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Review

Emergence of an adaptive immune paradigm to explain celiac disease: a perspective on new evidence and implications for future interventions and diagnosis

Pages 75-91 | Received 21 Jul 2021, Accepted 11 Nov 2021, Published online: 06 Feb 2022

References

  • Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for coeliac disease and related terms. Gut. 2013;62(1):43–52.
  • Al-Toma A, Volta U, Auricchio R, et al. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United Eur Gastroenterol J. 2019;7(5):583–613.
  • Vriezinga SL, Auricchio R, Bravi E, et al. Randomized feeding intervention in infants at high risk for celiac disease. N Engl J Med. 2014;371(14):1304–1315.
  • Schuppan D, Maki M, Lundin KEA, et al. A randomized trial of a transglutaminase 2 inhibitor for celiac disease. N Engl J Med. 2021;385(1):35–45.
  • Lahdeaho ML, Scheinin M, Vuotikka P, et al. Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study. Lancet Gastroenterol Hepatol. 2019;4(12):948–959.
  • Daveson AJM, Popp A, Taavela J, et al. Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten‐free diet. GastroHep. 2020;2(1):22–30.
  • Comino I, Fernandez-Banares F, Esteve M, et al. Fecal gluten peptides reveal limitations of serological tests and food questionnaires for monitoring gluten-free diet in celiac disease patients. Am J Gastroenterol. 2016;111(10):1456–1465.
  • Tye-Din JA, Daveson AJM, Goldstein KE, et al. Patient factors influencing acute gluten reactions and cytokine release in treated coeliac disease. BMC Med. 2020;18(1):362.
  • Leffler DA, Kelly CP, Green PH, et al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology. 2015;148(7):1311–1319 e1316.
  • Murray JA, Kelly CP, Green PHR, et al. No difference between latiglutenase and placebo in reducing villous atrophy or improving symptoms in patients with symptomatic celiac disease. Gastroenterology. 2017;152(4):787–798 e782.
  • Truitt KE, Anderson RP. Editorial: a non-dietary treatment for coeliac disease-two steps forward, one step back? Authors’ reply. Aliment Pharmacol Ther. 2019;50(8):956–957.
  • Daveson AJM, Tye-Din JA, Goel G, et al. Masked bolus gluten challenge low in FODMAPs implicates nausea and vomiting as key symptoms associated with immune activation in treated coeliac disease. Aliment Pharmacol Ther. 2020;51(2):244–252.
  • Goel G, Tye-Din JA, Qiao SW, et al. Cytokine release and gastrointestinal symptoms after gluten challenge in celiac disease. Sci Adv. 2019;5(8):eaaw7756.
  • Tye-Din JA, Daveson AJM, Ee HC, et al. Elevated serum interleukin-2 after gluten correlates with symptoms and is a potential diagnostic biomarker for coeliac disease. Aliment Pharmacol Ther. 2019;50(8):901–910.
  • Leffler D, Kupfer SS, Lebwohl B, et al. Development of celiac disease therapeutics: report of the third gastroenterology regulatory endpoints and advancement of therapeutics workshop. Gastroenterology. 2016;151(3):407–411.
  • Sollid LM, Koning F. Lack of relationship of AT1001 to zonulin and prehaptoglobin-2: clinical implications. Gut. 2020;70:2211–2212.
  • Jabri B, Sollid LM. T cells in celiac disease. J Immunol. 2017;198(8):3005–3014.
  • Lebwohl B, Sanders DS, Green PHR. Coeliac Dis. Lancet. 2018;391(10115):70–81.
  • D’Avino P, Serena G, Kenyon V, et al. An updated overview on celiac disease: from immuno-pathogenesis and immuno-genetics to therapeutic implications. Expert Rev Clin Immunol. 2021;17(3):269–284.
  • Lindfors K, Ciacci C, Kurppa K, et al. Coeliac disease. Nat Rev Dis Primers. 2019;5(1):3.
  • Caio G, Volta U, Sapone A, et al. Celiac disease: a comprehensive current review. BMC Med. 2019;17(1):142.
  • Leonard MM, Sapone A, Catassi C, et al. Celiac disease and nonceliac gluten sensitivity: a review. JAMA. 2017;318(7):647–656.
  • Sapone A, Bai JC, Ciacci C, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012;10(1):13.
  • Auricchio R, Troncone R. Can celiac disease be prevented? Front Immunol. 2021;12:672148.
