Papers - Takahashi, Daisuke

Sox8 is essential for M-cell maturation to accelerate IgA response at the early stage after weaning in mice

Shunsuke Kimura, Nobuhide Kobayashi, Yutaka Nakamura, Takashi Kanaya, Daisuke Takahashi, Ryoji Fujiki, Mami Mutoh, Yuuki Obata, Toshihiko Iwanaga, Tomoo Nakagawa, Naoya Kato, Shintaro Sato, Tsuneyasu Kaisho, Hiroshi Ohno, and Koji Hase

Journal of Experimental Medicine (Rockefeller University Press)  216 ( 4 ) 831 - 846 2019.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0022-1007

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Microfold (M) cells residing in the follicle-associated epithelium (FAE) of the gut-associated lymphoid tissue are specialized for antigen uptake to initiate mucosal immune responses. The molecular machinery and biological significance of M cell differentiation, however, remain to be fully elucidated. Here, we demonstrate that Sox8, a member of the SRY-related HMG box transcription factor family, is specifically expressed by M cells in the intestinal epithelium. The expression of Sox8 requires activation of RANKL-RelB signaling. Chromatin immunoprecipitation and luciferase assays revealed that Sox8 directly binds the promoter region of Gp2 to increase Gp2 expression, which is the hallmark of functionally mature M cells. Furthermore, genetic deletion of Sox8 causes a marked decrease in the number of mature M cells, resulting in reduced antigen uptake in Peyer's patches. Consequently, juvenile Sox8-deficient mice showed attenuated germinal center reactions and antigen-specific IgA responses. These findings indicate that Sox8 plays an essential role in the development of M cells to establish mucosal immune responses.

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A partial agonist for retinoid X receptor mitigates experimental colitis.

Onuki, Masayoshi; Watanabe, Masaki; Ishihara, Narumi; Suzuki, Koichiro; Takizawa, Kei; Hirota, Masato; Yamada, Takahiro; Egawa, Aiko; Shibahara, Osamu; Nishii, Midori; Fujihara, Michiko; Makishima, Makoto; Takahashi, Daisuke; Furusawa, Yukihiro; Kakuta, Hiroki; Hase, Koji

International immunology (International Immunology)  31 ( 4 ) 251 - 262 2018.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09538178

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Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is an intractable disease of the gastrointestinal tract. Multiple environmental factors, including food ingredients, have been implicated in the development of these diseases. For example, animal fat-rich diets are predisposing factors for ulcerative colitis, whereas n-3 unsaturated fatty acids such as docosahexaenoic acid (DHA) show protective effects in experimental colitis and are negatively correlated with the incidence of ulcerative colitis and Crohn's disease. Given that DHA exhibits agonistic activity on retinoid X receptor (RXR), activation of RXR could be a therapeutic strategy for IBD. However, conventional full RXR agonists are known to show considerable adverse effects. We therefore took advantage of a partial RXR agonist, CBt-PMN, to minimize the adverse effects, and evaluated its efficacy in dextran sodium sulfate-induced colitis. Administration of CBt-PMN efficiently ameliorated the symptoms of colitis. This effect was attributed to the down-regulation of pro-inflammatory cytokines such as Tnf and Il6 in colon-infiltrating monocytes. Down-regulation of pro-inflammatory cytokines by CBt-PMN was also evident in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs). Among many RXR-associated nuclear receptors, activation of peroxisome proliferator-activated receptor δ (PPARδ) and nuclear hormone receptor 77 (Nur77) suppressed cytokine production by BMDMs. These observations suggest that the activation of PPARδ/RXR and Nur77/RXR heterodimers by CBt-PMN through the permissive mechanism is responsible for diminishing the monocyte-mediated inflammatory response in the gut. Our data highlight the importance of RXR activation in the regulation of colitis.

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LIGHT-HVEM Signaling in Innate Lymphoid Cell Subsets Protects Against Enteric Bacterial Infection

Goo-YoungSeo, Jr-WenShui, Daisuke Takahashi, Christina Song, Qingyang Wang, Kenneth Kim, Zbigniew Mikulski, Shilpi Chandra, Daniel A.Giles, Sonja Zahner, Pyeung-Hyeun Kim, Hilde Cheroutre, Marco Colonna, Mitchell Kronenberg

Cell Host & Microbe (Cell Press)  24 ( 2 ) 249 - 260 2018.08

Research paper (scientific journal), Single Work, Accepted,  ISSN  1931-3128

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Intestinal epithelial cell-specific deletion of α-mannosidase II ameliorates experimental colitis.

Suzuki K Yamada T, Yamazaki K, Hirota M, Ishihara N, Sakamoto M, Takahashi D, Iijima H, Hase K.

Cell Struct Funct. (Japan Society for Cell Biology)  43 ( 1 ) 25 - 39 2018.01

Research paper (scientific journal), Accepted,  ISSN  1347-3700

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Inflammatory bowel disease (IBD) is a refractory disease of the gastrointestinal tract that is believed to develop in genetically susceptible individuals. Glycosylation, a type of post-translational modification, is involved in the development of a wide range of diseases, including IBD, by modulating the function of various glycoproteins. To identify novel genes contributing to the development of IBD, we analyzed single nucleotide polymorphisms (SNPs) of glycosylation-related genes in IBD patients and identified MAN2A1, encoding alphamannosidase II (α-MII), as a candidate gene. α-MII plays a crucial, but not exclusive, role in the maturation of Nglycans. We also observed that intestinal epithelial cells (IECs), which establish the first-line barrier and regulate gut immunity, selectively expressed α-MII with minimal expression of its isozyme, alpha-mannosidase IIx (α-MIIx). This led us to hypothesize that IEC-intrinsic α-MII is implicated in the pathogenesis of IBD. To test this hypothesis, we generated IEC-specific α-MII-deficient (α-MIIΔIEC) mice. Although α-MII deficiency has been shown to have a minimal effect on N-glycan maturation in most cell types due to the compensation by α-MIIx, ablation of α-MII impaired the maturation of N-glycans in IECs. α-MIIΔIEC mice were less susceptible to dextran sulfate sodium-induced colitis compared with control littermates. In accordance with this, neutrophil infiltration in the colonic mucosa was attenuated in α-MIIΔIEC mice. Furthermore, gene expression levels of neutrophilattracting chemokines were downregulated in the colonic tissue. These results suggest that IEC-intrinsic α-MII promotes intestinal inflammation by facilitating chemokine expression. We propose SNPs in MAN2A1 as a novel genetic factor for IBD.

