The adaptive immune response in celiac disease

Springer Science and Business Media LLC - Tập 34 - Trang 523-540 - 2012
Shuo-Wang Qiao1, Rasmus Iversen1, Melinda Ráki1,2, Ludvig M. Sollid1
1Department of Immunology and Centre for Immune Regulation, University of Oslo, Oslo University Hospital—Rikshospitalet, Oslo, Norway
2Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway

Tóm tắt

Compared to other human leukocyte antigen (HLA)-associated diseases such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, fundamental aspects of the pathogenesis in celiac disease are relatively well understood. This is mostly because the causative antigen in celiac disease—cereal gluten proteins—is known and the culprit HLA molecules are well defined. This has facilitated the dissection of the disease-relevant CD4+ T cells interacting with the disease-associated HLA molecules. In addition, celiac disease has distinct antibody responses to gluten and the autoantigen transglutaminase 2, which give strong handles to understand all sides of the adaptive immune response leading to disease. Here we review recent developments in the understanding of the role of T cells, B cells, and antigen-presenting cells in the pathogenic immune response of this instructive disorder.

Tài liệu tham khảo

Shewry PR, Tatham AS, Kasarda DD (1992) Cereal proteins and coeliac disease. In: Marsh MN (ed) Coeliac disease. Blackwell Scientific, Oxford, pp 305–348 Janatuinen EK, Pikkarainen PH, Kemppainen TA, Kosma VM, Järvinen RMK, Uusitupa MIJ et al (1995) A comparison of diets with and without oats in adults with celiac disease. N Engl J Med 333(16):1033–1037 Greco L, Romino R, Coto I, Di Cosmo N, Percopo S, Maglio M et al (2002) The first large population based twin study of coeliac disease. Gut 50(5):624–628 Nisticò L, Fagnani C, Coto I, Percopo S, Cotichini R, Limongelli MG et al (2006) Concordance, disease progression, and heritability of coeliac disease in Italian twins. Gut 55(6):803–808 van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M et al (2007) A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 39(7):827–829 Hunt KA, Zhernakova A, Turner G, Heap GAR, Franke L, Bruinenberg M et al (2008) Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40(4):395–402 Dubois PCA, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A et al (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42(4):295–302 Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A et al (2011) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet 43(12):1193–1201 Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E (1989) Evidence for a primary association of celiac disease to a particular HLA-DQ α/β heterodimer. J Exp Med 169(1):345–350 Sollid LM (2002) Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2(9):647–655 Thorsby E, Lie BA (2005) HLA associated genetic predisposition to autoimmune diseases: genes involved and possible mechanisms. Transpl Immunol 14(3–4):175–182 Bergseng E, Sidney J, Sette A, Sollid LM (2008) Analysis of the binding of gluten T-cell epitopes to various human leukocyte antigen class II molecules. Hum Immunol 69(2):94–100 Johansen BH, Buus S, Vartdal F, Viken H, Eriksen JA, Thorsby E et al (1994) Binding of peptides to HLA-DQ molecules: peptide binding properties of the disease-associated HLA-DQ(α1*0501, β1*0201) molecule. Int Immunol 6(3):453–461 van de Wal Y, Kooy YMC, Drijfhout JW, Amons R, Koning F (1996) Peptide binding characteristics of the coeliac disease-associated DQ(α1*0501, β1*0201) molecule. Immunogenetics 44(4):246–253 Vartdal F, Johansen BH, Friede T, Thorpe CJ, Stevanovic S, Eriksen JE et al (1996) The peptide binding motif of the disease associated HLA-DQ (α1*0501, β1*0201) molecule. Eur J Immunol 26(11):2764–2772 van de Wal Y, Kooy YMC, Drijfhout JW, Amons R, Papadopoulos GK, Koning F (1997) Unique peptide binding characteristics of the disease-associated DQ(α1*0501, β1*0201) vs the non-disease-associated DQ(α1*0201, β1*0202) molecule. Immunogenetics 46(6):484–492 Kim CY, Quarsten H, Bergseng E, Khosla C, Sollid LM (2004) Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc Natl Acad Sci U S A 101(12):4175–4179 Bergseng E, Xia J, Kim CY, Khosla C, Sollid LM (2005) Main chain hydrogen bond interactions in the binding of proline-rich gluten peptides to the celiac disease-associated HLA-DQ2 molecule. J Biol Chem 280(23):21791–21796 Ploski R, Ek J, Thorsby E, Sollid LM (1993) On the HLA-DQ(α1*0501, β1*0201)-associated susceptibility in celiac-disease—a possible gene dosage effect of DQB1*0201. Tissue Antigens 41(4):173–177 Louka AS, Nilsson S, Olsson M, Talseth B, Lie BA, Ek J et al (2002) HLA in coeliac disease families: a novel test of risk modification by the 'other' haplotype when at least one DQA1*05-DQB1*02 haplotype is carried. Tissue Antigens 60(2):147–154 Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L et al (2003) HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European genetics cluster on celiac disease. Hum Immunol 64(4):469–477 Johansen BH, Jensen T, Thorpe CJ, Vartdal F, Thorsby E, Sollid LM (1996) Both the alpha- and the beta-chain polymorphisms determine the specificity of the disease-associated HLA-DQ2 molecules, with beta chain residues being most influential. Immunogenetics 45:142–150 Qiao SW, Bergseng E, Molberg O, Jung G, Fleckenstein B, Sollid LM (2005) Refining the rules of gliadin T cell epitope binding to the disease-associated DQ2 molecule in celiac disease: Importance of proline spacing and glutamine deamidation. J Immunol 175(1):254–261 Vader W, Stepniak D, Kooy Y, Mearin L, Thompson A, van Rood JJ 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. Proc Natl Acad Sci U S A 100(21):12390–12395 Fallang LE, Bergseng E, Hotta K, Berg-Larsen A, Kim CY, Sollid LM (2009) Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nat Immunol 10(10):1096–1101 Henrickson SE, Mempel TR, Mazo IB, Liu B, Artyomov MN, Zheng H et al (2008) T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nat Immunol 9(3):282–291 Bodd M, Kim C, Lundin KEA, Sollid LM (2012) T-cell response to gluten in patients with HLA-DQ2.2 reveals requirement of peptide-MHC stability in celiac disease. Gastroenterology 142(3):552–561 Abadie V, Sollid LM, Barreiro LB, Jabri B (2011) Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Nat Rev Immunol 29:493–525 Festen EA, Goyette P, Green T, Boucher G, Beauchamp C, Trynka G et al (2011) A meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, TAGAP, and PUS10 as shared risk loci for Crohn's disease and celiac disease. PLoS Genet 7(1):e1001283 Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JHM et al (2008) Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 359(26):2767–2777 Zhernakova A, van Diemen CC, Wijmenga C (2009) Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet 10(1):43–55 Zhernakova A, Stahl EA, Trynka G, Raychaudhuri S, Festen EA, Franke L et al (2011) Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet 7(2):e1002004 Cotsapas C, Voight BF, Rossin E, Lage K, Neale BM, Wallace C et al (2011) Pervasive sharing of genetic effects in autoimmune disease. PLoS Genet 7(8):e1002254 Marsh MN (1988) Studies of intestinal lymphoid-tissue. XI—the immunopathology of cell-mediated reactions in gluten sensitivity and other enteropathies. Scanning Microsc 2(3):1663–1684 Halstensen TS, Brandtzaeg P (1993) Activated T lymphocytes in the celiac lesion—nonproliferative activation (CD25) of CD4+ αβ cells in the lamina propria but proliferation (Ki-67) of αβ and γδ cells in the epithelium. Eur J Immunol 23(2):505–510 Halstensen TS, Farstad IN, Scott H, Fausa O, Brandtzaeg P (1990) Intraepithelial TCRα/β+ lymphocytes express CD45RO more often than the TCRγ/δ+ counterparts in celiac-disease. Immunology 71(4):460–466 Halstensen TS, Scott H, Fausa O, Brandtzaeg P (1993) Gluten stimulation of celiac mucosa in-vitro induces activation (CD25) of lamina propria CD4(+) T-cells and macrophages but no crypt-cell hyperplasia. Scand J Immunol 38(6):581–590 Lundin KE, Scott H, Hansen T, Paulsen G, Halstensen TS, Fausa O et al (1993) 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(1):187–196 Molberg O, Kett K, Scott H, Thorsby E, Sollid LM, Lundin KEA (1997) 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(1):103–108 Nilsen EM, Lundin KEA, Krajci P, Scott H, Sollid LM, Brandtzaeg P (1995) Gluten specific, HLA-DQ restricted T-cells from celiac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon-gamma. Gut 37(6):766–776 Bodd M, Ráki M, Tollefsen S, Fallang LE, Bergseng E, Lundin KEA et al (2010) HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22. Mucosal Immunol 3(6):594–601 Sjöström H, Lundin KEA, Molberg O, Korner R, McAdam SN, Anthonsen D et al (1998) Identification of a gliadin T-cell epitope in coeliac disease: general importance of gliadin deamidation for intestinal T-cell recognition. Scand J Immunol 48(2):111–115 Arentz-Hansen H, Korner R, Molberg O, Quarsten H, Vader W, Kooy YMC et al (2000) The intestinal T cell response to a-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med 191(4):603–612 Arentz-Hansen H, McAdam SN, Molberg O, Fleckenstein B, Lundin KE, Jorgensen TJ et al (2002) Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues. Gastroenterology 123(3):803–809 Vader LW, de Ru A, van der Wal Y, Kooy YM, Benckhuijsen W, Mearin ML et al (2002) Specificity of tissue transglutaminase explains cereal toxicity in celiac disease. J Exp Med 195(5):643–649 Molberg O, McAdam SN, Korner R, Quarsten H, Kristiansen C, Madsen L et al (1998) Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 4(6):713–717 van de Wal Y, Kooy Y, van Veelen P, Pena S, Mearin L, Papadopoulos G et al (1998) Cutting edge: selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 161(4):1585–1588 Molberg O, McAdam S, Lundin KE, Kristiansen C, Arentz-Hansen H, Kett K et al (2001) T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase. Eur J Immunol 31(5):1317–1323 Fleckenstein B, Molberg O, Qiao SW, Schmid DG, der Mulbe F, Elgstoen K et al (2002) Gliadin T cell epitope selection by tissue transglutaminase in celiac disease. J Biol Chem 277(37):34109–34116 Dørum S, Arntzen MO, Qiao SW, Holm A, Koehler CJ, Thiede B et al (2010) The preferred substrates for transglutaminase 2 in a complex wheat gluten digest are peptide fragments harboring celiac disease T-cell epitopes. PLoS One 5(11):e14056 Xia J, Sollid LM, Khosla C (2005) Equilibrium and kinetic analysis of the unusual binding behavior of a highly immunogenic gluten peptide to HLA-DQ2. Biochemistry 44(11):4442–4449 Henderson KN, Tye-Din JA, Reid HH, Chen Z, Borg NA, Beissbarth T et al (2007) A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease. Immunity 27(1):23–34 Tye-Din JA, Stewart JA, Dromey JA, Beissbarth T, van Heel DA, Tatham A et al (2010) Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci Transl Med 2(41):41ra51 Sollid LM, Qiao SW, Anderson RP, Gianfrani C, Koning F (2012) Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics. doi:10.1007/s00251-012-0599-z Quarsten H, McAdam SN, Jensen T, rentz-Hansen H, Molberg O, Lundin KEA et al (2001) Staining of celiac disease-relevant T cells by peptide-DQ2 multimers. J Immunol 167(9):4861–4868 Qiao SW, Ráki M, Gunnarsen KS, Løset GÅ, Lundin KEA, Sandlie I et al (2011) Posttranslational modification of gluten shapes TCR usage in celiac disease. J Immunol 187(6):3064–3071 Shan L, Molberg O, Parrot I, Hausch F, Filiz F, Gray GM et al (2002) Structural basis for gluten intolerance in celiac sprue. Science 297(5590):2275–2279 Qiao SW, Bergseng E, Molberg