Celiac Disease: An Immunological Jigsaw

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Celiac Disease: An Immunological Jigsaw Bertrand Meresse, Georgia Malamut, Nadine Cerf-Bensussan  Immunity  Volume 36, Issue 6, Pages 907-919 (June 2012) DOI: 10.1016/j.immuni.2012.06.006 Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 1 Human Leukocyte Antigen Class II Associations with Celiac Disease and Type 1 Diabetes The majority of CD patients express the HLA-DQ2.5 heterodimer encoded by the HLA-DQA1∗05 (α-chain) and HLA-DQB1∗02 (β-chain) alleles. These two alleles are carried either in cis on the DR3-DQ2.5 haplotype or in trans in individuals who are DR5DQ7 and DR7DQ2 heterozygous. HLA-DQ8 that is encoded by the DR4DQ8 haplotype confers a lesser risk of CD. In individuals who are DR3DQ2.5 and DR4DQ8 heterozygous, transdimers DQ8.5 can form and confer high susceptibility to TID. Immunity 2012 36, 907-919DOI: (10.1016/j.immuni.2012.06.006) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 2 Activation of Gluten-Specific CD4+ T Cell Responses by HLA-DQ2.5 Molecule Transglutaminase 2 (TG2) binds to and deamidates glutamine residues in Q-X-P sequences of gluten peptides into glutamic acid, introducing a negative charge that can interact with a positively charged lysine residue in position 6 of the peptide pocket of HLA-DQ2.5, resulting in enhanced peptide avidity for HLA-DQ2.5. HLA-DQ2.5-gluten peptide complexes expressed on antigen-presenting cells (APCs) can prime gluten-specific CD4 T cells. As for other dietary antigens, priming may occur in Peyer's patches or in mesenteric lymph nodes after migration of CD103+ dendritic cells loaded with gluten peptides in lamina propria (Worbs et al., 2006). Unusual priming outside the gut has however been reported in HLA-DQ2 mice (Du Pré et al., 2011). Priming is followed by selection and clonal expansion of T cells diplaying high-avidity TCR (Qiao et al., 2011). Immunity 2012 36, 907-919DOI: (10.1016/j.immuni.2012.06.006) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 3 Hypothetical Role of Non-HLA CD-Associated Genes in Immune Responses Non-HLA loci associated with CD are enriched in genes predicted to control T cell activation (TCR signaling, antigen presentation, and recruitment differentiation into effector cells) and B cell help. Loci specific for CD are in red. Those shared with other autoimmune diseases (including T1D) are in black. Hypothetical groups of genes that may participate in T cell activation, T cell cytotoxicity, IL-21 production, and IgA response, are shown. The possible interplay between IL-21 and IL-15 in tissue damage is suggested (see also Figure 4 and text). Immunity 2012 36, 907-919DOI: (10.1016/j.immuni.2012.06.006) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 4 Hypothetic Scheme of Immune Responses in CD As shown on the left, the B cell response. IgA-producing B cells primed in gut-associated lymphoid tissue (GALT, center) migrate into LP and differentiate into plasma cells, which produce dimeric IgA released into the intestinal lumen as secretory IgA. In active CD, SIgA-gluten complexes formed in the intestinal lumen can bind the CD71 receptor up-regulated at the apical surface of enterocytes, resulting in their rapid retro-transport into LP. Binding of SIgA to CD71 may also activate signal transduction into epithelial cells. These mechanisms may exacerbate immune responses. Intestinal dimeric IgA can be released into blood and participate in extra-intestinal autoimmunity, notably in dermatitis herpertiformis (see text). As shown on the right, the T cell response. In active CD, IL-15, produced by enterocytes and LP dendritic cells and macrophages, favors the activation of IFN-γ-producing and cytotoxic CD8+ IELs harboring NK cell receptors. Gluten-specific CD4+ T cells may participate in IEL activation via cross-priming or via the production of IL-21 that synergizes with IL-15 to activate cytotoxic CD8+ T cells. In the presence of IL-15, CD8-T IELs can induce epithelial lesions via the interactions of their NK receptors NKG2D and NKG2C with their respective ligands MICA and HLA-E upregulated on enterocytes. IL-15 and IL-21 may also cooperate and enable autoreactive CD8+ T cells to respond to weakly agonistic TCR self-ligands (bottom right). IL-15 then favors accumulation of activated CD8+ T cells by stimulating their survival and inhibiting their responses to immunoregulatory mechanisms, further increasing the risk of developing T-dependent autoimmune diseases (T1D), thyroiditis, and perhaps type I refractory celiac disease (RCDI). Finally, IL-15 can promote the emergence of unusual IEL-derived T lymphomas sharing characteristics of both NK and T cells and able to drive epithelial lesions. Onset of lymphoma is revealed by refractoriness to the gluten-free-diet. In a majority of patients, the lymphoma is first intraepithelial (type II refractory celiac disease [RCDII]) and can secondarily transform into overt enteropathy-associated type T lymphoma (EATL). Immunity 2012 36, 907-919DOI: (10.1016/j.immuni.2012.06.006) Copyright © 2012 Elsevier Inc. Terms and Conditions