Immunopathogenesis and environmental triggers in coeliac disease

Abstract

Coeliac disease (CD) is a frequent immune enteropathy induced by gluten in genetically predisposed individuals. Its pathogenesis has been extensively studied and CD has emerged as a model disease to decipher how the interplay between environmental and genetic factors can predispose to autoimmunity and promote lymphomagenesis. The keystone event is the activation of a gluten-specific immune response that is driven by molecular interactions between gluten, the indispensable environmental factor, HLA-DQ2/8, the main predisposing genetic factor and transglutaminase 2, the CD-specific autoantigen. The antigluten response is however not sufficient to induce epithelial damage which requires the activation of cytotoxic CD8+ intraepithelial lymphocytes (IEL). In a plausible scenario, cooperation between cytokines released by gluten-specific CD4+ T cells and interleukin-15 produced in excess in the coeliac gut, licenses the autoimmune-like attack of the gut epithelium, likely via sustained activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in IEL. Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. A current challenge is to transfer the considerable mechanistic insight gained into CD pathogenesis into benefits for the patients, notably to alleviate the gluten-free diet, a burden for many patients.

Pro-inflammatory cytokine expression and the STAT1/3 pathway in canine chronic enteropathy and intestinal T-cell lymphoma

“…15,36 However, IL-2 and IL-15 expression remained unchanged in canine IEL + CE. Although IL-12 is considered to be less important in the pathogenesis of celiac disease, 17,27 the expression of IL-12p35 and IL-12p40 increased in canine IEL + CE.…”

New Developments in Celiac Disease Treatment

“…The IL-15 receptor consists of three chains: (a) a common cytokine receptor γ-chain that is shared with the receptors for IL-2, IL-4, IL-7, IL-9, and IL-21; a β-chain (IL-15Rβ) that is shared with the IL-2 receptor; and an IL-15 specific α-chain (IL-15Rα) [ 71 ]. The IL-15 receptor signals through the Janus kinase–signal transducer and activator of transcription (JAK/STAT) [ 107 ].…”

Replacing the Burden of the Gluten Free Diet: Then, Now, and the Future

“…These haplotypes are found in approximately 30–40% of the general population and although necessary for disease occurrence, they are not sufficient [ 14 ]. Regional variants have been observed in the frequency of these haplotypes in CD; however, their distribution is ubiquitous [ 15 ]. Exposure to gluten, the known CD exogenous antigen, is mandatory, but the quantity, quality, and timing of exposure are still a matter of debate.…”