  • Kivela L, Caminero A, Leffler DA, et al. Current and emerging therapies for coeliac disease. Nature reviews. Gastroenterol Hepatol. 2021;18(3):181–195.
  • Khaleghi S, Ju JM, Lamba A, et al. The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate. Therap Adv Gastroenterol. 2016;9(1):37–49.
  • Lahdeaho ML, Kaukinen K, Laurila K, et al. Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology. 2014;146(7):1649–1658.
  • Canestaro WJ, Edwards TC, Patrick DL. Systematic review: patient-reported outcome measures in coeliac disease for regulatory submissions. Aliment Pharmacol Ther. 2016;44(4):313–331.
  • Skodje GI, Sarna VK, Minelle IH, et al. Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity. Gastroenterology. 2018;154(3):529–539 e522.
  • Gibson PR. Editorial: inaccuracies in attribution of symptoms due to gluten-not just in those with self-reported noncoeliac gluten sensitivity. Aliment Pharmacol Ther. 2020;51(3):402–403.
  • Sollid LM, Jabri B. Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol. 2013;13(4):294–302.
  • Smyth DJ, Plagnol V, Walker NM, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med. 2008;359(26):2767–2777.
  • Dicke WK, Weijers HA, Van De Kamer JH. Coeliac disease. II. The presence in wheat of a factor having a deleterious effect in cases of coeliac disease. Acta Paediatr. 1953;42(1):34–42.
  • Dicke WK. Coeliac disease. Investigation of the harmful effects of certain types of cereal on patients with coeliac disease. The Netherlands: University of Utrecht; 1950.
  • Anderson CM, Gracey M, Burke V. Coeliac disease. Some still controversial aspects. Arch Dis Child. 1972;47(252):292–298.
  • Taylor KB, Truelove SC, Thomson DL, et al. An immunological study of coeliac disease and idiopathic steatorrhoea. Serological reactions to gluten and milk proteins. Br Med J. 1961;2(5269):1727–1731.
  • Anderson WH, Mackay IR. Gut reactions–from celiac affection to autoimmune model. N Engl J Med. 2014;371(1):6–7.
  • Dunne MR, Byrne G, Chirdo FG, et al. Coeliac disease pathogenesis: the uncertainties of a well-known immune mediated disorder. Front Immunol. 2020;11:1374.
  • Goel G, King T, Daveson AJ, et al. Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies. Lancet Gastroenterol Hepatol. 2017;2(7):479–493.
  • Molberg O, McAdam SN, Korner R, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med. 1998;4(6):713–717.
  • Arentz-Hansen H, Korner R, Molberg O, et al. The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med. 2000;191(4):603–612.
  • Anderson RP, Degano P, Godkin AJ, et al. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat Med. 2000;6(3):337–342.
  • Christophersen A, Lund EG, Snir O, et al. Distinct phenotype of CD4(+) T cells driving celiac disease identified in multiple autoimmune conditions. Nat Med. 2019;25(5):734–737.
  • Tye-Din JA, Stewart JA, Dromey JA, et al. Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci Transl Med. 2010;2(41):41ra51.
  • Bodd M, Raki M, Bergseng E, et al. Direct cloning and tetramer staining to measure the frequency of intestinal gluten-reactive T cells in celiac disease. Eur J Immunol. 2013;43(10):2605–2612.
  • Van De Wal Y, Kooy Y, Van Veelen P, et al. Cutting edge: selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol. 1998;161(4):1585–1588.
  • Osman AA, Gunnel T, Dietl A, et al. B cell epitopes of gliadin. Clin Exp Immunol. 2000;121(2):248–254.
  • Raki M, Fallang LE, Brottveit M, et al. Tetramer visualization of gut-homing gluten-specific T cells in the peripheral blood of celiac disease patients. Proc Natl Acad Sci USA. 2007;104(8):2831–2836.
  • Christophersen A, Zuhlke S, Lund EG, et al. Pathogenic T cells in celiac disease change phenotype on gluten challenge: implications for T-cell-directed therapies. Adv Sci. 2021;8:e2102778.
  • Dorum S, Qiao SW, Sollid LM, et al. A quantitative analysis of transglutaminase 2-mediated deamidation of gluten peptides: implications for the T-cell response in celiac disease. J Proteome Res. 2009;8(4):1748–1755.
