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• W2038884625 abstract "Celiac disease is characterized by small intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals following the dietary ingestion of “gluten.” The pathogenesis of disease involves interactions between environmental, genetic, and immunologic factors.1Kagnoff M.F. Celiac disease A gastrointestinal disease with environmental, genetic, and immunologic components.Gastroenterol Clin North Am. 1992; 21: 405-425Abstract Full Text PDF PubMed Google Scholar This brief overview of celiac disease and its pathogenesis is designed to place this disease, and current views of its pathogenesis, in a context appropriate for further consideration within the framework of questions being posed by the NIH Consensus Conference on Celiac Disease.Pathology and clinical symptomsFirst, a brief overview of disease pathology and clinical symptoms. The luminal surface of a small intestinal mucosal biopsy specimen from a healthy subject and an individual with celiac disease with total villous atrophy, as viewed through a dissecting microscope, are shown in Figure 1A and 1B, respectively. The normal biopsy specimen shows abundant villi (looking much like the shag household carpets of a prior era), whereas the biopsy specimen from the patient with celiac disease shows a complete loss of villi, with a flat mucosal surface accentuated by ridges and numerous openings of the crypts onto the luminal surface. Microscopic analysis of a normal H&E-stained, small intestinal mucosal biopsy specimen is shown in Figure 1C. Characteristic features include tall villi lined by a single layer of columnar epithelial cells with basally oriented nuclei, a “smattering” of intraepithelial lymphocytes (IEL) occurring at a ratio of approximately 1 per 6–10 epithelial cells, a normal complement of lymphocytes and plasma cells in the lamina propria consistent with the normal “physiologic inflammation” of the small intestine, and a villous to crypt ratio of ∼4–5:1. Contrast that biopsy specimen with the biopsy specimen from a celiac disease patient with total villous atrophy as shown in Figure 1D. The latter reveals a complete loss of villi, markedly abnormal squamoid surface epithelial cells, an increase in intraepithelial lymphocytes, a chronic lymphocyte and plasma cell infiltrate in the lamina propria, and marked crypt hyperplasia with increased crypt mitoses. The pathology shown in this celiac biopsy specimen reflects the more severe end of the pathologic spectrum of disease, which, as indicated in Figure 2, can vary markedly among affected individuals.Figure 2Spectrum of pathology and malabsorption in celiac disease. The extent of the mucosal abnormality can vary markedly in celiac disease. Consistent with this, the extent of nutrient malabsorption also varies from minimal to severe.View Large Image Figure ViewerDownload (PPT)Just as the pathology can vary markedly among patients, so can the spectrum of clinical symptoms, which can range from severe to subtle (Figure 3). The proportion of individuals presenting with more dramatic symptoms of diarrhea, severe weight loss, and malnutrition is decreasing when compared with those presenting with mild or minimal symptoms or asymptomatic individuals in which disease is discovered only when investigating nongastrointestinal symptoms, for example, iron deficiency anemia or osteopenia.2Lo W. Sano K. Lebwohl B. Diamond B. Green P.H. Changing presentation of adult celiac disease.Dig Dis Sci. 2003; 48: 395-398Crossref PubMed Scopus (208) Google Scholar A more detailed explanation of the clinical presentation of celiac disease in children and adults is presented in later articles in this series.Figure 3Spectrum of symptoms in celiac disease. Consistent with the marked variability in the extent of disease, the spectrum of symptoms varies markedly in individuals with celiac disease.View Large Image Figure ViewerDownload (PPT)Pathogenesis of celiac diseaseEnvironmental, genetic, and immunologic factors, some of which are clear and others that are only now beginning to come into focus, are important in the pathogenesis of celiac disease.1Kagnoff M.F. Celiac disease A gastrointestinal disease with environmental, genetic, and immunologic components.Gastroenterol Clin North Am. 1992; 21: 405-425Abstract Full Text PDF PubMed Google Scholar, 3Kagnoff M.F. Coeliac disease genetic, immunological and environmental factors in disease pathogenesis.Scand J Gastroenterol Suppl. 