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NALT M cells are important for immune induction for the common mucosal immune system

Yasuhiro Date, Masashi Ebisawa, Shinji Fukuda, Hideaki Shima, Yuuki Obata, Daisuke Takahashi, Tamotsu Kato, Misaho Hanazato, Gaku Nakato, Ifor R. Williams, Koji Hase, Hiroshi Ohno

International Immunology (Oxford University Press)  29 ( 10 ) 471 - 478 2017.10

Research paper (scientific journal), Accepted,  ISSN  0953-8178

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Nasopharynx-associated lymphoid tissue (NALT) is one of the major constituents of the mucosa-associated lymphoid tissue (MALT), and has the ability to induce antigen-specific immune responses. However, the molecular mechanisms responsible for antigen uptake from the nasal cavity into the NALT remain largely unknown. Immunohistochemical analysis showed that CCL9 and CCL20 were co-localized with glycoprotein 2 (GP2) in the epithelium covering NALT, suggesting the existence of M cells in NALT. In analogy with the reduced number of Peyer's patch M cells in CCR6-deficient mice, the number of NALT M cells was drastically decreased in CCR6-deficient mice compared with the wild-type mice. Translocation of nasally administered Salmonella enterica serovar Typhimurium into NALT via NALT M cells was impaired in CCR6-deficient mice, whereas S. Typhimurium demonstrated consistent co-localization with NALT M cells in wild-type mice. When wild-type mice were nasally administered with an attenuated vaccine strain of S. Typhimurium, the mice were protected from a subsequent challenge with wild-type S. Typhimurium. Antigen-specific fecal and nasal IgA was detected after nasal immunization with the attenuated vaccine strain of S. Typhimurium only in wild-type mice but not in CCR6-deficient mice. Taken together, these observations demonstrate that NALT M cells are important as a first line of defense against infection by enabling activation of the common mucosal immune system (CMIS).

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The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells

Obata, Yuuki, Furusawa, Yukihiro, Endo, Takaho A., Sharif, Jafar, Takahashi, Daisuke, Atarashi, Koji, Nakayama, Manabu, Onawa, Satoshi, Fujimura, Yumiko, Takahashi, Masumi, Ikawa, Tomokatsu, Otsubo, Takeshi, Kawamura, Yuki I., Dohi, Taeko, Tajima, Shoji, Masumoto, Hiroshi, Ohara, Osamu, Honda, Kenya, Hori, Shohei, Ohno, Hiroshi, Koseki, Haruhiko, Hase, Koji

NATURE IMMUNOLOGY (NATURE PUBLISHING GROUP)  15 ( 6 ) 571 - 579 2014.06

Research paper (scientific journal), Accepted,  ISSN  1529-2908

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Intestinal regulatory T cells (T-reg cells) are necessary for the suppression of excessive immune responses to commensal bacteria. However, the molecular machinery that controls the homeostasis of intestinal ireg cells has remained largely unknown. Here we report that colonization of germ-free mice with gut microbiota upregulated expression of the DNA-methylation adaptor Uhrf1 in T-reg cells. Mice with T cell specific deficiency in Uhrf1 (Uhrf1(fl/fl)Cd4-Cre mice) showed defective proliferation and functional maturation of colonic T-reg cells. Uhrf1 deficiency resulted in derepression of the gene (Cdkn1a) that encodes the cyclin-dependent kinase inhibitor p21 due to hypomethylation of its promoter region, which resulted in cell-cycle arrest of T-reg cells. As a consequence, Uhrf1(fl/fl)Cd4-Cre mice spontaneously developed severe colitis. Thus, Uhrf1-dependent epigenetic silencing of Cdknla was required for the maintenance of gut immunological homeostasis. This mechanism enforces symbiotic host-microbe interactions without an inflammatory response.

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Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells (vol 504, pg 446, 2013)

Furusawa, Yukihiro, Obata, Yuuki, Fukuda, Shinji, Endo, Takaho A., Nakato, Gaku, Takahashi, Daisuke, Nakanishi, Yumiko, Uetake, Chikako, Kato, Keiko, Kato, Tamotsu, Takahashi, Masumi, Fukuda, Noriko N., Murakami, Shinnosuke, Miyauchi, Eiji, Hino, Shingo, Atarashi, Koji, Onawa, Satoshi, Fujimura, Yumiko, Lockett, Trevor, Clarke, Julie M., Topping, David L., Tomita, Masaru, Hori, Shohei, Ohara, Osamu, Morita, Tatsuya, Koseki, Haruhiko, Kikuchi, Jun, Honda, Kenya, Hase, Koji, Ohno, Hiroshi

NATURE 506 ( 7487 )  2014.02

Research paper (scientific journal),  ISSN  0028-0836

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Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Takaho A. Endo, Gaku Nakato, Daisuke Takahashi, Yumiko Nakanishi, Chikako Uetake, Keiko Kato, Tamotsu Kato, Masumi Takahashi, Noriko N. Fukuda, Shinnosuke Murakami, Eiji Miyauchi, