Mucosal Immunity

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Coeliac disease is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that occurs in a subset of genetically susceptible individuals who express either the HLA-DQ8 or HLA-DQ2 haplotypes1,2. The need to develop non-dietary treatments is now widely recognized3, but no pathophysiologically relevant gluten- and HLA-dependent preclinical model exists. Furthermore, although studies in humans have led to major advances in our understanding of the pathogenesis of coeliac disease4, the respective roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in the development of tissue damage, have not been directly demonstrated. Here we describe a mouse model that reproduces the overexpression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that is characteristic of active coeliac disease, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy after ingestion of gluten. Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease. In addition, CD4+ T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. We also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By reflecting the complex interaction between gluten, genetics and IL-15-driven tissue inflammation, this mouse model provides the opportunity to both increase our understanding of coeliac disease, and develop new therapeutic strategies. An HLA- and gluten-dependent mouse model of coeliac disease with villous atrophy provides evidence for the cooperative role of IL-15 and gluten-specific CD4+ T cells in licensing the full activation of cytotoxic T cells that are necessary for inducing epithelial damage.

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KEY POINTS The number of MAIT cells significantly correlated with time after CBT. Significantly decreased numbers of circulating MAIT cells were observed in patients with cGVHD. The riboflavin pathway of microbiomes correlated with MAIT cell reconstitution. Abstract Mucosal-associated invariant T (MAIT) cells are a type of innate lymphocyte and recognize riboflavin (vitamin B2) synthesis products presented by MHC-related protein 1. We investigated long-term reconstitution of MAIT cells and its association with chronic graft-versus-host disease (cGVHD) in a cross-sectional cohort of 173 adult patients after allogeneic hematopoietic cell transplantation. According to donor source, the number of MAIT cells significantly correlated with time after cord blood transplantation (CBT) but not with time after bone marrow transplantation or peripheral blood stem cell transplantation. The number of MAIT cells was significantly lower in patients with cGVHD compared with patients without cGVHD. We also examined the association between MAIT cell reconstitution and gut microbiota as evaluated by 16S ribosomal sequencing of stool samples 1 mo post-CBT in 27 adult patients undergoing CBT. The diversity of gut microbiota was positively correlated with better MAIT cell reconstitution after CBT. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis indicated that amounts of ribB and ribA genes were significantly higher in the microbiomes of patients with subsequent MAIT cell reconstitution after CBT. In conclusion, long-term MAIT cell reconstitution is dependent on the type of donor source. Our data also unveiled an important role for the interaction of circulating MAIT cells with gut microbiota in humans. Footnotes This work was supported in part by grants-in-aid from the Japanese Society for the Promotion of Science, the Takeda Science Foundation, the Yakult Bio-Science Foundation, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to T.K.). The online version of this article contains supplemental material. Received June 18, 2019. Accepted January 2, 2020. Copyright © 2020 by The American Association of Immunologists, Inc.

A team of researchers at the University of Texas Southwestern Medical Center has identified the gene...

To determine the transfer of rituximab, an anti-CD20 monoclonal antibody widely used for neurologic conditions, into mature breast milk.Breast milk samples were collected from 9 women with MS who received rituximab 500 or 1,000 mg intravenous once or ...

The human gastrointestinal tract is colonized by trillions of microorganisms that interact with the host to maintain structural and functional homeostasis. Acting as the interface between the site of the highest microbial burden in the human body and the richest immune compartment, a single layer of intestinal epithelial cells specializes in nutrient absorption, stratifies microorganisms to limit colonization of tissues and shapes the responses of the subepithelial immune cells. In this Review, we focus on the expression, regulation and functions of Toll-like receptors (TLRs) in the different intestinal epithelial lineages to analyse how epithelial recognition of bacteria participates in establishing homeostasis in the gut. In particular, we elaborate on the involvement of epithelial TLR signalling in controlling crypt dynamics, enhancing epithelial barrier integrity and promoting immune tolerance towards the gut microbiota. Furthermore, we comment on the regulatory mechanisms that fine-tune TLR-driven immune responses towards pathogens and revisit the role of TLRs in epithelial repair after injury. Finally, we discuss how dysregulation of epithelial TLRs can lead to the generation of dysbiosis, thereby increasing susceptibility to colitis and tumorigenesis. Interactions between intestinal epithelial cells, the gut microbiota and immune cells have a key role in maintaining gut homeostasis. This Review describes how epithelial recognition of bacteria through Toll-like receptors participates in establishing homeostasis, and how dysregulation of these receptors can lead to dysbiosis, increasing susceptibility to colitis and tumorigenesis.

Abstract The mammalian intestine is a complex environment that is constantly exposed to Ags derived from food, microbiota, and metabolites. Intestinal dendritic cells (DC) have the responsibility of establishing oral tolerance against these Ags while initiating immune responses against mucosal pathogens. We now know that DC are a heterogeneous population of innate immune cells composed of classical and monocyte-derived DC, Langerhans cells, and plasmacytoid DC. In the intestine, DC are found in organized lymphoid tissues, such as the mesenteric lymph nodes and Peyer’s patches, as well as in the lamina propria. In this Brief Review, we review recent work that describes a division of labor between and collaboration among gut DC subsets in the context of intestinal homeostasis and inflammation. Understanding relationships between DC subtypes and their biological functions will rationalize oral vaccine design and will provide insights into treatments that quiet pathological intestinal inflammation. Footnotes Abbreviations used in this article: cDC classical DC cDC1 type 1 cDC cDC2 type 2 cDC CSR class switch recombination DC dendritic cell FAE follicle-associated epithelium IBD inflammatory bowel disease ILC innate lymphoid cell LN lymph node LP lamina propria LTβR lymphotoxin β receptor MHC-II MHC class II MLN mesenteric lymph node pDC plasmacytoid DC PP Peyer’s patch RA retinoid acid RALDH retinaldehyde dehydrogenase SILT solitary isolated lymphoid tissue Tfh T follicular helper cell Treg T regulatory cell. This work was supported by a Foundation Grant (15992) from the Canadian Institutes of Health Research to J.L.G. Received June 24, 2019. Accepted October 11, 2019. Copyright © 2020 by The American Association of Immunologists, Inc.

Abstract Immunoglobulin (Ig) A is the most abundant antibody isotype present at mucosal surfaces and the second most abundant in human serum. In addition to preventing pathogen entry at mucosal sur...

ABSTRACTMucosal immunity is dominated by secretory IgA and IgM, although these are less favorable compared to IgG molecules for therapeutic development. Polymeric IgA and IgM are actively transport...