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Review
, 62 (10), 641-51

Celiac Disease: How Complicated Can It Get?

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Review

Celiac Disease: How Complicated Can It Get?

Jennifer May-Ling Tjon et al. Immunogenetics.

Abstract

In the small intestine of celiac disease patients, dietary wheat gluten and similar proteins in barley and rye trigger an inflammatory response. While strict adherence to a gluten-free diet induces full recovery in most patients, a small percentage of patients fail to recover. In a subset of these refractory celiac disease patients, an (aberrant) oligoclonal intraepithelial lymphocyte population develops into overt lymphoma. Celiac disease is strongly associated with HLA-DQ2 and/or HLA-DQ8, as both genotypes predispose for disease development. This association can be explained by the fact that gluten peptides can be presented in HLA-DQ2 and HLA-DQ8 molecules on antigen presenting cells. Gluten-specific CD4(+) T cells in the lamina propria respond to these peptides, and this likely enhances cytotoxicity of intraepithelial lymphocytes against the intestinal epithelium. We propose a threshold model for the development of celiac disease, in which the efficiency of gluten presentation to CD4(+) T cells determines the likelihood of developing celiac disease and its complications. Key factors that influence the efficiency of gluten presentation include: (1) the level of gluten intake, (2) the enzyme tissue transglutaminase 2 which modifies gluten into high affinity binding peptides for HLA-DQ2 and HLA-DQ8, (3) the HLA-DQ type, as HLA-DQ2 binds a wider range of gluten peptides than HLA-DQ8, (4) the gene dose of HLA-DQ2 and HLA-DQ8, and finally,(5) additional genetic polymorphisms that may influence T cell reactivity. This threshold model might also help to understand the development of refractory celiac disease and lymphoma.

Figures

Fig. 1
Fig. 1
Prevalence of CD and complicated CD in the Caucasian population. Approximately 25% of the general Caucasian population is HLA-DQ2+. From these genetically susceptible individuals, only 4% develop CD. In majority of the CD patients, the disease course is uncomplicated. Roughly 3% of the CD patients will not respond to a gluten-free diet and develop RCD. A subset of RCD patients develop RCD II of which approximately 50% develop RCD-associated lymphoma (not shown)
Fig. 2
Fig. 2
Self-amplifying loops in the development of CD. HLA-DQ2+ or HLADQ8+ individuals can present native gluten peptides on their APC to CD4+ T cells. The IFN-γ released in this process can in turn boost HLA-DQ2/8 expression. This low-grade inflammation might eventually lead to tissue damage with TG2 release. TG2 is able to expand the presentable gluten peptide repertoire by deamidation. As a result, the CD4+ T cell response is strongly enhanced, leading to more IFN-γ, tissue damage, and increased release of TG2. The end result is full-blown CD
Fig. 3
Fig. 3
Crosstalk between the CD4+ Tcell response and IEL cytotoxicity. The CD4+ T cell response to gluten may lead to IFN-γ production and potentially to upregulation of IL-15, which in turn boosts IEL-mediated cytotoxicity. Activated IELs lyse the epithelium, which leads to TG2 release and subsequent deamidation of gluten peptides. This may constitute yet another self-amplifying feedback loop, as deamidation of gluten peptides will enhance the CD4+ T cell response (see Fig. 2)
Fig. 4
Fig. 4
Threshold model for CD development. As HLA-DQ2.5 homozygous individuals can present more gluten peptides on their APC than HLA-DQ2.5 heterozygous individuals, HLA-DQ2.5 homozygotes have a higher risk of CD development a priori. In steady state conditions, presentation of native gluten peptides is unlikely to induce disease. This steady state can be breached by frequent viral infections and low-grade T cell responses to native gluten peptides that lead to release of TG2 upon tissue damage. TG2 activity will expand the presentable gluten peptide repertoire extensively, thereby increasing the risk to develop CD. The recently uncovered non-HLA genes associated with CD likely lower the threshold to develop CD

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