analytic review. Inflamm. Bowel Dis. 4, 29–39 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Mattner, J. et al. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe 3, 304–315 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Shewry, R. P., Tatham, A. & Kasarda, D. D. in Coeliac disease (ed. Marsh, M. N.) (Blackwell Scientific Publications, 1992).

    Google Scholar 

  101. Alp, M. H. & Wright, R. Autoantibodies to reticulin in patients with idiopathic steatorrhoea, coeliac disease, and Crohn's disease, and their relation to immunoglobulins and dietary antibodies. Lancet 2, 682–685 (1971).

    Article  CAS  PubMed  Google Scholar 

  102. Seah, P. P., Fry, L., Rossiter, M. A., Hoffbrand, A. V. & Holborow, E. J. Anti-reticulin antibodies in childhood coeliac disease. Lancet 2, 681–682 (1971).

    Article  CAS  PubMed  Google Scholar 

  103. Chorzelski, T. P. et al. IgA anti-endomysium antibody. A new immunological marker of dermatitis herpetiformis and coeliac disease. Br. J. Dermatol. 111, 395–402 (1984).

    Article  CAS  PubMed  Google Scholar 

  104. Ladinser, B., Rossipal, E. & Pittschieler, K. Endomysium antibodies in coeliac disease: an improved method. Gut 35, 776–778 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sanchez, D. et al. Occurrence of IgA and IgG autoantibodies to calreticulin in coeliac disease and various autoimmune diseases. J. Autoimmun. 15, 441–449 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Clemente, M. G. et al. Enterocyte actin autoantibody detection: a new diagnostic tool in celiac disease diagnosis: results of a multicenter study. Am. J. Gastroenterol. 99, 1551–1556 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Rostom, A. et al. The diagnostic accuracy of serologic tests for celiac disease: a systematic review. Gastroenterology 128, S38–S46 (2005).

    Article  PubMed  Google Scholar 

  108. Husby, S. et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J. Pediatr. Gastroenterol. Nutr. 54, 136–160 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Lorand, L. & Graham, R. M. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nature Rev. Mol. Cell. Biol. 4, 140–156 (2003).

    Article  CAS  Google Scholar 

  110. Piper, J. L., Gray, G. M. & Khosla, C. High selectivity of human tissue transglutaminase for immunoactive gliadin peptides: implications for celiac sprue. Biochemistry 41, 386–393 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Stamnaes, J., Pinkas, D. M., Fleckenstein, B., Khosla, C. & Sollid, L. M. Redox regulation of transglutaminase 2 activity. J. Biol. Chem. 285, 25402–25409 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Dorum, S. et al. The preferred substrates for transglutaminase 2 in a complex wheat gluten digest are peptide fragments harboring celiac disease T-cell epitopes. PLoS ONE 5, e14056 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Maslowski, K. M. & Mackay, C. R. Diet, gut microbiota and immune responses. Nature Immunol. 12, 5–9 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work was supported by grants from the Research Council of Norway, the European Research Council and the South-East Norway Regional Health Authority to L.M.S. and by grants from the US National Institutes of Health (grants RO1DK063158, RO1DK58727and P30DK42086) to B.J.

Author information

Authors and Affiliations

  1. Ludvig M. Sollid is at the Centre for Immune Regulation and the Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, N-0372 Oslo, Norway. l.m.sollid@medisin.uio.no,

    Ludvig M. Sollid

  2. Bana Jabri is at the Departments of Medicine, Pathology and Pediatrics, University of Chicago, Chicago, Illinois 60637, USA. bjabri@bsd.uchicago.edu,

    Bana Jabri

Authors
  1. Ludvig M. Sollid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bana Jabri
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Ludvig M. Sollid's homepage

Bana Jabri's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sollid, L., Jabri, B. Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol 13, 294–302 (2013). https://doi.org/10.1038/nri3407

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3407

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing