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A Comprehensive Understanding of the Gut Mucosal Immune System in Allergic Inflammation

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A Comprehensive Understanding of the Gut Mucosal Immune System in Allergic Inflammation Allergology International xxx (2018) 1e9 Contents lists available at ScienceDirect Allergology International journal homepage: http://www.elsevier.com/locate/alit Invited Review Article A comprehensive understanding of the gut mucosal immune system in allergic inflammation Daisuke Tokuhara a, b, c, d, e, Yosuke Kurashima a, b, c, f, g, h, Mariko Kamioka a, b, c, * Toshinori Nakayama i, Peter Ernst c, d, j, Hiroshi Kiyono a, b, c, d, a Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan b International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan c Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, University of California San Diego, San Diego, CA, USA d Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, CA, USA e Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan f Department of Mucosal Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan g Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan h Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan i Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan j Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, CA, USA article info abstract Article history: Despite its direct exposure to huge amounts of microorganisms and foreign and dietary antigens, the gut Received 13 September 2018 mucosa maintains intestinal homeostasis by utilizing the mucosal immune system. The gut mucosal Received in revised form immune system protects the host from the invasion of infectious pathogens and eliminates harmful non- 17 September 2018 self antigens, but it allows the cohabitation of commensal bacteria in the gut and the entry of dietary Accepted 18 September 2018 non-self antigens into the body via the mucosal surface. These physiological and immunological activities Available online xxx are regulated by the ingenious gut mucosal immune network, comprising such features as gut-associated lymphoid tissue, mucosal immune cells, cytokines, chemokines, antimicrobial peptides, secretory IgA, Keywords: fi Allergy and commensal bacteria. The gut mucosal immune network keeps a ne tuned balance between active Microbiota immunity (against pathogens and harmful non-self antigens) and immune tolerance (to commensal Mucosal immunity microbiota and dietary antigens), thus maintaining intestinal healthy homeostasis. Disruption of gut Oral tolerance homeostasis results in persistent or severe gastrointestinal infection, inflammatory bowel disease, or Regulatory T cell allergic inflammation. In this review, we comprehensively introduce current knowledge of the gut mucosal immune system, focusing on its interaction with allergic inflammation. Abbreviations: Copyright © 2018, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access DC, dendritic cell; Foxp3, forkhead box P3; article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). GALT, gut-associated lymphoid tissue; IDO, indoleamine 2,3-dioxygenase; LP, lamina propria; LTi, lymphoid tissue inducer; MLN, mesenteric lymph node; OVA, ovalbumin; pIgR, polymeric Ig receptor; PP, Peyer’s patch; RA, retinoic acid; RORgt, retinoic acid receptor-related orphan receptor gt; SIgA, secretory IgA; TGF-b, transforming growth factor b; S1P, sphingosine 1-phosphate; MALT, mucosa-associated lymphoid tissues; NALT, nasopharyngeal-associated lymphoid tissue; ILF, isolated lymphoid follicle; MAdCAM-1, mucosal vascular addressin cell adhesion molecule 1 * Corresponding author. Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail address: [email protected] (H. Kiyono). Peer review under responsibility of Japanese Society of Allergology. https://doi.org/10.1016/j.alit.2018.09.004 1323-8930/Copyright © 2018, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Please cite this article in press as: Tokuhara D, et al., A comprehensive understanding of the gut mucosal immune system in allergic inflammation, Allergology International (2018), https://doi.org/10.1016/j.alit.2018.09.004 2 D. Tokuhara et al. / Allergology International xxx (2018) 1e9 Introduction both MLN- and PP-deficient mice.24 In an ovalbumin (OVA)- induced allergy model, deficiency of PPs alone resulted in failed The gastrointestinal tractdthe tube-like structure covered by induction of oral tolerance to OVA and the development of severe mucosa