O, Xia J, Fleckenstein B, Khosla C et al (2004) Antigen presentation to celiac lesion-derived T cells of a 33-mer gliadin peptide naturally formed by gastrointestinal digestion. J Immunol 173(3):1757–1762 Pinkas DM, Strop P, Brunger AT, Khosla C (2007) Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol 5(12):e327 Siegel M, Strnad P, Watts RE, Choi K, Jabri B, Omary MB et al (2008) Extracellular transglutaminase 2 is catalytically inactive, but is transiently activated upon tissue injury. PLoS One 3(3):e1861 Stamnaes J, Pinkas DM, Fleckenstein B, Khosla C, Sollid LM (2010) Redox regulation of transglutaminase 2 activity. J Biol Chem 285(33):25402–25409 Castellani P, Angelini G, Delfino L, Matucci A, Rubartelli A (2008) The thiol redox state of lymphoid organs is modified by immunization: role of different immune cell populations. Eur J Immunol 38(9):2419–2425 Anderson RP, Degano P, Godkin AJ, Jewell DP, Hill AVS (2000) In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant α-gliadin T-cell epitope. Nat Med 6(3):337–342 Ráki M, Fallang LE, Brottveit M, Bergseng E, Quarsten H, Lundin KEA et al (2007) Tetramer visualization of gut-homing gluten-specific T cells in the peripheral blood of celiac disease patients. Proc Natl Acad Sci U S A 104(8):2831–2836 Baklien K, Brandtzaeg P, Fausa O (1977) Immunoglobulins in jejunal mucosa and serum from patients with adult coeliac disease. Scand J Gastroenterol 12(2):149–159 Dieterich W, Storch WB, Schuppan D (2000) Serum antibodies in celiac disease. Clin Lab 46(7–8):361–364 Berger E, Bürgin-Wolff A, Freudenberg E (1964) Diagnostische Bewertung des Nachweises von Gliadin-Antikörpern bei Cöliakie. Klin Wochenschr 42(16):788–790 Kilander AF, Dotevall G, Fallstrom SP, Gillberg RE, Nilsson LA, Tarkowski A (1983) Evaluation of gliadin antibodies for detection of coeliac disease. Scand J Gastroenterol 18(3):377–383 Michaëlsson G, Gerdén B, Hagforsen E, Nilsson B, Pihl-Lundin I, Kraaz W et al (2000) Psoriasis patients with antibodies to gliadin can be improved by a gluten-free diet. Bri J Dermatol 142(1):44–51 Ruuskanen A, Kaukinen K, Collin P, Huhtala H, Valve R, Mäki M et al (2010) Positive serum antigliadin antibodies without celiac disease in the elderly population: does it matter? Scand J Immunol 45(10):1197–1202 Rostom A, Dubé C, Cranney A, Saloojee N, Sy R, Garritty C et al (2005) The diagnostic accuracy of serologic tests for celiac disease: a systematic review. Gastroenterology 128(4, Supplement 1):S38–S46 Osman AA, Gunnel T, Dietl A, Uhlig HH, Amin M, Fleckenstein B et al (2000) B cell epitopes of gliadin. Clin Exp Immunol 121(2):248–254 Mothes T (2007) Deamidated gliadin peptides as targets for celiac disease-specific antibodies. Adv Clin Chem 44:35–63 Prince HE (2006) Evaluation of the INOVA diagnostics enzyme-linked immunosorbent assay kits for measuring serum immunoglobulin G (IgG) and IgA to deamidated gliadin peptides. Clin Vaccine Immunol 13(1):150–151 Lewis NR, Scott BB (2010) Meta-analysis: deamidated gliadin peptide antibody and tissue transglutaminase antibody compared as screening tests for coeliac disease. Aliment Pharmacol Ther 31(1):73–81 Alp MH, Wright R (1971) Autoantibodies to reticulin in patients with idiopathic steatorrhoea, coeliac disease, and Crohn's disease, and their relation to immunoglobulins and dietary antibodies. Lancet 2(7726):682–685 Seah PP, Fry L, Rossiter MA, Hoffbrand AV, Holborow EJ (1971) Anti-reticulin antibodies in childhood coeliac disease. Lancet 2(7726):681–682 Chorzelski TP, Beutner EH, Sulej J, Tchorzewska H, Jablonska S, Kumar V et al (1984) IgA anti-endomysium antibody. A new immunological marker of dermatitis herpetiformis and coeliac disease. Br J Dermatol 111(4):395–402 Ladinser B, Rossipal E, Pittschieler K (1994) Endomysium antibodies in coeliac disease: an improved method. Gut 35(6):776–778 Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO et al (1997) Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 3(7):797–801 Korponay-Szabo IR, Sulkanen S, Halttunen T, Maurano F, Rossi M, Mazzarella G et al (2000) Tissue transglutaminase is the target in both rodent and primate tissues for celiac disease-specific autoantibodies. J Pediatr Gastroenterol Nutr 31(5):520–527 Dahlbom I, Olsson M, Forooz NK, Sjöholm AG, Truedsson L, Hansson T (2005) Immunoglobulin G (IgG) anti-tissue transglutaminase antibodies used as markers for IgA-deficient celiac disease patients. Clin Diagn Lab Immunol 12(2):254–258 Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R et al (2012) European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 54(1):136–160 Salmi TT, Collin P, Korponay-Szabo IR, Laurila K, Partanen J, Huhtala H et al (2006) Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits. Gut 55(12):1746–1753 Borrelli M, Maglio M, Agnese M, Paparo F, Gentile S, Colicchio B et al (2010) High density of intraepithelial γδ lymphocytes and deposits of immunoglobulin (Ig)M anti-tissue transglutaminase antibodies in the jejunum of coeliac patients with IgA deficiency. Clin Exp Immunol 160(2):199–206 Salmi TT, Collin P, Jarvinen O, Haimila K, Partanen J, Laurila K et al (2006) Immunoglobulin A autoantibodies against transglutaminase 2 in the small intestinal mucosa predict forthcoming coeliac disease. Aliment Pharmacol Ther 24(3):541–552 Alaedini A, Green PHR (2008) Autoantibodies in celiac disease. Autoimmunity 41(1):19–26 Sárdy M, Kárpáti S, Merkl B, Paulsson M, Smyth N (2002) Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med 195(6):747–757 Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, Aeschlimann D (2008) Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol 64(3):332–343 Sulkanen S, Halttunen T, Laurila K, Kaija L, Korponay S, Sarnesto A et al (1998) Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease. Gastroenterology 115(6):1322–1328 Barone MV, Caputo I, Ribecco MT, Maglio M, Marzari R, Sblattero D et al (2007) Humoral immune response to tissue transglutaminase is related to epithelial cell proliferation in celiac disease. Gastroenterology 132(4):1245–1253 Halttunen T, Maki M (1999) Serum immunoglobulin A from patients with celiac disease inhibits human T84 intestinal crypt epithelial cell differentiation. Gastroenterology 116(3):566–572 Zanoni G, Navone R, Lunardi C, Tridente G, Bason C, Sivori S et al (2006) In celiac disease, a subset of autoantibodies against transglutaminase binds Toll-like receptor 4 and induces activation of monocytes. PLoS Medicine 3(9):e358 Rauhavirta T, Qiao SW, Jiang Z, Myrsky E, Loponen J, Korponay-Szabo IR et al (2011) Epithelial transport and deamidation of gliadin peptides: a role for coeliac disease patient immunoglobulin A. Clin Exp Immunol 164(1):127–136 Cervio E, Volta U, Verri M, Boschi F, Pastoris O, Granito A et al (2007) Sera of patients with celiac disease and neurologic disorders evoke a mitochondrial-dependent apoptosis in vitro. Gastroenterology 133(1):195–206 Di Simone N, Silano M, Castellani R, Di Nicuolo F, D'Alessio MC, Franceschi F et al (2010) Anti-tissue transglutaminase antibodies from celiac patients are responsible for trophoblast damage via apoptosis in vitro. Am J Gastroenterol 105(10):2254–2261 Myrsky E, Kaukinen K, Syrjanen M, Korponay-Szabo IR, Maki M, Lindfors K (2008) Coeliac disease-specific autoantibodies targeted against transglutaminase 2 disturb angiogenesis. Clin Exp Immunol 152(1):111–119 Myrsky E, Caja S, Simon-Vecsei Z, Korponay-Szabo I, Nadalutti C, Collighan R et al (2009) Celiac disease IgA modulates vascular permeability in vitro through the activity of transglutaminase 2 and RhoA. Cell Mol Life Sci 66(20):3375–3385 Freitag T, Schulze-Koops H, Niedobitek G, Melino G, Schuppan D (2004) The role of the immune