Celiac Disease: Molecular Basis


Celiac disease (CD) is an inflammatory and multifactorial disorder triggered by cereal gluten in genetically predisposed individuals. CD has several clinical and histological forms characterised by different grade of small intestinal inflammation. Several studies have demonstrated the key role of adaptive CD4+ T lymphocytes in gluten‐dependent enteropathy, although it has been clear that the intraepithelial CD8+ T lymphocytes of innate immunity, highly infiltrating CD mucosa, are pivotal in the induction of intestinal mucosa alteration and malfunction. Recent evidences also highlighted how adaptive CD8+ T lymphocytes restricted by HLA class I molecules contribute to the enterocytes damage through a TCR‐dependent cytotoxic activity. The recent findings on the involvement of HLA class I genes in CD susceptibility are also discussed.

Key Concepts

  • Celiac disease is an immune‐mediated disorder triggered by dietary gluten.
  • Enteropathy is the main form of celiac disease, but extra‐intestinal manifestations are also frequent.
  • Celiac disease has autoimmune features characterised by the production of antitissue transglutaminase antibodies, with high diagnostic relevance.
  • Gluten‐reactive CD4+ T cells are key players as pathogenic T helper cells.
  • Cytotoxic CD8+ T cells, of both innate and adaptive branches, are involved in the intestinal villous atrophy.
  • The current therapy is the avoidance of gluten from the diet.

Keywords: celiac disease; gluten; autoimmunity; cytotoxic CD8+ T lymphocytes; HLA class I

Figure 1. Role of CD8 T cells in celiac disease. A hallmark of CD intestinal biopsies is a massive infiltration of the epithelium and lamina propria by CD8+ T lymphocytes, of either TCRαβ+ and TCRγδ+ lineages. Gliadin peptides are able to activate both intraepithelial lymphocytes (IELs), in particular CD8+ TCRαβ+ lymphocyte bearing the CD94 receptor (NKT cells), and lamina propria CD8+TCRαβ+ lymphocytes of the adaptive immunity. Several gluten peptides (as p123–132) are able to bind to HLA‐class I molecules (in particular to HLA‐A1, A2 and B8) expressed on the surface of both dendritic cells and epithelial cells, and are specifically recognised by CD8+TCRαβ+ in the lamina propria. Once activated by the MHC/gluten‐peptide complexes, CD8 T cells acquire the capacity to lyse the target cells, including enterocytes. On the other hand, peptides such as 31–43 or 31–55 of α‐gliadin stimulate enterocyte to produce IL15 that, in turn, induces the autocrine overexpression of stress molecules MICA and MICB. In addition, IL15 upregulates on T cells the NKG2C/D activating NK receptor, while, in normal condition, IELs express inhibitory NK receptors NKG2A. The interaction between MICA and MICB on enterocytes and NKG2D expressed on CD8+ T cells mediates the enterocyte death and tissue damage.


Abadie V , Sollid LM , Barreiro LB , et al. (2011) Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annual Review of Immunology 29: 493–525.

Bodd M , Ráki M , Tollefsen S , et al. (2010) HLA‐DQ2‐restricted gluten‐reactive T cells produce IL‐21 but not IL‐17 or IL‐22. Mucosal Immunology 3 (6): 594–601.

Bolognesi E , Karell K , Percopo S , et al. (2003) Additional factor in some HLA DR3/DQ2 haplotypes confers a fourfold increased genetic risk of celiac disease. Tissue Antigens 61 (4): 308–316.

Bouziat R , Hinterleitner R , Brown JJ , et al. (2017) Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356 (6333): 44–50.

Byrne G and Feighery CF (2015) Celiac disease: diagnosis. Methods in Molecular Biology 1326: 15–22.

Camarca A , Anderson RP , Mamone G , et al. (2009) Intestinal T cell responses to gluten peptides are largely heterogeneous: implications for a peptide‐based therapy in celiac disease. The Journal of Immunology 182 (7): 4158–4166.

Costes LM , Meresse B , Cerf‐Bensussan N , et al. (2015) The role of animal models in unravelling therapeutic targets in coeliac disease. Best Practice & Research. Clinical Gastroenterology 29 (3): 437–450.

Di Sabatino A , Vanoli A , Giuffrida P , et al. (2012) The function of tissue transglutaminase in celiac disease. Autoimmunity Reviews 11 (10): 746–753.

Du Pré MF and Sollid LM (2015) T‐cell and B‐cell immunity in celiac disease. Best Practice & Research. Clinical Gastroenterology 29 (3): 413–423.

Gianfrani C , Troncone R , Magione P , et al. (2003) Celiac disease association with CD8+ T cell responses: identification of a novel gliadin‐derived HLA‐A2‐restricted epitope. The Journal of Immunology 170 (5): 2719–2726.

Gianfrani C , Troncone R and La Cava A (2008) Autoimmunity and celiac disease. Mini‐Reviews in Medicinal Chemistry 8 (2): 129–134.