  • Dorum S, Arntzen MO, Qiao SW, 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. 2010;5(11):e14056.
  • Hardy MY, Girardin A, Pizzey C, et al. Consistency in polyclonal T-cell responses to gluten between children and adults with celiac disease. Gastroenterology. 2015;149(6):1541–1552 e1542.
  • Sollid LM, Tye-Din JA, Qiao SW, et al. Update 2020: nomenclature and listing of celiac disease-relevant gluten epitopes recognized by CD4(+) T cells. Immunogenetics. 2020;72(1–2):85–88.
  • Vriz R, Moreno FJ, Koning F, et al. Ranking of immunodominant epitopes in celiac disease: identification of reliable parameters for the safety assessment of innovative food proteins. Food Chem Toxicol. 2021;157:112584.
  • Pinto-Sanchez MI, Causada-Calo N, Bercik P, et al. Safety of adding oats to a gluten-free diet for patients with celiac disease: systematic review and meta-analysis of clinical and observational studies. Gastroenterology. 2017;153(2):395–409 e393.
  • Arentz-Hansen H, Fleckenstein B, Molberg O, et al. The molecular basis for oat intolerance in patients with celiac disease. PLoS Med. 2004;1(1):e1.
  • Hardy MY, Tye-Din JA, Stewart JA, et al. Ingestion of oats and barley in patients with celiac disease mobilizes cross-reactive T cells activated by avenin peptides and immuno-dominant hordein peptides. J Autoimmun. 2015;56:56–65.
  • Dorum S, Steinsbo O, Bergseng E, et al. Gluten-specific antibodies of celiac disease gut plasma cells recognize long proteolytic fragments that typically harbor T-cell epitopes. Sci Rep. 2016;6:25565.
  • Snir O, Chen X, Gidoni M, et al. Stereotyped antibody responses target posttranslationally modified gluten in celiac disease. JCI Insight. 2017;2(17). doi:https://doi.org/10.1172/jci.insight.93961.
  • Matysiak-Budnik T, Moura IC, Arcos-Fajardo M, et al. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J Exp Med. 2008;205(1):143–154.
  • Schumann M, Richter JF, Wedell I, et al. Mechanisms of epithelial translocation of the alpha(2)-gliadin-33mer in coeliac sprue. Gut. 2008;57(6):747–754.
  • Rauhavirta T, Qiao SW, Jiang Z, et al. Epithelial transport and deamidation of gliadin peptides: a role for coeliac disease patient immunoglobulin A. Clin Exp Immunol. 2011;164(1):127–136.
  • Rauhavirta T, Oittinen M, Kivisto R, et al. Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study. J Clin Immunol. 2013;33(1):134–142.
  • Iversen R, Amundsen SF, Kleppa L, et al. Evidence that pathogenic transglutaminase 2 in celiac disease derives from enterocytes. Gastroenterology. 2020;159(2):788–790.
  • Vader LW, de Ru A, van der Wal Y, et al. Specificity of tissue transglutaminase explains cereal toxicity in celiac disease. J Exp Med. 2002;195(5):643–649.
  • Fleckenstein B, Molberg O, Qiao SW, et al. Gliadin T cell epitope selection by tissue transglutaminase in celiac disease. Role of enzyme specificity and pH influence on the transamidation versus deamidation process. J Biol Chem. 2002;277(37):34109–34116.
  • Ting YT, Dahal-Koirala S, Kim HSK, et al. A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease. Proc Natl Acad Sci USA. 2020;117(6):3063–3073.
  • Stamnaes J, Iversen R, Du Pre MF, et al. Enhanced B-cell receptor recognition of the autoantigen transglutaminase 2 by efficient catalytic self-multimerization. PLoS One. 2015;10(8):e0134922.
  • Marsh MN. Transglutaminase, gluten and celiac disease: food for thought. Transglutaminase is identified as the autoantigen of celiac disease. Nat Med. 1997;3(7):725–726.
  • Stamnaes J, Sollid LM. Celiac disease: autoimmunity in response to food antigen. Semin Immunol. 2015;27(5):343–352.
  • Dafik L, Albertelli M, Stamnaes J, et al. Activation and inhibition of transglutaminase 2 in mice. PLoS One. 2012;7(2):e30642.
  • Bretscher PA. A two-step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci USA. 1999;96(1):185–190.
