Current concepts of celiac disease pathogenesis Detlef Schuppan  Gastroenterology  Volume 119, Issue 1, Pages 234-242 (July 2000) DOI: 10.1053/gast.2000.8521 Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 1 Celiac disease–associated HLA-DQ2 locus. More than 95% of patients with celiac disease are either heterozygous for DR3 or for DR5 and DR7, encoding HLA-DQ2 in cis or trans, respectively. (Data from Sollid et al.15) Gastroenterology 2000 119, 234-242DOI: (10.1053/gast.2000.8521) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 2 Protein cross-linking by tTG. tTG catalyzes a calcium-dependent glutamyl-lysine transfer that results in irreversible protein cross-linking by an ε-(γ-glutamyl)-lysine bond. Although glutamyl acceptors are numerous, the number of glutamyl donors is limited. Gastroenterology 2000 119, 234-242DOI: (10.1053/gast.2000.8521) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 3 Deamidation can enhance binding of gliadin peptides to HLA-DQ2. tTG can deamidate gliadin peptides that generate acidic, negatively charged glutamic acid residues from neutral glutamines. Because negatively charged residues are preferred in positions 4, 6, and 7 of the antigen-binding grove of HLA-DQ2,44 some of the deamidated gliadin variants may elicit stronger T-cell responses. The underlined E denominates a glutamic acid residue generated by tTG from a deamidated glutamine in vitro.45 H, hydrophobic pocket; −, negatively charged region on HLA-DQ2. Amino acids are depicted in the one-letter code: D, aspartic acid; F, phenylalanine; I, isoleucine; L, leucine; M, methionine; P, proline, Q, glutamine; R, arginine; V, valine; Y, tyrosine; W, tryptophane. Gastroenterology 2000 119, 234-242DOI: (10.1053/gast.2000.8521) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 4 Antigen presentation and generation of IgA antibodies to gliadin and tTG. A B cell serves as an HLA-DQ–positive APC. Gliadin, deamidated gliadin, or a gliadin-tTG complex is swallowed (the monoclonal reactivity of different B-cell clones has been contracted to a single cell, to simplify the illustration), processed intracellularly, and presented to CD4+ helper T cells (pathway a-1, b-1, a-2, b-2, or c-2). The T cells then provide help for production of antibodies to gliadin. Autoantibodies to tTG can be generated when spurious B-cell clones that produce antibodies to tTG present gliadin peptides via HLA-DQ to gliadin-specific CD4+ T cells. The presented gliadin peptides may be generated from the processing of tTG-gliadin complexes, which serve as hapten-carrier complexes. These T cells then provide help for tTG-antibody production (pathway d-1). Alternatively, but still unproven, there may be T cells that recognize tTG or tTG-gliadin cross-links in the context of HLA-DQ, triggering production of the respective antibodies by their B-cell counterparts (pathway d-3 or e-4). Gastroenterology 2000 119, 234-242DOI: (10.1053/gast.2000.8521) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 5 Gliadin as trigger for antibody production and mucosal remodeling. Traces of dietary gliadin reach the lamina propria, especially when mucosal integrity is compromised, as in small intestinal infections or after chemical injury. In genetically predisposed (HLA-DQ2– or HLA-DQ8–positive) individuals, gliadin is presented on professional APCs such as B cells (see Figure 4) macrophages (MΦ) and dendritic cells (DC), which drive T-cell responses toward antibody production (Th2) or toward inflammation and tissue remodeling (Th1). The monoclonal reactivity of different T- and B-cell clones has been contracted to single cells, to simplify the illustration. Th1 cells release TNF, which causes release of MMPs from intestinal fibroblasts. MMP-3 appears to play a central role in tissue remodeling, because it degrades various noncollagenous matrix components and activates MMP-1, which degrades fibrillar collagens. In the inflammatory environment, mononuclear cells and fibroblasts are also the major source of tTG, which further enhances immune activation by gliadin deamidation or cross-linking. Tcyt, cytotoxic T cell. Gastroenterology 2000 119, 234-242DOI: (10.1053/gast.2000.8521) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 6 Potential pathogenic role of tTG autoantibodies. The T84 crypt epithelial cell line spontaneously forms differentiated acinar structures in a fibroblast coculture model. Differentiation is inhibited by addition of blocking antibodies to TGF-β or of IgA purified from the serum of celiac patients. TGF-β can promote epithelial differentiation, and both tTG and plasmin are required to generate active TGF-β from the inactive (latent) TGF-β precursor. Gastroenterology 2000 119, 234-242DOI: (10.1053/gast.2000.8521) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 7 Potential role of γ/δ T cells. Residing in the epithelium, γ/δ T cells are pathognomonic for celiac disease. They recognize bacterial nonpeptide antigens and stress-related proteins. Localized at the interface between the external and internal environment, γ/δ T cells serve as a link between the innate (unspecific) immune system involving monocytes/macrophages, neutrophils, and eosinophils, aimed at limiting the spread of infection, and the acquired immune system involving T and B cells, which target specific antigenic structures. γ/δ T cells secrete chemokines that activate the innate immune system and IL-4, which supports the maturation of Th2 cells. Gastroenterology 2000 119, 234-242DOI: (10.1053/gast.2000.8521) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 8 Triggers and predisposing factors in celiac disease. Gastroenterology 2000 119, 234-242DOI: (10.1053/gast.2000.8521) Copyright © 2000 American Gastroenterological Association Terms and Conditions