Gianfrani C , Camarca A , Mazzarella G , et al. (2015) Extensive in vitro gastrointestinal digestion markedly reduces the immune‐toxicity of Triticum monococcum wheat: implication for celiac disease. Molecular Nutrition & Food Research 59 (9): 1844–1854.

Gibert A , Kruizinga AG , Neuhold S , et al. (2013) Might gluten traces in wheat substitutes pose a risk in patients with celiac disease? A population‐based probabilistic approach to risk estimation. American Journal of Clinical Nutrition 97 (1): 109–116.

Goel G , King T , Daveson AJ , et al. (2017) Epitope‐specific immunotherapy targeting CD4‐positive T cells in coeliac disease: two randomised, double‐blind, placebo‐controlled phase 1 studies. The Lancet Gastroenterology & Hepatology 2 (7): 479–493.

Greco L , Romino R , Coto I , et al. (2002) The first large population based twin study of coeliac disease. Gut 50 (5): 624–628.

Gutierrez‐Achury J , Zhernakova A , Pulit SL , et al. (2015) Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease. Nature Genetics 47 (6): 577–578.

Han A , Newell EW , Glanville J , et al. (2013) Dietary gluten triggers concomitant activation of CD4+ and CD8+ αβ T cells and γδ T cells in celiac disease. Proceedings of the National Academy of Sciences of the United States of America 110 (32): 13073–13078.

Hardy MY , Girardin A , Pizzey C , et al. (2015) Consistency in polyclonal T‐cell responses to gluten between children and adults with celiac disease. Gastroenterology 149 (6): 1541–1552.

van Heel D , Franke L , Hunt KA , et al. (2007) A genome‐wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nature Genetics 39 (7): 827–829.

Hue S , Mention J‐J , Montiero RC , et al. (2004) A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21 (3): 367–377.

Hunt KA , Zhernakova A , Turner G , et al. (2008) Newly identified genetic risk variants for celiac disease related to the immune response. Nature Genetics 40 (4): 395–402.

Husby S , Koletzko S , Korponay‐Szabó IR , et al. (2012) European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. Journal of Pediatric Gastroenterology and Nutrition 54 (1): 136–160.

Koning F (2012) Celiac disease: quantity matters. Seminars in Immunopathology 34 (4): 541–549.

Kutlu T , Brousse N , Rambaud C , et al. (1993) Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet. Gut 34 (2): 208–214.

Leffler DA , Kelly CP , Green PH , et al. (2015) Larazotide acetate for persistent symptoms of celiac disease despite a gluten‐free diet: a randomized controlled trial. Gastroenterology 148 (7): 1311–1319.e6.

Lebreton C , Ménard S , Abed J , et al. (2012) Interactions among secretory immunoglobulin A, CD71, and transglutaminase‐2 affect permeability of intestinal epithelial cells to gliadin peptides. Gastroenterology 143 (3): 698–707.

Lionetti E and Catassi C (2015) The role of environmental factors in the development of celiac disease: what is new? Diseases 3 (4): 282–293.

Lohi S , Mustalahti K , Kaukinen K , et al. (2007) Increasing prevalence of coeliac disease over time. Alimentary Pharmacology and Therapeutics 26 (9): 1217–1225.

Ludvigsson JF , Card TR , Kaukinen K , et al. (2015) Screening for celiac disease in the general population and in high‐risk groups. United European Gastroenterology Journal 3 (2): 106–120.

Lundin KE , Scott H , Hansen T , et al. (1993) Gliadin‐specific, HLA‐DQ(a1*0501,b1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. The Journal of Experimental Medicine 178 (1): 187–196.

Margaritte‐Jeannin P , Babron MC , Bourgey M , et al. (2004) HLA‐DQ relative risks for coeliac disease in European populations: a study of the European Genetics Cluster on coeliac disease. Tissue Antigens 63 (6): 562–567.

Marsh MN (1992) Gluten, major histocompatibility complex and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten sensitivity. Gastroenterology 102 (1): 330–354.

Mazzarella G , Stefanile R , Camarca A , et al. (2008) Gliadin activates HLA Class‐I restricted CD8+ T cells in celiac disease intestinal mucosa and induces the enterocyte apoptosis. Gastroenterology 134 (4): 1017–1027.

Mazzarella G , Salvati VM , Iaquinto G , et al. (2012) Reintroduction of gluten following flour transamidation in adult celiac patients: a randomized, controlled clinical study. Clinical & Developmental Immunology 2012: 10 329150.

Meresse B , Chen Z , Ciszewski C , et al. (2004) Coordinated induction by IL15 of a TCR‐independent NKG2D signaling pathway converts CTL into lymphokine‐activated killer cells in celiac disease. Immunity 21 (3): 357–366.

Meresse B , Malamut G and Cerf‐Bensussan N (2012) Celiac disease: an immunological jigsaw. Immunity 36 (6): 907–919.

Murray JA , Kelly CP , Green PHR , et al. (2017) No difference between latiglutenase and placebo in reducing villous atrophy or improving symptoms in patients with symptomatic celiac disease. Gastroenterology 152 (4): 787–798.e2.

