論文 - 高橋　大輔

AP-1B regulates interactions of epithelial cells and intraepithelial lymphocytes in the intestine.

Matsumoto R, Ogata K, Takahashi D, Kinashi Y, Yamada T, Morita R, Tanaka K, Hattori K, Endo M, Fujimura Y, Sasaki N, Ohno H, Ishihama Y, Kimura S, Hase K

Cellular and molecular life sciences : CMLS （Springer Science and Business Media LLC）  81 （ 1 ） 425 2024年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1420-682X

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Intestinal epithelium dysfunctions cause IgA deposition in the kidney glomeruli of intestine-specific Ap1m2-deficient mice.

Kinashi Y, Tanaka K, Kimura S, Hirota M, Komiyama S, Shindo T, Hashiguchi A, Takahashi D, Shibata S, Karaki SI, Ohno H, Hase K

EBioMedicine 106   105256 - 105256 2024年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2352-3964

　概要を見る

Background: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. Methods: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. Findings: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA–IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. Interpretation: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. Funding: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.

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Sugar and arginine facilitate oral tolerance by ensuring the functionality of tolerogenic immune cell subsets in the intestine.

Nagai M, Okawa T, Nakata K, Takahashi D, Miyajima R, Shiratori H, Yamanaka D, Nakamura A, Oyama C, Takahashi SI, Toyama-Sorimachi N, Suzuki K, Ohashi W, Dohi T, Kawamura YI, Hase K

Cell reports （Elsevier BV）  43 （ 7 ） 114490 - 114490 2024年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2211-1247

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Although oral tolerance is a critical system in regulating allergic disorders, the mechanisms by which dietary factors regulate the induction and maintenance of oral tolerance remain unclear. To address this, we explored the differentiation and function of various immune cells in the intestinal immune system under fasting and ad libitum-fed conditions before oral ovalbumin (OVA) administration. Fasting mitigated OVA-specific Treg expansion, which is essential for oral tolerance induction. This abnormality mainly resulted from functional defects in the CX3CR1+ cells responsible for the uptake of luminal OVA and reduction of tolerogenic CD103+ dendritic cells. Eventually, fasting impaired the preventive effect of oral OVA administration on asthma and allergic rhinitis development. Specific food ingredients, namely carbohydrates and arginine, were indispensable for oral tolerance induction by activating glycolysis and mTOR signaling. Overall, prior food intake and nutritional signals are critical for maintaining immune homeostasis by inducing tolerance to ingested food antigens.

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A purified diet affects intestinal epithelial proliferation and barrier functions through gut microbial alterations.

Shiratori H, Hattori KM, Nakata K, Okawa T, Komiyama S, Kinashi Y, Kabumoto Y, Kaneko Y, Nagai M, Shindo T, Moritoki N, Kawamura YI, Dohi T, Takahashi D, Kimura S, Hase K

International immunology （Oxford University Press (OUP)）  36 （ 5 ） 223 - 240 2024年01月

研究論文（学術雑誌）, 査読有り,  ISSN  0953-8178

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The gut microbiota plays a crucial role in maintaining epithelial barrier function. Although multiple studies have demonstrated the significance of dietary factors on gut microbiota and mucosal barrier function, the impact of a purified diet, which has long been used in various animal experiments, on intestinal homeostasis remains to be elucidated. Here, we compared the impact of two different types of diets, a crude diet and an AIN-93G-formula purified diet, on epithelial integrity and the gut microbiota. Purified diet-fed mice exhibited shorter villi and crypt lengths and slower epithelial turnover, particularly in the ileum. In addition, antimicrobial products, including islet-derived protein 3γ (REG3γ), were substantially decreased in purified diet-fed mice. Purified diet feeding also suppressed α1,2-fucosylation on the epithelial surface. Furthermore, purified diet induced metabolic rewiring to fatty acid oxidation and ketogenesis. 16S ribosomal RNA gene sequencing of the ileal contents and mucus layer revealed distinct gut microbiota compositions between the purified and crude diet-fed mice. Purified diet feeding reduced the abundance of segmented filamentous bacteria (SFB), which potently upregulate REG3γ and fucosyltransferase 2 (Fut2) by stimulating group 3 innate lymphoid cells (ILC3) to produce IL-22. These observations illustrate that the intake of a crude diet secures epithelial barrier function by facilitating SFB colonization, whereas a purified diet insufficiently establishes the epithelial barrier, at least partly owing to the loss of SFB. Our data suggest that the influence of purified diets on the epithelial barrier integrity should be considered in experiments using purified diets.

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Safe and efficient oral allergy immunotherapy using one-pot-prepared mannan-coated allergen nanoparticles.

Li S, Toriumi H, Takahashi D, Kamasaki T, Fujioka Y, Nagatoishi S, Li J, Liu Y, Hosokawa T, Tsumoto K, Ohba Y, Katayama Y, Murakami D, Hase K, Mori T

Biomaterials （Elsevier BV）  303   122381 - 122381 2023年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0142-9612

　概要を見る

Allergen immunotherapy (AIT) is the only curative treatment for allergic diseases. However, AIT has many disadvantages related to efficiency, safety, long-term duration, and patient compliance. Dendritic cells (DCs) have an important role in antigen-specific tolerance induction; thus, DC-targeting strategies to treat allergies such as glutaraldehyde crosslinked antigen to mannoprotein (MAN) have been established. However, glutaraldehyde crosslinking may reduce the antigen presentation efficiency of DCs. To overcome this, we developed a MAN-coated ovalbumin (OVA) nanoparticle (MDO), which uses intermolecular disulfide bond to crosslink OVA and MAN. MDO effectively targeted DCs resulting in tolerogenic DCs, and promoted higher antigen presentation efficiency by DCs compared with OVA or glutaraldehyde crosslinked nanoparticles. In vitro and in vivo experiments showed that DCs exposed to MDO induced Treg cells. Moreover, MDO had low reactivity with anti-OVA antibodies and did not induce anaphylaxis in allergic mice, demonstrating its high safety profile. In a mouse model of allergic asthma, MDO had significant preventative and therapeutic effects when administered orally or subcutaneously. Therefore, MDO represents a promising new approach for the efficient and safe treatment of allergies.

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α-Glucosidase inhibitors boost gut immunity by inducing IgA responses in Peyer's patches.

Hattori-Muroi K, Naganawa-Asaoka H, Kabumoto Y, Tsukamoto K, Fujisaki Y, Fujimura Y, Komiyama S, Kinashi Y, Kato M, Sato S, Takahashi D, Hase K

Front Immunol. （Frontiers Media SA）  14   1277637 2023年11月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り,  ISSN  1664-3224

　概要を見る

Peyer’s patches (PPs) are specialized gut-associated lymphoid tissues that initiate follicular helper T (Tfh)-mediated immunoglobulin A (IgA) response to luminal antigens derived from commensal symbionts, pathobionts, and dietary sources. IgA-producing B cells migrate from PPs to the small intestinal lamina propria and secrete IgA across the epithelium, modulating the ecological balance of the commensal microbiota and neutralizing pathogenic microorganisms. α-glucosidase inhibitors (α-GIs) are antidiabetic drugs that inhibit carbohydrate digestion in the small intestinal epithelium, leading to alterations in the commensal microbiota composition and metabolic activity. The commensal microbiota and IgA responses exhibit bidirectional interactions that modulate intestinal homeostasis and immunity. However, the effect of α-GIs on the intestinal IgA response remains unclear. We investigated whether α-GIs affect IgA responses by administering voglibose and acarbose to mice via drinking water. We analyzed Tfh cells, germinal center (GC) B cells, and IgA-producing B cells in PPs by flow cytometry. We also assessed pathogen-specific IgA responses. We discovered that voglibose and acarbose induced Tfh cells, GCB cells, and IgA-producing B cells in the PPs of the proximal small intestine in mice. This effect was attributed to the modification of the microbiota rather than a shortage of monosaccharides. Furthermore, voglibose enhanced secretory IgA (S-IgA) production against attenuated Salmonella Typhimurium. Our findings reveal a novel mechanism by which α-GIs augment antigen-specific IgA responses by stimulating Tfh-GCB responses in PPs, and suggest a potential therapeutic application as an adjuvant for augmenting mucosal vaccines.