response against tissue transglutaminase in the pathogenesis of coeliac disease. Autoimmun Rev 3(2):13–20 Di Niro R, Sblattero D, Florian F, Stebel M, Zentilin L, Giacca M et al (2008) Anti-idiotypic response in mice expressing human autoantibodies. Mol Immunol 45(6):1782–1791 Boscolo S, Lorenzon A, Sblattero D, Florian F, Stebel M, Marzari R et al (2010) Anti transglutaminase antibodies cause ataxia in mice. PLoS One 5(3):e9698 Esposito C, Paparo F, Caputo I, Rossi M, Maglio M, Sblattero D et al (2002) Anti-tissue transglutaminase antibodies from coeliac patients inhibit transglutaminase activity both in vitro and in situ. Gut 51(2):177–181 Dieterich W, Trapp D, Esslinger B, Leidenberger M, Piper J, Hahn E et al (2003) Autoantibodies of patients with coeliac disease are insufficient to block tissue transglutaminase activity. Gut 52(11):1562–1566 Király R, Vecsei Z, Deményi T, Korponay-Szabó IR, Fésüs L (2006) Coeliac autoantibodies can enhance transamidating and inhibit GTPase activity of tissue transglutaminase: dependence on reaction environment and enzyme fitness. J Autoimmun 26(4):278–287 Di Niro R, Mesin L, Zheng NY, Stamnaes J, Morrissey M, Lee J-H et al (2012) High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat Med 18(3):441–445 Seissler J, Wohlrab U, Wuensche C, Scherbaum WA, Boehm BO (2001) Autoantibodies from patients with coeliac disease recognize distinct functional domains of the autoantigen tissue transglutaminase. Clin Exp Immunol 125(2):216–221 Sblattero D, Florian F, Azzoni E, Zyla T, Park M, Baldas V et al (2002) The analysis of the fine specificity of celiac disease antibodies using tissue transglutaminase fragments. Eur J Biochem 269(21):5175–5181 Nakachi K, Powell M, Swift G, Amoroso MA, Ananieva-Jordanova R, Arnold C et al (2004) Epitopes recognised by tissue transglutaminase antibodies in coeliac disease. J Autoimmun 22(1):53–63 Simon-Vecsei Z, Király R, Bagossi P, Tóth B, Dahlbom I, Caja S et al (2012) A single conformational transglutaminase 2 epitope contributed by three domains is critical for celiac antibody binding and effects. Proc Natl Acad Sci U S A 109(2):431–436 Lindfors K, Koskinen O, Kurppa K, Laurila K, Collin P, Haimila K et al (2011) Serodiagnostic assays for celiac disease based on the open or closed conformation of the autoantigen, transglutaminase 2. J Clin Immunol 31(3):436–442 Byrne G, Ryan F, Jackson J, Feighery C, Kelly J (2007) Mutagenesis of the catalytic triad of tissue transglutaminase abrogates coeliac disease serum IgA autoantibody binding. Gut 56(3):336–341 Marzari R, Sblattero D, Florian F, Tongiorgi E, Not T, Tommasini A et al (2001) Molecular dissection of the tissue transglutaminase autoantibody response in celiac disease. J Immunol 166(6):4170–4176 Sollid LM, Molberg O, McAdam S, Lundin KEA (1997) Autoantibodies in coeliac disease: tissue transglutaminase—guilt by association? Gut 41(6):851–852 Björck S, Brundin C, Lorinc E, Lynch KF, Agardh D (2010) Screening detects a high proportion of celiac disease in young HLA-genotyped children. J Pediatr Gastroenterol Nutr 50(1):49–53 Korponay-Szabo IR, Vecsei Z, Kiraly R, Dahlbom I, Chirdo F, Nemes E et al (2008) Deamidated gliadin peptides form epitopes that transglutaminase antibodies recognize. J Pediatr Gastroenterol Nutr 46(3):253–261 Fleckenstein B, Qiao SW, Larsen MR, Jung G, Roepstorff P, Sollid LM (2004) Molecular characterization of covalent complexes between tissue transglutaminase and gliadin peptides. J Biol Chem 279(17):17607–17616 Dieterich W, Esslinger B, Trapp D, Hahn E, Huff T, Seilmeier W et al (2006) Cross linking to tissue transglutaminase and collagen favours gliadin toxicity in coeliac disease. Gut 55(4):478–484 Pabst O, Mowat AM (2012) Oral tolerance to food protein. Mucosal Immunol 5(3):232–239 Ráki M, Tollefsen S, Molberg O, Lundin KEA, Sollid LM, Jahnsen FL (2006) A