Paparo F , Petrone E , Tosco A , et al. (2005) Clinical, HLA, and small bowel immunohistochemical features of children with positive serum antiendomysium antibodies and architecturally normal small intestinal mucosa. The American Journal of Gastroenterology 100 (10): 2294–2298.

Picascia S , Sidney J , Camarca A , et al. (2017) Gliadin‐specific CD8+ T cell responses restricted by HLA class I A*0101 and B*0801 molecules in celiac disease patients. The Journal of Immunology 198 (5): 1838–1845.

Pisapia L , Camarca A , Picascia S , et al. (2016) HLA‐DQ2.5 genes associated with celiac disease risk are preferentially expressed with respect to non‐predisposing HLA genes: implication for anti‐gluten T cell response. Journal of Autoimmunity 70: 63–72.

Shan L , Molberg O , Parrot I , et al. (2002) Structural basis for gluten intolerance in celiac sprue. Science 297 (5590): 2275–2279.

Sjöström H , Lundin KE , Molberg O , et al. (1998) Identification of a gliadin T‐cell epitope in coeliac disease: general importance of gliadin deamidation for intestinal T‐cell recognition. Scandinavian Journal of Immunology 48 (2): 111–115.

Sollid LM and Khosla C (2011) Novel therapies for coeliac disease. Journal of Internal Medicine 269 (6): 604–613.

Stamnaes J and Sollid LM (2015) Celiac disease: autoimmunity in response to food antigen. Seminars in Immunology 27 (5): 343–352.

Tye‐Din J , Stewart J , Dromey J , et al. (2010) Design of peptide‐based immunotherapy and diagnostics for celiac disease based upon comprehensive, quantitative mapping of T‐cell epitopes in gluten. Science Translational Medicine 2 (41): 41ra51.

Vader W , Stepniak D , Kooy Y , et al. (2003) The HLA‐DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten‐specific T cell responses. Proceedings of the National Academy of Sciences of the United States of America 14 (21): 12390–12395.

Vitale S , Picascia S and Gianfrani C (2016) The cross‐talk between enterocytes and intraepithelial lymphocytes. Molecular and Cellular Pediatrics 3 (1): 20.

Vriezinga SL , Auricchio R , Bravi E , et al. (2014) Randomized feeding intervention in infants at high risk for celiac disease. The New England Journal of Medicine 371 (14): 1304–1315.

Wolf C , Siegel JB , Tinberg C , et al. (2015) Engineering of Kuma030: a gliadin peptidase that rapidly degrades immunogenic gliadin peptides in gastric conditions. Journal of the American Chemical Society 137 (40): 13106–13113.

Yokoyama S , Watanabe N , Sato N , et al. (2009) Antibody‐mediated blockade of IL‐15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL‐15 in enterocytes. Proceedings of the National Academy of Sciences of the United States of America 106: 15849–15854.

Further Reading

Auricchio R , Tosco A , Piccolo E , et al. (2014) Potential celiac children: 9‐year follow‐up on a gluten‐containing diet. The American Journal of Gastroenterology 109 (6): 913–921.

Lamacchia C , Camarca A , Picascia S , et al. (2014) Cereal‐based gluten‐free food: how to reconcile nutritional and technological properties of wheat proteins with safety for celiac disease patients. Nutrients 6 (2): 575–590.

Lebwohl B , Sanders DS and Green PHR (2017) Coeliac disease. Lancet S0140‐6736 (17): 31796–31798.

Lopez‐Vazquez A , Fuentes D , Rodrigo L , et al. (2004) MHC class I region plays a role in the development of diverse clinical forms of celiac disease in a Saharawi population. The American Journal of Gastroenterology 99 (4): 662–667.

Marino M , Casale R , Borghini R , et al. (2017) The effects of modified versus unmodified wheat gluten administration in patients with celiac disease. International Immunopharmacology 47: 1–8.

Mills JR and Murray JA (2016) Contemporary celiac disease diagnosis: is a biopsy avoidable? Current Opinion in Gastroenterology 32 (2): 80–85.

Pyle GG , Paaso B , Anderson BE , et al. (2005) Effect of pretreatment of food gluten with prolyl endopeptidase on gluten‐induced malabsorbtion in celiac sprue. Clinical Gastroenterology and Hepatology 3 (7): 629–630.

Shuppan D , Tennis MD and Kelly CP (2005) Celiac disease: epidemiology, pathogenesis, diagnosis, and nutritional menagement. Nutrition in Clinical Care 8 (2): 54–69.

Sollid LM (2017) The roles of MHC class II genes and post‐translational modification in celiac disease. Immunogenetics 69 (8‐9): 605–616.

Waldmann TA , Conlon KC , Stewart DM , et al. (2013) Phase 1 trial of IL‐15 trans presentation blockade using humanized Mikβ1 mAb in patients with T‐cell large granular lymphocytic leukemia. Blood 121 (3): 476–484.

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Picascia, Stefania, Camarca, Alessandra, and Gianfrani, Carmen(Jan 2018) Celiac Disease: Molecular Basis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027650]