from the oral cavity to the anusdis continuously and allergic signs upon OVA challenge, unlike in wild-type mice.25,26 directly exposed to inputs from the external environment and entry Moreover, the absence of MLNs alone is sufficient to impair the of dietary antigens and pathogens. A major physiological function induction of oral tolerance to OVA.24 These findings suggested that of the gastrointestinal tract is the digestion of food, absorption of the presence and maturation of GALT play one of key roles for the nutrients and water, and elimination of unnecessary wasted establishment of balanced gut mucosal immune system contrib- products; the intestine is a major site of entry for many bacterial uted by the SIgA and oral tolerance induction. and viral pathogens and has a vast and diverse microbial commu- The cellular and molecular mechanisms of PP and MLN devel- nity.1,2 Despite the complexity of the outer environment, intestinal opment have been clarified in murine studies. Although the homeostasis is ingeniously maintained under the control of the development of PP and MLN structures is guided by different sig- unique gut mucosal immune network, which is characterized by nals to some extent, in both cases development requires the such features as gut-associated lymphoid tissues (GALT or Peyer's interaction between lymphoid tissue inducer (LTi) cells (or patches; PPs), secretory IgA (SIgA), antimicrobial peptides (e.g. currently termed as type 3 innate lymphoid cells: ILC3)27 and defensins), mucosal immune cells (e.g. Th1, Th2, Th17, Tfh and Treg lymphoid tissue organizer cells (Fig. 1).3,28 In addition, the differ- þ cells), cytokines (e.g. IL-10), chemokines (e.g. CCR9), and entiation of LTi cells from IL-7R-a lymphoid progenitors requires e commensal bacteria.3 8 the expression of inhibitor of DNA binding 2 (ID2) and the retinoic Food allergy, which generally occurs in early childhood, is trig- acid receptor-related orphan receptor gt(RORgt) in developing PPs gered by the ingestion of a dietary antigen via the gut mucosal and MLNs.29,30 Signaling via IL-7Ra or TNF-related activation- membrane; it causes clinical signs such as gastrointestinal disor- induced cytokine receptor, or both, leads to the expression of ders, urticarial, and distant airway inflammation, ranging in LTa1b2 by LTi cells, which promote lymphoid tissue formation.31 severity from mild to life-threatening.9 Because the prevalence of Development of the gut mucosal immune system is influenced food allergy seems to be increasing in developed countries,9,10 the by the outer environment in the form of nutrition and commensal e development of effective clinical methods for the prevention and bacteria.27,32 35 As an example of nutritional involvement, retinoic treatment of the allergic disease would be of substantial social and acid (RA), a metabolite of vitamin A, plays a crucial role in induction financial values, but we first need to acquire a better understanding of the chemokine CXCL13 leading to the formation of lymphoid cell of the underlying gut mucosal immune system for the regulation of clusters (Fig. 1).32 Inhibition of RA synthesis reduces the formation allergic immune response. The healthy mucosal immune system is of LTi cell-mediated lymphoid cell clusters; therefore, maternal inducing and sustaining the unresponsiveness status to dietary levels of dietary retinoids control the size of secondary lymphoid antigensdthat is known as “oral tolerance” characterized by the organs in the gut.27 Commensal bacteria promote gut development. e depletion or anergy of reactive (or pathogenic) T cells,11 13 and/or Compared with conventionally raised animals, germ-free animals the induction of Tregs cells at mucosal sites.14,15 Disruption of the have fewer goblet cells, a thinner mucus layer, reduced villus gut mucosal immune system can lead to failure to induce protective thickness, and impaired brush border differentiation.33 In addition, immunity and/or tolerance, thus causing severe gastrointestinal PPs and MLNs are underdeveloped in germ-free mice.34 In contrast, infection, inflammatory bowel disease, or food allergy.16,17 Here, we postnatal microbial colonization promotes the maturation of GALT highlight current knowledge regarding the role of the gut mucosal including their size and the formation of germinal center in PPs.35 immune system in shaping and maintaining intestinal homeostasis, Bacterial products such as LPS and peptidoglycan have
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