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Gut microbiota-derived lipid metabolites facilitate regulatory T cell differentiation.

Shiratori H, Oguchi H, Isobe Y, Han KH, Sen A, Yakebe K, Takahashi D, Fukushima M, Arita M, Hase K

Sci Rep. （Springer Science and Business Media LLC）  13 （ 1 ） 8903 2023年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2045-2322

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Commensal bacteria-derived metabolites are critical in regulating the host immune system. Although the impact of gut microbiota-derived hydrophilic metabolites, such as short-chain fatty acids, on immune cell functions and development has been well documented, the immunomodulatory effects of gut microbiota-derived lipids are still of interest. Here, we report that lipid extracts from the feces of specific-pathogen-free (SPF), but not germ-free (GF), mice showed regulatory T (Treg)-cell-inducing activity. We conducted RP-HPLC-based fractionation and liquid chromatography–tandem mass spectrometry (LC–MS/MS)-based lipidome profiling and identified two bioactive lipids, 9,10-dihydroxy-12Z-octadecenoic acid (9,10-DiHOME) and all-trans retinoic acid (atRA), with Treg-inducing activity in vitro. The luminal abundance of 9,10-DiHOME in the large intestine was significantly decreased by dextran sulfate sodium (DSS)-induced colitis, indicating that 9,10-DiHOME may be a potential biomarker of colitis. These observations implied that commensal bacteria-derived lipophilic metabolites might contribute to Treg development in the large intestine.

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Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84

Ryuji Ohue-Kitano, Hazuki Nonaka, Akari Nishida, Yuki Masujima, Daisuke Takahashi, Takako Ikeda, Akiharu Uwamizu, Miyako Tanaka, Motoyuki Kohjima, Miki Igarashi, Hironori Katoh, Tomohiro Tanaka, Asuka Inoue, Takayoshi Suganami, Koji Hase, Yoshihiro Ogawa, Junken Aoki, Ikuo Kimura

JCI insight 8 （ 2 ） e165469 2022年12月

研究論文（学術雑誌）, 共著, 査読有り

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Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. G protein–coupled 84 (GPR84) acts as a receptor for MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84 signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84-deficient mice exhibited nonalcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage overactivation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake–induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively improved NASH in mouse models. Therefore, exogenous GPR84 stimulation is a potential strategy for treating NASH.

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A Novel HDAC1-Selective Inhibitor Attenuates Autoimmune Arthritis by Inhibiting Inflammatory Cytokine Production.

Zhe W, Hoshina N, Itoh Y, Tojo T, Suzuki T, Hase K, Takahashi D

Biological & pharmaceutical bulletin （Pharmaceutical Society of Japan）  9 （ 1 ） 1364 - 1372 2022年09月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り,  ISSN  0918-6158

　概要を見る

Rheumatoid arthritis (RA) is systemic autoimmune arthritis that causes joint inflammation and destruction. Accumulating evidence has shown that inhibitors of class I histone deacetylases (HDACs) (i.e., HDAC1, 2, 3, and 8) are potential therapeutic candidates as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Nevertheless, the inhibition of class I HDACs has severe adverse effects because of their broad spectrum. We evaluated the therapeutic effect of a novel selective HDAC1 inhibitor TTA03-107 for collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models in mice. We also examined the effect of TTA03-107 in bone marrow-derived macrophages (BMDMs) and T helper 17 (Th17) cells in vitro. Here, we delineate that TTA03-107 reduced the severity of autoimmune arthritis without obvious adverse effects in CIA and CAIA models. Moreover, TTA03-107 suppressed the production of inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-17A, in serum and joint tissue. In vitro treatment of BMDMs with TTA03-107 dampened the M1 differentiation and inflammatory cytokine production. TTA03-107 also suppressed the differentiation of Th17 cells. These results demonstrate that TTA03-107 can attenuate the development of arthritis in experimental RA models by inhibiting the differentiation and activation of macrophages and Th17 cells. Therefore, TTA03-107 is a potential tsDMARD candidate.

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Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection

Seo, Goo-Young Takahashi, Daisuke Wang, Qingyang Mikulski, Zbigniew Chen, Angeline Chou, Ting-Fang Marcovecchio, Paola McArdle, Sara Sethi, Ashu Shui, Jr-Wen Takahashi, Masumi Surh, Charles D. Cheroutre, Hilde Kronenberg, Mitchell

Science Immunology （AAAS）  7   eabm6931 2022年07月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り

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Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice

Ryohtaroh Matsumoto, Daisuke Takahashi, Masaki Watanabe, Shunsuke Nakatani, Yuta Takamura, Yuji Kurosaki, Hiroki Kakuta, Koji Hase

Front Pharmacol （Frontiers Media SA）  12   Article 715752  2021年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1663-9812

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Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RBhighCD4+ T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-γ-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs.

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Intestinal immunity: to be, or not to be, induced? That is the question.

Daisuke Takahashi, Shunsuke Kimura, Koji Hase

International immunology （International Immunology）  33 （ 12 ） 755 - 759 2021年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  09538178

　概要を見る

The intestinal immune system maintains intestinal homeostasis in collaboration with diverse immune cell subsets residing at the epithelial layer, lamina propria and gut-associated lymphoid tissue (GALT). Bacterial components and their metabolites are essential for the establishment of the gut immune system. In addition, nutritional signals contribute to maintaining the mucosal immune response. Specialized epithelial microfold (M) cells in GALT facilitate immune surveillance on the mucosal surface by actively taking up external antigens to transport them into the lymphoid follicles. Because hyperplasia of M cells causes an excessive immune response in GALT, there is a self-regulatory mechanism to control the development of M cells appropriately. In this review, we will discuss the molecular mechanisms of mucosal immune regulation and their biological importance.

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Symbiotic polyamine metabolism regulates epithelial proliferation and macrophage differentiation in the colon

Atsuo Nakamura, Shin Kurihara, Daisuke Takahashi, Wakana Ohashi, Yutaka Nakamura, Shunsuke Kimura, Masayoshi Onuki, Aiko Kume, Yukiko Sasazawa, Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Shinji Saiki, Mitsuharu Matsumoto, Koji Hase

Nat Commun （Springer Science and Business Media LLC）  12 （ 1 ） 2105 2021年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2041-1723

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<title>Abstract</title>Intestinal microbiota-derived metabolites have biological importance for the host. Polyamines, such as putrescine and spermidine, are produced by the intestinal microbiota and regulate multiple biological processes. Increased colonic luminal polyamines promote longevity in mice. However, no direct evidence has shown that microbial polyamines are incorporated into host cells to regulate cellular responses. Here, we show that microbial polyamines reinforce colonic epithelial proliferation and regulate macrophage differentiation. Colonisation by wild-type, but not polyamine biosynthesis-deficient, <italic>Escherichia coli</italic> in germ-free mice raises intracellular polyamine levels in colonocytes, accelerating epithelial renewal. Commensal bacterium-derived putrescine increases the abundance of anti-inflammatory macrophages in the colon. The bacterial polyamines ameliorate symptoms of dextran sulfate sodium-induced colitis in mice. These effects mainly result from enhanced hypusination of eukaryotic initiation translation factor. We conclude that bacterial putrescine functions as a substrate for symbiotic metabolism and is further absorbed and metabolised by the host, thus helping maintain mucosal homoeostasis in the intestine.