1985; 114: 45-54Crossref PubMed Scopus (17) Google Scholar, 4Kagnoff M.F. Immunopathogenesis of celiac disease.Immunol Invest. 1989; 18: 499-508Crossref PubMed Scopus (12) Google Scholar, 5Kagnoff M.F. Understanding the molecular basis of coeliac disease.Gut. 1990; 31: 497-499Crossref PubMed Scopus (34) Google Scholar, 6Kagnoff M.F. Celiac disease pathogenesis the plot thickens.Gastroenterology. 2002; 123: 939-943Abstract Full Text Full Text PDF PubMed Scopus (13) Google ScholarEnvironmental factorsProteins in the dietary cereal grains wheat, rye, and barley are the major known environmental factors that are required for disease activation. Collectively, the disease-activating proteins in wheat, rye, and barley are widely termed “gluten.” Strictly speaking however, gluten is the scientific name for only the disease-activating proteins in wheat. Gluten itself contains 2 major protein fractions, the gliadins and the glutenins, both of which contain disease-activating proteins.7van de Wal Y. Kooy Y.M. van Veelen P. Vader W. August S.A. Drijfhout J.W. Pena S.A. Koning F. Glutenin is involved in the gluten-driven mucosal T cell response.Eur J Immunol. 1999; 29: 3133-3139Crossref PubMed Scopus (166) Google Scholar, 8Molberg O. Solheim Flaete N. Jensen T. Lundin K.E. Arentz-Hansen H. Anderson O.D. Kjersti Uhlen A. Sollid L.M. Intestinal T-cell responses to high-molecular-weight glutenins in celiac disease.Gastroenterology. 2003; 125: 337-344Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar The closely related proteins in barley and rye that activate disease are termed hordeins and secalins, respectively.9Shewry P.R. Tatham A.S. Kasarda D.D. Cereal proteins and coeliac disease.in: Marsh M.N. Coeliac disease. Blackwell Scientific Publications, London1992: 305-342Google Scholar, 10Kasarda D.D. Gluten and gliadin precipitating factors in coeliac disease.in: Maki M. Collin P. Visakorpi J.K. Coeliac disease. Coeliac Study Group Institute of Medical Technology, Tampere, Finland1997: 195-212Google Scholar Wheat, rye, and barley have a common ancestral origin in the grass family. Oats, which only rarely, if at all, activates celiac disease, and then only in a small fraction of patients,11Janatuinen E.K. Kemppainen T.A. Julkunen R.J. Kosma V.M. Maki M. Heikkinen M. Uusitupa M.I. No harm from five-year ingestion of oats in coeliac disease.Gut. 2002; 50: 332-335Crossref PubMed Scopus (236) Google Scholar, 12Hogberg L. Laurin P. Falth-Magnusson K. Grant C. Grodzinsky E. Jansson G. Ascher H. Browaldh L. Hammersjo J.A. Lindberg E. Myrdal U. Stenhammar L. Oats to children with newly diagnosed coeliac disease a randomised double blind study.Gut. 2004; 53: 649-654Crossref PubMed Scopus (130) Google Scholar is more distantly related to wheat, rye, and barley, whereas proteins in rice, maize, sorghum, and millet are still more distantly related and do not activate celiac disease (Figure 4).9Shewry P.R. Tatham A.S. Kasarda D.D. Cereal proteins and coeliac disease.in: Marsh M.N. Coeliac disease. Blackwell Scientific Publications, London1992: 305-342Google Scholar, 10Kasarda D.D. Gluten and gliadin precipitating factors in coeliac disease.in: Maki M. Collin P. Visakorpi J.K. Coeliac disease. Coeliac Study Group Institute of Medical Technology, Tampere, Finland1997: 195-212Google ScholarFigure 4Taxonomy of some dietary grains. Wheat, barley, and rye, which contain gluten, hordein, and secalin, respectively, are derived from the Triticaeae tribe of the grass (Gramilneae) family. In contrast, oats, which contains few disease-activating proteins, is more distantly related as are rice, maize, sorghum, and