  • Seder RA, Darrah PA, Roederer M. T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol. 2008;8(4):247–258.
  • Christophersen A, Raki M, Bergseng E, et al. Tetramer-visualized gluten-specific CD4+ T cells in blood as a potential diagnostic marker for coeliac disease without oral gluten challenge. United Eur Gastroenterol J. 2014;2(4):268–278.
  • Vader W, Stepniak D, Kooy Y, et al. The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc Natl Acad Sci USA. 2003;100(21):12390–12395.
  • Liu E, Lee H-S, Aronsson CA, et al. Risk of pediatric celiac disease according to HLA haplotype and country. N Engl J Med. 2014;371(1):42–49.
  • King JA, Jeong J, Underwood FE, et al. Incidence of celiac disease is increasing over time: a systematic review and meta-analysis. Am J Gastroenterol. 2020;115(4):507–525.
  • Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–252.
  • Anderson RP, van Heel DA, Tye-Din JA, et al. T cells in peripheral blood after gluten challenge in coeliac disease. Gut. 2005;54(9):1217–1223.
  • Abadie V, Kim SM, Lejeune T, et al. IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature. 2020;578(7796):600–604.
  • Christophersen A, Risnes LF, Dahal-Koirala S, et al. Therapeutic and diagnostic implications of T cell scarring in celiac disease and beyond. Trends Mol Med. 2019;25(10):836–852.
  • Petersen J, Ciacchi L, Tran MT, et al. T cell receptor cross-reactivity between gliadin and bacterial peptides in celiac disease. Nat Struct Mol Biol. 2020;27(1):49–61.
  • Falta MT, Fontenot AP, Rosloniec EF, et al. Class II major histocompatibility complex-peptide tetramer staining in relation to functional avidity and T cell receptor diversity in the mouse CD4(+) T cell response to a rheumatoid arthritis-associated antigen. Arthritis Rheum. 2005;52(6):1885–1896.
  • Dahal-Koirala S, Risnes LF, Neumann RS, et al. Comprehensive analysis of CDR3 sequences in gluten-specific T-cell receptors reveals a dominant R-motif and several new minor motifs. Front Immunol. 2021;12:639672.
  • Raki M, Dahal-Koirala S, Yu H, et al. Similar responses of intestinal T cells from untreated children and adults with celiac disease to deamidated gluten epitopes. Gastroenterology. 2017;153(3):787–798 e784.
  • Shan L, Molberg O, Parrot I, et al. Structural basis for gluten intolerance in celiac sprue. Science. 2002;297(5590):2275–2279.
  • Dieterich W, Esslinger B, Trapp D, et al. Cross linking to tissue transglutaminase and collagen favours gliadin toxicity in coeliac disease. Gut. 2006;55(4):478–484.
  • Lanzavecchia A. Antigen-specific interaction between T and B cells. Nature. 1985;314(6011):537–539.
  • McSorley HJ, Gaze S, Daveson J, et al. Suppression of inflammatory immune responses in celiac disease by experimental hookworm infection. PLoS One. 2011;6(9):e24092.
  • Nilsen EM, Lundin KE, Krajci P, et al. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut. 1995;37(6):766–776.
  • Hardy MY, Goel G, Russell AK, et al. A sensitive whole blood assay detects antigen-stimulated cytokine release from CD4+ T cells and facilitates immunomonitoring in a phase 2 clinical trial of nexvax2 in coeliac disease. Front Immunol. 2021;12:661622.
  • Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–763.
  • Billiau A. Interferon-gamma: biology and role in pathogenesis. Adv Immunol. 1996;62:61–130.
  • Boehm U, Klamp T, Groot M, et al. Cellular responses to interferon-gamma. Annu Rev Immunol. 1997;15:749–795.
  • Beaurepaire C, Smyth D, McKay DM. Interferon-gamma regulation of intestinal epithelial permeability. J Interferon Cytokine Res. 2009;29(3):133–144.
  • Nava P, Koch S, Laukoetter MG, et al. Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. Immunity. 2010;32(3):392–402.
  • Kooy-Winkelaar YM, Bouwer D, Janssen GM, et al. CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes. Proc Natl Acad Sci USA. 2017;114(6):E980–E989.
  • Ye C, Brand D, Zheng SG. Targeting IL-2: an unexpected effect in treating immunological diseases. Signal Transduct Target Ther. 2018;3:2.