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Identification of Novel Histone Deacetylase 6-Selective Inhibitors Bearing 3,3,3-Trifluorolactic Amide (TFLAM) Motif as a Zinc Binding Group

Takashi Kurohara, Keita Tanaka, Daisuke Takahashi, Satoshi Ueda, Yasunobu Yamashita, Yuri Takada, Hirokazu Takeshima, Shengwang Yu, Yukihiro Itoh, Koji Hase, Takayoshi Suzuki

Chembiochem 16 （ 22 ） 3156 - 3163 2021年07月

研究論文（学術雑誌）, 査読有り,  ISSN  1439-4227

　概要を見る

Pharmacological inhibition of histone deacetylase 6 (HDAC6) is an effective therapeutic strategy for cancer and immunological diseases. Most of the previously reported HDAC6 inhibitors have a hydroxamate group as a zinc binding group (ZBG), which coordinates to the catalytic zinc ion of HDAC6. The hydroxamate group is liable to metabolically generate mutagenetic hydroxylamine; therefore, non-hydroxamate HDAC6 inhibitors would be advantageous. In this study, to identify novel non-hydroxamate HDAC6-selective inhibitors, screening of a chemical library and the subsequent structural optimization were performed, which led to the identification of HDAC6-selective inhibitors with 3,3,3-trifluorolactic amide (TFLAM) as a novel ZBG. The identified inhibitor showed potent and selective HDAC6-inhibitory activity in cells and induced regulatory T (Treg) cell differentiation.

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Polyamines polarized Th2/Th9 cell-fate decision by regulating GATA3 expression

Atsuo Nakamura, Daisuke Takahashi, Yutaka Nakamura, Takahiro Yamada, Mitsuharu Matsumoto, Koji Hase

Arch Biochem Biophys （Elsevier {BV}）  693   108587 - 108587 2020年10月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0003-9861

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Polyamines produced by both prokaryotes and eukaryotes are bioactive substances with pleiotropic effects. Accumulating evidence has demonstrated that polyamines contribute to anti-inflammatory responses by suppressing the expression of proinflammatory cytokines in mononuclear cells and macrophages. However, the effects of polyamines on CD4+ T cell responses remain to be elucidated. Here, we investigated the effect of polyamines on cell fate decisions of naïve CD4+ T cells in vitro. We found that endogenously generated polyamines are essential for the development of T helper 2 (Th2) cells. Treatment with DL-2-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, diminished GATA3 expression in CD4+ T cells under Th2-skewed conditions. Supplementation of exogenous polyamines rescued GATA3 downregulation caused by DFMO treatment in CD4+ T cells. Transcriptome analysis revealed that deprivation of endogenous polyamines resulted in upregulated Th9-related genes, such as Il9, Irf4, and Batf3, even under the Th2-skewing conditions. Depletion of intracellular polyamines reduced GATA3 expression but increased IL-9-producing CD4+ T cells under both Th2 and Th9-skewing conditions. Furthermore, oral administration of DFMO increased IL-9-producing CD4+ T cells in small intestine in mice. Thus, our data indicate that polyamines play a critical role in the regulation of the Th2/Th9 balance.

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Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells

2020年08月

研究論文（学術雑誌）, 共著, 査読有り

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Microfold cell-dependent antigen transport alleviates infectious colitis by inducing antigen-specific cellular immunity.

Nakamura Y, Mimuro H, Kunisawa J, Furusawa Y, Takahashi D, Fujimura Y, Kaisho T, Kiyono H, Hase K

Mucosal immunology （Springer Science and Business Media LLC）  13 （ 4 ） 679 - 690 2020年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1933-0219

　概要を見る

Infectious colitis is one of the most common health issues worldwide. Microfold (M) cells actively transport luminal antigens to gut-associated lymphoid tissue to induce IgA responses; however, it remains unknown whether M cells contribute to the induction of cellular immune responses. Here we report that M cell-dependent antigen transport plays a critical role in the induction of Th1, Th17, and Th22 responses against gut commensals in the steady state. The establishment of commensal-specific cellular immunity was a prerequisite for preventing bacterial dissemination during enteropathogenic Citrobacter rodentium infection. Therefore, M cell-null mice developed severe colitis with increased bacterial dissemination. This abnormality was associated with mucosal barrier dysfunction. These observations suggest that antigen transport by M cells may help maintain gut immune homeostasis by eliciting antigen-specific cellular immune responses.

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Commensal-bacteria-derived butyrate promotes the T-cell-independent IgA response in the colon.

Isobe J, Maeda S, Obata Y, Iizuka K, Nakamura Y, Fujimura Y, Kimizuka T, Hattori K, Kim YG, Morita T, Kimura I, Offermanns S, Adachi T, Nakao A, Kiyono H, Takahashi D, Hase K

International immunology （Oxford University Press）  32 （ 4 ） 243 - 258 2019年12月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0953-8178

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Abstract

Secretory immunoglobulin A (SIgA), the most abundant antibody isotype in the body, maintains a mutual relationship with commensal bacteria and acts as a primary barrier at the mucosal surface. Colonization by commensal bacteria induces an IgA response, at least partly through a T-cell-independent process. However, the mechanism underlying the commensal-bacteria-induced T-cell-independent IgA response has yet to be fully clarified. Here, we show that commensal-bacteria-derived butyrate promotes T-cell-independent IgA class switching recombination (CSR) in the mouse colon. Notably, the butyrate concentration in human stools correlated positively with the amount of IgA. Butyrate up-regulated the production of transforming growth factor β1 and all-trans retinoic acid by CD103+CD11b+ dendritic cells, both of which are critical for T-cell-independent IgA CSR. This effect was mediated by G-protein-coupled receptor 41 (GPR41/FFA3) and GPR109a/HCA2, and the inhibition of histone deacetylase. The butyrate-induced IgA response reinforced the colonic barrier function, preventing systemic bacterial dissemination under inflammatory conditions. These observations demonstrate that commensal-bacteria-derived butyrate contributes to the maintenance of the gut immune homeostasis by facilitating the T-cell-independent IgA response in the colon.

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Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses

Daisuke Takahashi

Cell （Cell）  178 （ 5 ） 1072 - 1087 2019年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0092-8674

　概要を見る

© 2019 Elsevier Inc. Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer&#039;s patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis. Temporary fasting drastically reduces the levels of B cells in Peyer&#039;s patches, with germinal center B cells undergoing apoptos

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MZB1 promotes the secretion of J-chain–containing dimeric IgA and is critical for the suppression of gut inflammation

Ermeng Xiong, Yingqian Li, Qing Min, Chaoqun Cui, Jun Liu, Rongjian Hong, Nannan Lai, Ying Wang, Jiping Sun, Ryohtaroh Matsumoto, Daisuke Takahashi, Koji Hase, Reiko Shinkura, Takeshi Tsubata, Ji-Yang W

Proceedings of the National Academy of Sciences of the United States of America （National Academy of Sciences）  116 （ 27 ） 13480 - 13489 2019年07月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1091-6490

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<jats:p>IgA is the most abundantly produced antibody in the body and plays a crucial role in gut homeostasis and mucosal immunity. IgA forms a dimer that covalently associates with the joining (J) chain, which is essential for IgA transport into the mucosa. Here, we demonstrate that the marginal zone B and B-1 cell-specific protein (MZB1) interacts with IgA through the α-heavy-chain tailpiece dependent on the penultimate cysteine residue and prevents the intracellular degradation of α-light-chain complexes. Moreover, MZB1 promotes J-chain binding to IgA and the secretion of dimeric IgA. MZB1-deficient mice are impaired in secreting large amounts of IgA into the gut in response to acute inflammation and develop severe colitis. Oral administration of a monoclonal IgA significantly ameliorated the colitis, accompanied by normalization of the gut microbiota composition. The present study identifies a molecular chaperone that promotes J-chain binding to IgA and reveals an important mechanism that controls the quantity, quality, and function of IgA.</jats:p>

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