millet.View Large Image Figure ViewerDownload (PPT)The very high glutamine and proline content in the gliadins and glutenins of wheat, as well as in the hordeins and secalins, plays a key role in disease pathogenesis (Figure 5). The high proline content renders these proteins relatively resistant to proteolytic digestion by gastric, pancreatic, and brush border enzymes in the human intestine. This results in the generation and presence of relatively large peptides, with a high proline and glutamine content in the small intestine. However, this alone does not seem sufficient to cause disease because, currently, there is no known difference in protein digestion between healthy individuals and those susceptible to developing celiac disease. Nonetheless, it is conceivable that the failure to degrade these proteins may be exaggerated in the small intestine of individuals with active disease who have marked epithelial cell brush border injury and in those with accompanying pancreatic dysfunction. Interestingly, prolyl endopeptidases produced by bacteria can digest these proline-rich gluten peptides, and treatment with such enzymes has been suggested as a possible therapeutic adjunct to the standard “gluten” free diet13Hausch F. Shan L. Santiago N.A. Gray G.M. Khosla C. Intestinal digestive resistance of immunodominant gliadin peptides.Am J Physiol Gastrointest Liver Physiol. 2002; 283: G996-G1003Crossref PubMed Scopus (296) Google Scholar, 14Shan L. Molberg O. Parrot I. Hausch F. Filiz F. Gray G.M. Sollid L.M. Khosla C. Structural basis for gluten intolerance in celiac sprue.Science. 2002; 297: 2275-2279Crossref PubMed Scopus (1239) Google Scholar (hereafter, I will use “gluten” and “gluten” peptides to refer to the disease-activating proteins and peptides in wheat, rye, and barley).Figure 5Proteins that activate celiac disease are rich in glutamine and proline residues. The proteins in wheat, rye, and barley that activate celiac disease are characterized by a high content of glutamine (Q) and proline (P) as seen in this example, which is the primary amino acid sequence of an α gliadin (A-gliadin). This is only one of many different α gliadins present in wheat.View Large Image Figure ViewerDownload (PPT)Genetic factors: HLA class II genes and tissue transglutaminaseGenetics clearly play a key role in the pathogenesis of celiac disease. This was first appreciated from clinical observations indicating an ∼5%–15% prevalence of multiple cases of celiac disease within affected families and the striking ∼70%–75% concordance of celiac disease among monozygotic twin pairs.15Greco L. Romino R. Coto I. Di Cosmo N. Percopo S. Maglio M. Paparo F. Gasperi V. Limongelli M.G. Cotichini R. D’Agate C. Tinto N. Sacchetti L. Tosi R. Stazi M.A. The first large population based twin study of coeliac disease.Gut. 2002; 50: 624-628Crossref PubMed Scopus (347) Google Scholar It is unequivocal that celiac disease is strongly associated with specific HLA class II genes that map to the DQ locus.16Kagnoff M.F. HLA genes in coeliac disease.in: Auricchio S.G.L. Maiuri L. Troncone R. Coeliac disease. JCG Editions, Naples, Italy2000: 5-14Google Scholar The presence of specific alleles at the HLA-DQ locus appears to be necessary, although not sufficient, for the phenotypic expression of disease in virtually all individuals, with few if any exceptions.17Karell K. Louka A.S. Moodie S.J. Ascher H. Clot F. Greco L. Ciclitira P.J. Sollid L.M. Partanen J. 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. 2003; 64: 469-477Crossref PubMed Scopus (470) Google Scholar, 18Margaritte-Jeannin P. Babron M.C. Bourgey M. Louka A.S. Clot F. Percopo S. Coto I. Hugot J.P. Ascher H. Sollid L.M. Greco L. Clerget-Darpoux F. HLA-DQ relative risks for coeliac disease in European populations a study of the European Genetics Cluster on Coeliac Disease.Tissue Antigens. 