  • Jabri B, Abadie V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat Rev Immunol. 2015;15(12):771–783.
  • Voisine J, Abadie V. Interplay between gluten, HLA, innate and adaptive immunity orchestrates the development of coeliac disease. Front Immunol. 2021;12:674313.
  • Dios A, Elek R, Szabo I, et al. Gamma-gliadin specific celiac disease antibodies recognize p31-43 and p57-68 alpha gliadin peptides in deamidation related manner as a result of cross-reaction. Amino Acids. 2021;53(7):1051–1063.
  • Truitt KE, Daveson AJM, Ee HC, et al. Randomised clinical trial: a placebo-controlled study of subcutaneous or intradermal NEXVAX2, an investigational immunomodulatory peptide therapy for coeliac disease. Aliment Pharmacol Ther. 2019;50(5):547–555.
  • Hoydahl LS, Richter L, Frick R, et al. Plasma cells are the most abundant gluten peptide MHC-expressing cells in inflamed intestinal tissues from patients with celiac disease. Gastroenterology. 2019;156(5):1428–1439 e1410.
  • Anderson RP, Goel G, Hardy MY, et al. Whole blood interleukin-2 release test to detect and characterise rare circulating gluten-specific t cell responses in coeliac disease. Clin Exp Immunol. 2021;204:321–334.
  • Lebreton C, Menard S, Abed J, et al. Interactions among secretory immunoglobulin A, CD71, and transglutaminase-2 affect permeability of intestinal epithelial cells to gliadin peptides. Gastroenterology. 2012;143(3):698–707.e694.
  • Kelly CP, Murray JA, Leffler DA, et al. TAK-101 nanoparticles induce gluten-specific tolerance in celiac disease: a randomized, double-blind, placebo-controlled study. Gastroenterology. 2021;161:66–80.e8.
  • Anderson RP, Jabri B. Vaccine against autoimmune disease: antigen-specific immunotherapy. Curr Opin Immunol. 2013;25(3):410–417.
  • Silvester JA, Graff LA, Rigaux L, et al. Symptomatic suspected gluten exposure is common among patients with coeliac disease on a gluten-free diet. Aliment Pharmacol Ther. 2016;44(6):612–619.
  • DePaolo RW, Abadie V, Tang F, et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature. 2011;471(7337):220–224.
  • Du Pre MF, Kozijn AE, van Berkel LA, et al. Tolerance to ingested deamidated gliadin in mice is maintained by splenic, type 1 regulatory T cells. Gastroenterology. 2011;141(2):610–620 e612.
  • Christophersen A, Risnes LF, Bergseng E, et al. Healthy HLA-DQ2.5+ subjects lack regulatory and memory T cells specific for immunodominant gluten epitopes of celiac disease. J Immunol. 2016;196(6):2819–2826.
  • Goel G, Daveson AJM, Hooi CE, et al. Serum cytokines elevated during gluten-mediated cytokine release in coeliac disease. Clin Exp Immunol. 2020;199(1):68–78.
  • Fasano A, Not T, Wang W, et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000;355(9214):1518–1519.
  • Wang W, Uzzau S, Goldblum SE, et al. Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci. 2000;113(Pt 24):4435–4440.
  • Leffler DA, Kelly CP, Abdallah HZ, et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am J Gastroenterol. 2012;107(10):1554–1562.
  • Ajamian M, Steer D, Rosella G, et al. Serum zonulin as a marker of intestinal mucosal barrier function: may not be what it seems. PLoS One. 2019;14(1):e0210728.
  • Massier L, Chakaroun R, and Kovacs P, et al. Blurring the picture in leaky gut research: how shortcomings of zonulin as a biomarker mislead the field of intestinal permeability. Gut. 2021;70(9):1801–1802 .
  • Sarna VK, Skodje GI, Reims HM, et al. HLA-DQ:gluten tetramer test in blood gives better detection of coeliac patients than biopsy after 14-day gluten challenge. Gut. 2018;67(9):1606–1613.
  • Leonard MM, Silvester JA, and Leffler D, et al. Evaluating responses to gluten challenge: a randomized, double-blind, 2-dose gluten challenge trial. Gastroenterology. 2021;160(3):720-733.
  • Abadie V, Jabri B. IL-15: a central regulator of celiac disease immunopathology. Immunol Rev. 2014;260(1):221–234.
  • Dotsenko V, Oittinen M, Taavela J, et al. Genome-wide transcriptomic analysis of intestinal mucosa in celiac disease patients on a gluten-free diet and postgluten challenge. Cell Mol Gastroenterol Hepatol. 2021;11(1):13–32.
  • Eckert RL, Kaartinen MT, Nurminskaya M, et al. Transglutaminase regulation of cell function. Physiol Rev. 2014;94(2):383–417.
  • Du Pre MF, Blazevski J, Dewan AE, et al. B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2. J Exp Med. 2020; 217(2). doi:https://doi.org/10.1084/jem.20190860
  • Ciccocioppo R, Finamore A, Mengheri E, et al. Isolation and characterization of circulating tissue transglutaminase-specific T cells in coeliac disease. Int J Immunopathol Pharmacol. 2010;23(1):179–191.
  • Caproni M, Capone M, Rossi MC, et al. T cell response toward tissue-and epidermal-transglutaminases in coeliac disease patients developing dermatitis herpetiformis. Front Immunol. 2021;12:645143.
  • Freitag T, Schulze-Koops H, Niedobitek G, et al. The role of the immune response against tissue transglutaminase in the pathogenesis of coeliac disease. Autoimmun Rev. 2004;3(2):13–20.
  • Kalliokoski S, Piqueras VO, Frias R, et al. Transglutaminase 2-specific coeliac disease autoantibodies induce morphological changes and signs of inflammation in the small-bowel mucosa of mice. Amino Acids. 2017;49(3):529–540.
  • Stamnaes J, Dorum S, Fleckenstein B, et al. Gluten T cell epitope targeting by TG3 and TG6; implications for dermatitis herpetiformis and gluten ataxia. Amino Acids. 2010;39(5):1183–1191.
  • Pinto-Sanchez MI, Silvester JA, and Lebwohl B, et al. Society for the study of celiac disease position statement on gaps and opportunities in coeliac disease. Nat Rev Gastroenterol Hepatol. 2021. doi:https://doi.org/10.1038/s41575-021-00511-8.
  • Kurppa K, Collin P, Viljamaa M, et al. Diagnosing mild enteropathy celiac disease: a randomized, controlled clinical study. Gastroenterology. 2009;136(3):816–823.
  • Lundin KE, Scott H, Hansen T, et al. Gliadin-specific, HLA-DQ(alpha 1*0501,beta 1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients. J Exp Med. 1993;178(1):187–196.
  • Du Pre MF, van Berkel LA, Raki M, et al. CD62L(neg)CD38 expression on circulating CD4 T cells identifies mucosally differentiated cells in protein fed mice and in human celiac disease patients and controls. Am J Gastroenterol. 2011;106(6):1147–1159.
  • Zuhlke S, Risnes LF, Dahal-Koirala S, et al. CD38 expression on gluten-specific T cells is a robust marker of gluten re-exposure in coeliac disease. United Eur Gastroenterol J. 2019;7(10):1337–1344.
  • Rao DA, Gurish MF, Marshall JL, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017;542(7639):110–114.
  • Risnes LF, Christophersen A, Dahal-Koirala S, et al. Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease. J Clin Invest. 2018;128(6):2642–2650.
  • Ontiveros N, Tye-Din JA, Hardy MY, et al. Ex-vivo whole blood secretion of interferon (IFN)-gamma and IFN-gamma-inducible protein-10 measured by enzyme-linked immunosorbent assay are as sensitive as IFN-gamma enzyme-linked immunospot for the detection of gluten-reactive T cells in human leucocyte antigen (HLA)-DQ2.5(+) -associated coeliac disease. Clin Exp Immunol. 2014;175(2):305–315.
  • Sarna VK, Lundin KEA, Morkrid L, et al. HLA-DQ-gluten tetramer blood test accurately identifies patients with and without celiac disease in absence of gluten consumption. Gastroenterology. 2018;154(4):886–896 e886.
  • Han A, Newell EW, Glanville J, et al. Dietary gluten triggers concomitant activation of CD4+ and CD8+ alpha beta T cells and gammadelta T cells in celiac disease. Proc Natl Acad Sci USA. 2013;110(32):13073–13078.
  • Jabri B, de Serre NP, Cellier C, et al. Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Gastroenterology. 2000;118(5):867–879.
  • Meresse B, Chen Z, Ciszewski C, et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity. 2004;21(3):357–366.
  • Meresse B, Curran SA, Ciszewski C, et al. Reprogramming of CTLs into natural killer-like cells in celiac disease. J Exp Med. 2006;203(5):1343–1355.
  • Setty M, Discepolo V, Abadie V, et al. Distinct and synergistic contributions of epithelial stress and adaptive immunity to functions of intraepithelial killer cells and active celiac disease. Gastroenterology. 2015;149(3):681–691 e610.
  • Kutlu T, Brousse N, Rambaud C, et al. 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. 1993;34(2):208–214.
  • Mayassi T, Ladell K, Gudjonson H, et al. Chronic inflammation permanently reshapes tissue-resident immunity in celiac disease. Cell. 2019;176(5):967–981 e919.
  • Eggesbo LM, Risnes LF, Neumann RS, et al. Single-cell TCR sequencing of gut intraepithelial gammadelta T cells reveals a vast and diverse repertoire in celiac disease. Mucosal Immunol. 2020;13(2):313–321.
  • Nielsen MM, Witherden DA, Havran WL. gammadelta T cells in homeostasis and host defence of epithelial barrier tissues. Nat Rev Immunol. 2017;17(12):733–745.
  • Fernandez-Banares F, Crespo L, Nunez C, et al. Gamma delta(+) intraepithelial lymphocytes and coeliac lymphogram in a diagnostic approach to coeliac disease in patients with seronegative villous atrophy. Aliment Pharmacol Ther. 2020;51(7):699–705.
  • Popp A, Taavela J, and Graziano P, et al. A new intraepithelial gammadelta T-lymphocyte marker for celiac disease classification in Formalin-Fixed Paraffin-Embedded (FFPE) duodenal biopsies. Dig Dis Sci. 2021;66(10):3352-3358 .
  • Tiittanen M, Westerholm-Ormio M, Verkasalo M, et al. Infiltration of forkhead box P3-expressing cells in small intestinal mucosa in coeliac disease but not in type 1 diabetes. Clin Exp Immunol. 2008;152(3):498–507.
  • Vorobjova T, Uibo O, Heilman K, et al. Increased FOXP3 expression in small-bowel mucosa of children with coeliac disease and type I diabetes mellitus. Scand J Gastroenterol. 2009;44(4):422–430.
  • Frisullo G, Nociti V, Iorio R, et al. Increased CD4+CD25+Foxp3+ T cells in peripheral blood of celiac disease patients: correlation with dietary treatment. Hum Immunol. 2009;70(6):430–435.
  • Gianfrani C, Levings MK, Sartirana C, et al. Gliadin-specific type 1 regulatory T cells from the intestinal mucosa of treated celiac patients inhibit pathogenic T cells. J Immunol. 2006;177(6):4178–4186.
  • Granzotto M, Dal Bo S, Quaglia S, et al. Regulatory T-cell function is impaired in celiac disease. Dig Dis Sci. 2009;54(7):1513–1519.
  • Hmida NB, Ben Ahmed M, Moussa A, et al. Impaired control of effector T cells by regulatory T cells: a clue to loss of oral tolerance and autoimmunity in celiac disease? Am J Gastroenterol. 2012;107(4):604–611.
  • Cook L, Munier CML, Seddiki N, et al. Circulating gluten-specific FOXP3(+)CD39(+) regulatory T cells have impaired suppressive function in patients with celiac disease. J Allergy Clin Immunol. 2017;140(6):1592–1603e1598.
  • Zanzi D, Stefanile R, Santagata S, et al. IL-15 interferes with suppressive activity of intestinal regulatory T cells expanded in Celiac disease. Am J Gastroenterol. 2011;106(7):1308–1317.
  • Ben Ahmed M, Belhadj Hmida N, Moes N, et al. IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway. J Immunol. 2009;182(11):6763–6770.
  • Daveson AJM, Ee HC, Andrews JM, et al. Epitope-specific immunotherapy targeting CD4-positive T cells in celiac disease: safety, pharmacokinetics, and effects on intestinal histology and plasma cytokines with escalating dose regimens of Nexvax2 in a randomized, double-blind, placebo-controlled phase 1 study. EBioMedicine. 2017;26:78–90.
  • Freitag TL, Podojil JR, Pearson RM, et al. Gliadin nanoparticles induce immune tolerance to gliadin in mouse models of celiac disease. Gastroenterology. 2020;158(6):1667–1681 e1612.

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