T Cells in Celiac Disease Jabri, Bana; Sollid, Ludvig M
The Journal of immunology (1950),
04/2017, Letnik:
198, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Celiac disease is a human T cell-mediated autoimmune-like disorder caused by exposure to dietary gluten in genetically predisposed individuals. This review will discuss how CD4 T cell responses ...directed against an exogenous Ag can cause an autoreactive B cell response and participate in the licensing of intraepithelial lymphocytes to kill intestinal epithelial cells. Furthermore, this review will examine the mechanisms by which intraepithelial cytotoxic T cells mediate tissue destruction in celiac disease.
Summary
Interleukin‐15 (IL‐15) exerts many biological functions essential for the maintenance and function of multiple cell types. Although its expression is tightly regulated, IL‐15 upregulation has ...been reported in many organ‐specific autoimmune disorders. In celiac disease, an intestinal inflammatory disorder driven by gluten exposure, the upregulation of IL‐15 expression in the intestinal mucosa has become a hallmark of the disease. Interestingly, because it is overexpressed both in the gut epithelium and in the lamina propria, IL‐15 acts on distinct cell types and impacts distinct immune components and pathways to disrupt intestinal immune homeostasis. In this article, we review our current knowledge of the multifaceted roles of IL‐15 with regard to the main immunological processes involved in the pathogenesis of celiac disease.
Coeliac disease is an inflammatory disorder with autoimmune features that is characterized by destruction of the intestinal epithelium and remodelling of the intestinal mucosa following the ingestion ...of dietary gluten. A common feature of coeliac disease and many organ-specific autoimmune diseases is a central role for T cells in causing tissue destruction. In this Review, we discuss the emerging hypothesis that, in coeliac disease, intestinal tissue inflammation--induced either by infectious agents or by gluten--is crucial for activating T cells and eliciting their tissue-destructive effector functions.
Death due to sepsis remains a persistent threat to critically ill patients confined to the intensive care unit and is characterized by colonization with multi-drug-resistant healthcare-associated ...pathogens. Here we report that sepsis in mice caused by a defined four-member pathogen community isolated from a patient with lethal sepsis is associated with the systemic suppression of key elements of the host transcriptome required for pathogen clearance and decreased butyrate expression. More specifically, these pathogens directly suppress interferon regulatory factor 3. Fecal microbiota transplant (FMT) reverses the course of otherwise lethal sepsis by enhancing pathogen clearance via the restoration of host immunity in an interferon regulatory factor 3-dependent manner. This protective effect is linked to the expansion of butyrate-producing Bacteroidetes. Taken together these results suggest that fecal microbiota transplantation may be a treatment option in sepsis associated with immunosuppression.
Large quantities of immunoglobulin A (IgA) are constitutively secreted by intestinal plasma cells to coat and contain the commensal microbiota, yet the specificity of these antibodies remains ...elusive. Here we profiled the reactivities of single murine IgA plasma cells by cloning and characterizing large numbers of monoclonal antibodies. IgAs were not specific to individual bacterial taxa but rather polyreactive, with broad reactivity to a diverse, but defined, subset of microbiota. These antibodies arose at low frequencies among naïve B cells and were selected into the IgA repertoire upon recirculation in Peyer's patches. This selection process occurred independent of microbiota or dietary antigens. Furthermore, although some IgAs acquired somatic mutations, these did not substantially influence their reactivity. These findings reveal an endogenous mechanism driving homeostatic production of polyreactive IgAs with innate specificity to microbiota.
The composite human microbiome of Western populations has probably changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Here we ...show that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia. This was associated with a pro-inflammatory T helper type 1 (T(H)1) immune response and increased incidence of colitis in genetically susceptible Il10(−/−), but not wild-type mice. These effects are mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10(−/−) mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts.
Finely tuned mechanisms enable the gastrointestinal tract to break down dietary components into nutrients without mounting, in the majority of cases, a dysregulated immune or functional host ...response. However, adverse reactions to food have been steadily increasing, and evidence suggests that this process is environmental. Adverse food reactions can be divided according to their underlying pathophysiology into food intolerances, when, for instance, there is deficiency of a host enzyme required to digest the food component, and food sensitivities, when immune mechanisms are involved. In this Review, we discuss the clinical and experimental evidence for enteric infections and/or alterations in the gut microbiota in inciting food sensitivity. We focus on mechanisms by which microorganisms might provide direct pro-inflammatory signals to the host promoting breakdown of oral tolerance to food antigens or indirect pathways that involve the metabolism of protein antigens and other dietary components by gut microorganisms. Better understanding of these mechanisms will help in the development of preventive and therapeutic strategies for food sensitivities.
Microbe-host interactions are generally homeostatic, but when dysfunctional, they can incite food sensitivities and chronic diseases. Celiac disease (CeD) is a food sensitivity characterized by a ...breakdown of oral tolerance to gluten proteins in genetically predisposed individuals, although the underlying mechanisms are incompletely understood. Here we show that duodenal biopsies from patients with active CeD have increased proteolytic activity against gluten substrates that correlates with increased Proteobacteria abundance, including Pseudomonas. Using Pseudomonas aeruginosa producing elastase as a model, we show gluten-independent, PAR-2 mediated upregulation of inflammatory pathways in C57BL/6 mice without villus blunting. In mice expressing CeD risk genes, P. aeruginosa elastase synergizes with gluten to induce more severe inflammation that is associated with moderate villus blunting. These results demonstrate that proteases expressed by opportunistic pathogens impact host immune responses that are relevant to the development of food sensitivities, independently of the trigger antigen.
Mucosal surfaces constantly encounter microbes. Toll-like receptors (TLRs) mediate recognition of microbial patterns to eliminate pathogens. By contrast, we demonstrate that the prominent gut ...commensal Bacteroides fragilis activates the TLR pathway to establish host-microbial symbiosis. TLR2 on CD4⁺ T cells is required for B. fragilis colonization of a unique mucosal niche in mice during homeostasis. A symbiosis factor (PSA, polysaccharide A) of B. fragilis signals through TLR2 directly on Foxp3⁺ regulatory T cells to promote immunologic tolerance. B. fragilis lacking PSA is unable to restrain T helper 17 cell responses and is defective in niche-specific mucosal colonization. Therefore, commensal bacteria exploit the TLR pathway to actively suppress immunity. We propose that the immune system can discriminate between pathogens and the microbiota through recognition of symbiotic bacterial molecules in a process that engenders commensal colonization.
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