2004; 63: 562-567Crossref PubMed Scopus (161) Google Scholar As shown in the Venn diagram in Figure 6, alleles that code for a specific HLA-DQ2 or -DQ8 heterodimer are relatively common in white populations. Moreover, HLA-DQ2 or -DQ8 is present in close to all individuals diagnosed correctly with celiac disease. The DQ2 heterodimer that confers celiac disease susceptibility is formed by a β chain encoded by the allele DQB1*02 (either DQB1*0201 or *0202) and an α chain encoded by the allele DQA1*05. DQ2 is present in approximately 90%–95% or more of celiac disease patients.16Kagnoff M.F. HLA genes in coeliac disease.in: Auricchio S.G.L. Maiuri L. Troncone R. Coeliac disease. JCG Editions, Naples, Italy2000: 5-14Google Scholar The HLA-DQ8-associated heterodimer is formed by a β chain and α chain encoded by DQB1*0302 and DQA1*03, respectively, and is present in the remaining 5%–10% of patients.18Margaritte-Jeannin P. Babron M.C. Bourgey M. Louka A.S. Clot F. Percopo S. Coto I. Hugot J.P. Ascher H. Sollid L.M. Greco L. Clerget-Darpoux F. HLA-DQ relative risks for coeliac disease in European populations a study of the European Genetics Cluster on Coeliac Disease.Tissue Antigens. 2004; 63: 562-567Crossref PubMed Scopus (161) Google Scholar, 19Louka A.S. Sollid L.M. HLA in coeliac disease unraveling the complex genetics of a complex disorder.Tissue Antigens. 2003; 61: 105-117Crossref PubMed Scopus (151) Google Scholar, 20Mazzarella G. Maglio M. Paparo F. Nardone G. Stefanile R. Greco L. van de Wal Y. Kooy Y. Koning F. Auricchio S. Troncone R. An immunodominant DQ8 restricted gliadin peptide activates small intestinal immune response in in vitro cultured mucosa from HLA-DQ8 positive but not HLA-DQ8 negative coeliac patients.Gut. 2003; 52: 57-62Crossref PubMed Scopus (74) Google ScholarFigure 6Venn diagram depicting the distribution of DQ2 and DQ8 in the general population and in celiac disease. HLA DQ2 and DQ8 are common in the general population, but, as shown, with few if any exceptions, patients with celiac disease carry the HLA class II alleles DQB1*02 and DQA1*05, which codes for the celiac disease-associated DQ heterodimer, or DQB1*0302 and DQA1*03, which codes for DQ8.View Large Image Figure ViewerDownload (PPT)The DQ2 susceptibility alleles can be inherited either in cis (ie, on 1 chromosome) or in trans, 1 DQ allele coming from a chromosome of each parent (Figure 7). Individuals who in past years were typed as DR3 by serology (or more recently as DR17) carry these alleles in cis, whereas those who type as heterozygous for DR5 (more recently termed DR11 or DR12) and DR 7 by serology carry these alleles in trans. However, in both cases, the relevant antigen-presenting cells of these individuals express the disease-related DQ2 heterodimer.21Kagnoff M.F. Harwood J.I. Bugawan T.L. Erlich H.A. Structural analysis of the HLA-DR, -DQ, and -DP alleles on the celiac disease-associated HLA-DR3 (DRw17) haplotype.Proc Natl Acad Sci U S A. 1989; 86: 6274-6278Crossref PubMed Scopus (93) Google Scholar, 22Sollid L.M. Thorsby E. The primary association of celiac disease to a given HLA-DQ α/β heterodimer explains the divergent HLA-DR associations observed in various Caucasian populations.Tissue Antigens. 1990; 36: 136-137Crossref PubMed Scopus (66) Google Scholar In individuals who are DR3 homozygous, all of the DQ molecules are DQ2; in those heterozygous for DR3(DR17)/17, ∼50% of the DQ molecules are DQ2, and, in those who are heterozygous for DR5/7 or DR3(DR17)/other, ∼25% of the DQ molecules are DQ2.23Vader W. Stepniak D. Kooy Y. Mearin L. Thompson A. van Rood J.J. Spaenij L. Koning F. 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. 2003; 100: 12390-12395Crossref PubMed Scopus (297) Google Scholar Celiac disease is much more prevalent in those in whom 100% or ∼50% of the DQ molecules are DQ2 than in those having ∼25% of the DQ molecules as DQ2.18Margaritte-Jeannin P. Babron M.C. Bourgey M. Louka A.S. Clot F. Percopo S. Coto I. Hugot J.P. Ascher H. Sollid L.M. Greco L. Clerget-Darpoux F. HLA-DQ relative risks for coeliac disease in European populations a study of the European Genetics Cluster on Coeliac Disease.Tissue Antigens. 2004; 63: 562-567Crossref PubMed Scopus (161) Google Scholar, 23Vader W. Stepniak D. Kooy Y. Mearin L. Thompson A. van Rood J.J. Spaenij L. Koning F. 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. 2003; 100: 12390-12395Crossref PubMed Scopus (297) Google Scholar, 24Ploski R. Ek J. Thorsby E. Sollid L.M. On the HLA-DQ(α 1*0501, β 1*0201)-associated susceptibility in celiac disease a possible gene dosage effect of DQB1*0201.Tissue Antigens. 1993; 41: 173-177Crossref PubMed Scopus (153) Google Scholar, 25Louka A.S. Nilsson S. Olsson M. Talseth B. Lie B.A. Ek J. Gudjonsdottir A.H. Ascher H. Sollid L.M. 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. 2002; 60: 147-154Crossref PubMed Scopus (45) Google Scholar Thus, although perhaps only 2% of the population is homozygous for DR3(DR17) (ie, the group with all of their DQ alleles being DQB1*0201 and DQB1*0501), this group may account for as many as 25% of all celiac patients. Nonetheless, once celiac disease develops, the clinical course is similar in those homozygous for DR3(DR17) or heterozygous for DR3(17)/7, DR5/7, or DR3(17)/other. Interestingly, and consistent with the known DQ genetics of disease susceptibility, celiac disease is rare in Japan where the disease-associated DQ alleles are also rare in the population.Figure 7Two ways to inherit the DQ2 heterodimer associated with celiac disease. DR17 haplotypes (formerly termed DR3) carry in cis (ie, on the same chromosome) the DQ alleles B1*0201, which encodes a β chain, and A1*05, which encodes an α chain. The β and α chain form a DQ heterodimer that is associated with celiac disease. DR7 haplotypes carry the very closely related DQB1*0202 allele on 1 chromosome. If the other chromosome carries a DR 11 or 12 haplotype (formerly termed DR5) that has the DQA1*05 allele, the β and α chains encoded by those alleles can pair in the cell and form the disease-associated DQ2 heterodimer. Please note that, if an individual is homozygous for DR17, or heterozygous for DR17/DR7, 100% and 50%, respectively, of their DQ molecules can be the celiac disease-associated HLA-DQ2.View Large Image Figure ViewerDownload (PPT)Extensive searches for additional genes associated with celiac disease have used genome-wide screening approaches. Candidate genetic regions have been identified, although with significantly weaker associations to disease than genes at the DQ locus, and the putative susceptibility genes involved at those loci and the possible mechanisms by which they may contribute to disease currently remain unknown.26Zhong F. McCombs C.C. Olson J.M. Elston R.C. Stevens F.M. McCarthy C.F. Michalski J.P. An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland.Nat Genet. 1996; 14: 329-333Crossref PubMed Scopus (164) Google Scholar, 27Greco L. Corazza G. Babron M.C. Clot F. Fulchignoni-Lataud M.C. Percopo S. Zavattari P. Bouguerra F. Dib C. Tosi R. Troncone R. Ventura A. Mantavoni W. Magazzu G. Gatti R. Lazzari R. Giunta A. Perri F. Iacono G. Cardi E. de Virgiliis S. Cataldo F. De Angelis G. Musumeci S. Ferrari R. Balli F. Bardella M.T. Volta U. Catassi C. Torre G. Eliaou J.F. Serre J.L. Clerget-Darpoux F. Genome search in celiac disease.Am J Hum Genet. 1998; 62: 669-675Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 28Naluai A.T. Nilsson S. Gudjonsdottir A.H. Louka A.S. Ascher H. Ek J. Hallberg B. Samuelsson L. Kristiansson B. Martinsson T. Nerman O. Sollid L.M. Wahlstrom J. Genome-wide linkage analysis of Scandinavian affected sib-pairs supports presence of susceptibility loci for celiac disease on chromosomes 5 and 11.Eur J Hum Genet. 2001; 9: 938-944Crossref PubMed Scopus (84) Google Scholar, 29Greco L. Babron M.C. Corazza G.R. Percopo S. Sica R. Clot F. Fulchignoni-Lataud M.C. Zavattari P. Momigliano-Richiardi P. Casari G. Gasparini P. Tosi R. Mantovani V. De Virgiliis S. Iacono G. D’Alfonso A. Selinger-Leneman H. Lemainque A. Serre J.L. Clerget-Darpoux F. Existence of a genetic risk factor on chromosome 5q in Italian coeliac disease families.Ann Hum Genet. 2001; 65: 35-41Crossref PubMed Scopus (81) Google Scholar, 30Liu J. Juo S.H. Holopainen P. Terwilliger J. Tong X. Grunn A. Brito M. Green P. Mustalahti K. Maki M. Gilliam T.C. Partanen J. Genomewide linkage analysis of celiac disease in Finnish families.Am J Hum Genet. 2002; 70: 51-59Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 31Van Belzen M.J. Meijer J.W. Sandkuijl L.A. Bardoel A.F. Mulder C.J. Pearson P.L. Houwen R.H. Wijmenga C. A major non-HLA locus in celiac disease maps to chromosome 19.Gastroenterology. 2003; 125: 1032-1041Abstract Full Text Full Text PDF PubMed Scopus (124) Google ScholarActivation of DQ restricted mucosal T cellsHow do HLA-DQ2 or -DQ8 play a role in the pathogenesis of celiac disease? These comments will largely focus on the DQ2 heterodimer encoded by DQB1*02 and DQA1*05, although similar considerations likely apply also to the closely related DQ8 heterodimer. HLA class II molecules are expressed on the surface of antigen-presenting cells where they can bind and subsequently present “foreign” peptides encountered in the extracellular environment to populations of CD4 T cells that recognize the DQ2- or DQ8-peptide complex. The peptides that bind to DQ2 or DQ8 in the case of celiac disease are presumed to be glutamine/proline-rich peptides that remain following the intestinal digestion of dietary “gluten”20Mazzarella G. Maglio M. Paparo F. Nardone G. Stefanile R. Greco L. van de Wal Y. Kooy Y. Koning F. Auricchio S. Troncone R. An immunodominant DQ8 restricted gliadin peptide activates small intestinal immune response in in vitro cultured mucosa from HLA-DQ8 positive but not HLA-DQ8 negative coeliac patients.Gut. 2003; 52: 57-62Crossref PubMed Scopus (74) Google Scholar, 32Lundin K.E. Sollid L.M. Qvigstad E. Markussen G. Gjertsen H.A. Ek J. Thorsby E. T lymphocyte recognition of a celiac disease-associated cis- or trans-encoded HLA-DQ α/β-heterodimer.J Immunol. 1990; 145: 136-139PubMed Google Scholar, 33Lundin 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. 1994; 41: 285-291Crossref PubMed Scopus (146) Google Scholar, 34Johansen B.H. Jensen T. Thorpe C.J. Vartdal F. Thorsby E. Sollid L.M. Both α and β chain polymorphisms determine the specificity of the disease-associated HLA-DQ2 molecules, with β chain residues being most influential.Immunogenetics. 1996; 45: 142-150Crossref PubMed Scopus (37) Google Scholar (Figure 8). However, this assumed pathway seemed an enigma for several years because “gluten” peptides largely lack the negatively charged amino acids that are preferred for binding to the disease-associated DQ2 or DQ8 heterodimers and, in the absence of binding, are unlikely to activate disease-relevant CD4 T cells. This dilemma was solved after the discovery that patients with celiac disease have autoantibodies to tissue transglutaminase.35Dieterich W. Ehnis T. Bauer M. Donner P. Volta U. Riecken E.O. Schuppan D. Identification of tissue transglutaminase as the autoantigen of celiac disease.Nat Med. 1997; 3: 797-801Crossref PubMed Scopus (1773) Google Scholar Investigators quickly recognized that tissue transglutaminase, which the antibodies are directed against, can deamidate glutamine, converting glutamine to negatively charged glutamic acid (Figure 9), in addition to its more common property of cross-linking proteins by forming isopeptide bonds between glutamine and lysine residues.36Molberg O. McAdam S.N. Korner R. Quarsten H. Kristiansen C. Madsen L. Fugger L. Scott H. Noren O. Roepstorff P. Lundin K.E. Sjostrom H. Sollid L.M. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease.Nat Med. 1998; 4: 713-717Crossref PubMed Scopus (972) Google Scholar, 37Fleckenstein B. Molberg O. Qiao S.W. Schmid D.G. von der Mulbe F. Elgstoen K. Jung G. Sollid L.M. 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: 34109-34116Crossref PubMed Scopus (197) Google Scholar, 38Fleckenstein B. Qiao S.W. Larsen M.R. Jung G. Roepstorff P. Sollid L.M. Molecular characterization of covalent complexes between tissue transglutaminase and gliadin peptides.J Biol Chem. 2004; 279: 17607-17616Crossref PubMed Scopus (133) Google Scholar Further studies revealed that tissue transglutaminase acts on only selected glutamines within the glutamine/proline-rich gluten peptides and that some “gluten” peptides became better binders to the disease relevant DQ2 or DQ8 molecules after the deamidation.36Molberg O. McAdam S.N. Korner R. Quarsten H. Kristiansen C. Madsen L. Fugger L. Scott H. Noren O. Roepstorff P. Lundin K.E. Sjostrom H. Sollid L.M. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease.Nat Med. 1998; 4: 713-717Crossref PubMed Scopus (972) Google Scholar, 39van de Wal Y. Kooy Y. van Veelen P. Pena S. Mearin L. Papadopoulos G. Koning F. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity.J Immunol. 1998; 161: 1585-1588PubMed Google Scholar Once bound to DQ2 or DQ8, the DQ-“gluten” peptide complexes were shown to activate DQ2 or DQ8 restricted T cells, respectively, that could be isolated from the small intestinal mucosa of patients with celiac disease. The activated T cells were found to produce mainly Th1 type cytokines, most notably γ-interferon. Of note, such T cells were not found in the intestinal mucosa of individuals without celiac disease, who, nonetheless, also have the relevant disease-associated DQ heterodimer.Figure 8DQ2 heterodimers on the surface of antigen-presenting cells bind “gluten” peptides. HLA class II molecules that are expressed on the cell surface of antigen-presenting cells (eg, macrophages, dendritic cells, B cells) bind foreign peptides encountered extracellularly. DQ2 and DQ8 are well suited to bind peptides of “gluten,” particularly if they contain deamidated glutamine residues.View Large Image Figure ViewerDownload (PPT)Figure 9Treatment of gluten peptides with tissue transglutaminase deamidates selected glutamine residues. Treatment of “gluten” peptides with tissue transglutaminase results in the conversion of glutamine (Q) residues with a neutral charge to glutamic acid (E) residues with a negative charge. This renders those peptides better binders to DQ2 or DQ8. Shown are examples of sites of glutamine deamidation that occur in 2 gluten peptides that can bind to DQ2 and a gluten peptide that can bind to DQ8.View Large Image Figure ViewerDownload (PPT)What makes DQ2 special for the binding of disease-activating “gluten” peptides?With the crystallization of a DQ2 molecule containing a deamidated gluten peptide in the peptide-binding groove, studies of DQ2 and its interaction with “gluten” peptides that activate host CD4 T cells present in the intestinal mucosa progressed to a more precise level of structural definition (Figure 10).40Arentz-Hansen H. McAdam S.N. Molberg O. Fleckenstein B. Lundin K.E. Jorgensen T.J. Jung G. Roepstorff P. Sollid L.M. Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues.Gastroenterology. 2002; 123: 803-809Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 41Kim C.Y. Quarsten H. Bergseng E. Khosla C. Sollid L.M. Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease.Proc Natl Acad Sci U S A. 2004; 101: 4175-4179Crossref PubMed Scopus (360) Google Scholar This has provided additional insights into the specialized characteristics of DQ2, which allow it to bind proline-rich “gluten” peptides that contain deamidated glutamine residues. One unique feature of the DQ2 molecule is the presence of several “pockets” that favor binding of negatively charged residues, such as those found in gluten peptides, when glutamine is deamidated to glutamic acid. In addition, DQ2, like other MHC class II molecules, favors binding peptides with a left-handed polyproline II helical configuration, which is characteristic of these gliadins peptides.10Kasarda D.D. Gluten and gliadin precipitating factors in coeliac disease.in: Maki M. Collin P. Visakorpi J.K. Coeliac disease. Coeliac Study Group Institute of Medical Technology," @default.
• W2038884625 created "2016-06-24" @default.
• W2038884625 creator A5090690603 @default.
• W2038884625 date "2005-04-01" @default.
• W2038884625 modified "2023-09-24" @default.
• W2038884625 title "Overview and pathogenesis of celiac disease" @default.
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