Abstract
Celiac disease (CeD), defined as gluten-induced enteropathy, is a frequent and largely underdiagnosed disease. Diagnosis relies on the detection of highly specific serum IgA anti-transglutaminase auto-antibodies and on the demonstration of duodenal villous atrophy. Treatment necessitates a strict gluten-free diet, which resolves symptoms and enables histological recovery. However, regular follow-up is necessary to assess mucosal healing, which emerges as an important prognostic factor. Recent work on CeD pathogenesis has highlighted how the cross-talk between gluten-specific CD4 + T cells and interleukin-15 can activate cytotoxic intraepithelial lymphocytes and trigger epithelial lesions. Moreover, acquisition by a subset of intraepithelial lymphocytes of somatic gain-of-function mutations in the JAK-STAT pathway was shown to be a decisive step in the progression toward lymphomas complicating CeD, thus opening new therapeutic perspectives for these rare but life-threatening complications.
Highlights
Celiac disease (CeD) is defined as a chronic immune-mediated small intestinal enteropathy driven by dietary gluten in genetically predisposed individuals carrying HLA-DQ2 or HLA-DQ8
Flow cytometry on intraepithelial lymphocytes (IELs) isolated from intestinal biopsies is useful, especially if the frequency of abnormal IELs is less than 50%, in order to demonstrate the absence of surface CD3 and T-cell receptor (TCR)[13] and the frequent expression of the natural killer (NK) receptor NKP4614
In contrast to RCDI, RCDII is a well-characterized entity that can be defined as a low-grade clonal intraepithelial lymphoproliferation with a high risk of transformation into overt enteropathy-associated T-cell lymphoma (EATL)
Summary
Celiac disease (CeD) is defined as a chronic immune-mediated small intestinal enteropathy driven by dietary gluten in genetically predisposed individuals carrying HLA-DQ2 or HLA-DQ8. In contrast to RCDI, RCDII is a well-characterized entity that can be defined as a low-grade clonal intraepithelial lymphoproliferation with a high risk of transformation into overt enteropathy-associated T-cell lymphoma (EATL) (reviewed in 13) In keeping with their intraepithelial origin, malignant IELs express the αE integrin (CD103), the expression of which may disappear with disease progression, notably in EATL (reviewed in 13 and personal observation). Following work showing that IL-15 provides signals to RCDII IELs which promote their expansion and cytotoxic activation (reviewed in 13,35), we recently showed that RCDII IELs frequently contain somatic JAK1 or STAT3 gain-of-function mutations (or both), which confer hyper-responsiveness to IL-1514 These mutations may promote response to other cytokines present in the intestine of patients with CeD, notably IL-2 and IL-21, which are produced by gluten-activated CD4+ T cells[63]. A recent follow-up study of a cohort of 1138 patients with CeD during 25 years revealed 29 cases of RCD, and seven cases of EATL, but only four cases of small bowel carcinomas[78]
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