unique dendritic cell subset accumulates in the celiac lesion and efficiently activates gluten-reactive T cells. Gastroenterology 131(2):428–438 Beitnes A-CR, Ráki M, Lundin KEA, Jahnsen J, Sollid LM, Jahnsen FL (2011) Density of CD163+CD11c+ dendritic cells increases and CD103+ dendritic cells decreases in the coeliac lesion. Scand J Immunol 74(2):186–194 Smythies LE, Maheshwari A, Clements R, Eckhoff D, Novak L, Vu HL et al (2006) Mucosal IL-8 and TGF-beta recruit blood monocytes: evidence for cross-talk between the lamina propria stroma and myeloid cells. J Leukoc Biol 80(3):492–499 Grimm MC, Pullman WE, Bennett GM, Sullivan PJ, Pavli P, Doe WF (1995) Direct evidence of monocyte recruitment to inflammatory bowel disease mucosa. J Gastroenterol Hepatol 10(4):387–395 Haniffa M, Ginhoux F, Wang XN, Bigley V, Abel M, Dimmick I et al (2009) Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation. J Exp Med 206(2):371–385 Smith PD, Smythies LE, Mosteller-Barnum M, Sibley DA, Russell MW, Merger M et al (2001) Intestinal macrophages lack CD14 and CD89 and consequently are down-regulated for LPS- and IgA-mediated activities. J Immunol 167:2651–2656 Smythies LE, Sellers M, Clements RH, Mosteller-Barnum M, Meng G, Benjamin WH et al (2005) Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest 115(1):66–75 Smith PD, Smythies LE, Shen R, Greenwell-Wild T, Gliozzi M, Wahl SM (2011) Intestinal macrophages and response to microbial encroachment. Mucosal Immunol 4(1):31–42 Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B (2007) Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 8(10):1086–1094 Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H et al (2009) Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 10(11):1178–1184 Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Auricchio S et al (2003) Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 362(9377):30–37 Tezuka H, Abe Y, Asano J, Sato T, Liu J, Iwata M et al (2011) Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction. Immunity 34(2):247–257 Yrlid U, Cerovic V, Milling S, Jenkins CD, Zhang J, Crocker PR et al (2006) Plasmacytoid dendritic cells do not migrate in intestinal or hepatic lymph. J Immunol 177(9):6115–6121 Jaensson E, Uronen-Hansson H, Pabst O, Eksteen B, Tian J, Coombes JL et al (2008) Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J Exp Med 205(9):2139–2149 Coombes JL, Siddiqui KRR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y et al (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-b and retinoic acid dependent mechanism. J Exp Med 204(8):1757–1764 Iliev ID, Spadoni I, Mileti E, Matteoli G, Sonzogni A, Sampietro GM et al (2009) Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells. Gut 58(11):1481–1489 Varol C, Vallon-Eberhard A, Elinav E, Aychek T, Shapira Y, Luche H et al (2009) Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31(3):502–512 Beitnes A-CR, Ráki M, Brottveit M, Lundin KEA, Jahnsen FL, Sollid LM (2012) Rapid accumulation of CD14+CD11c+ dendritic cells in gut mucosa of celiac disease after in vivo gluten challenge. PLoS One 7(3):e33556 Angel CE, Lala A, Chen CJ, Edgar SG, Ostrovsky LL, Dunbar PR (2007) CD14+ antigen-presenting cells in human dermis are less mature than their CD1a+ counterparts. Int Immunol 19(11):1271–1279 Kamada N, Hisamatsu T, Honda H, Kobayashi T, Chinen H, Kitazume MT et al (2009) Human CD14+ macrophages in intestinal lamina propria exhibit potent antigen-presenting ability. J Immunol 183(3):1724–1731 Rugtveit J, Nilsen EM, Bakka A, Carlsen H, Brandtzaeg P, Scott H (1997) Cytokine profiles differ in newly recruited and resident subsets of mucosal macrophages from inflammatory bowel disease. Gastroenterology 112(5):1493–1505 Cheong C, Matos I, Choi JH, Dandamudi DB, Shrestha E, Longhi MP et al (2010) Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209+ dendritic cells for immune T cell areas. Cell 143(3):416–429 Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL (2001) Plasmacytoid dendritic cells (natural interferon-α/β-producing cells) accumulate in cutaneous lupus erythematosus lesions. Am J Pathol 159(1):237–243 Gregorio J, Meller S, Conrad C, Di Nardo A, Homey B, Lauerma A et al (2010) Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons. J Exp Med 207(13):2921–2930 Jahnsen FL, Moloney ED, Hogan T, Upham JW, Burke CM, Holt PG (2001) Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge. Thorax 56(11):823–826 Verstege MI, ten Kate FJ, Reinartz SM, van Drunen CM, Slors FJ, Bemelman WA et al (2008) Dendritic cell populations in colon and mesenteric lymph nodes of patients with Crohn's disease. J Histochem Cytochem 56(3):233–241 Dillon SM, Rogers LM, Howe R, Hostetler LA, Buhrman J, McCarter MD et al (2010) Human intestinal lamina propria CD1c+ dendritic cells display an activated phenotype at steady state and produce IL-23 in response to TLR7/8 stimulation. J Immunol 184(12):6612–6621 Di Sabatino A, Pickard KM, Gordon JN, Salvati V, Mazzarella G, Beattie RM et al (2007) Evidence for the role of interferon-alfa production by dendritic cells in the Th1 response in celiac disease. Gastroenterology 133(4):1175–1187 Colonna M, Trinchieri G, Liu YJ (2004) Plasmacytoid dendritic cells in immunity. Nat Immunol 5(12):1219–1226 Takenaka S, Safroneeva E, Xing Z, Gauldie J (2007) Dendritic cells derived from murine colonic mucosa have unique functional and phenotypic characteristics. J Immunol 178(12):7984–7993 Cammarota G, Cuoco L, Cianci R, Pandolfi F, Gasbarrini G (2000) Onset of coeliac disease during treatment with interferon for chronic hepatitis C. Lancet 356(9240):1494–1495 Bardella MT, Marino R, Meroni PL (1999) Celiac disease during interferon treatment. Ann Intern Med 131(2):157–158 Monteleone G, Pender SLF, Alstead E, Hauer AC, Lionetti P, MacDonald TT (2001) Role of interferon a in promoting T helper cell type 1 responses in the small intestine in coeliac disease. Gut 48(3):425–429 Adinolfi LE, Durante Mangoni E, Andreana A (2001) Interferon and ribavirin treatment for chronic hepatitis C may activate celiac disease. Am J Gastroenterol 96(2):607–608 Farstad IN, Carlsen H, Morton HC, Brandtzaeg P (2000) Immunoglobulin A cell distribution in the human small intestine: phenotypic and functional characteristics. Immunology 101(3):354–363 Chowers Y, Marsh MN, De GL, Nyberg A, Theofilopoulos AN, Kagnoff MF (1997) Increased proinflammatory cytokine gene expression in the colonic mucosa of coeliac disease patients in the early period after gluten challenge. Clin Exp Immunol 107(1):141–147 Palova-Jelinkova L, Rozkova D, Pecharova B, Bartova J, Sediva A, Tlaskalova-Hogenova H et al (2005) Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J Immunol 175(10):7038–7045 Cinova J, Palová-Jelínková L, Smythies LE, Cerná M, Pecharová B, Dvorák M et al (2007) Gliadin peptides activate blood monocytes from patients with celiac disease. J Clin Immunol 27(2):201–209 Maloy KJ, Powrie F (2011) Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474(7351):298–306 Coombes JL, Maloy KJ (2007) Control of intestinal homeostasis by regulatory T cells and dendritic cells. Semin Immunol 19(2):116–126 Siddiqui KRR, Laffont S, Powrie F (2010) E-cadherin marks a subset of inflammatory dendritic cells that promote T cell-mediated colitis. Immunity 32(4):557–567 Laffont S, Siddiqui KRR, Powrie F (2010) Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells. Eur J Immunol 40(7):1877–1883 DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W et al (2011) Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471:220–224 Rimoldi M, Chieppa M, Salucci V, Avogadri F, Sonzogni A, Sampietro GM et al (2005) Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat Immunol 6(5):507–514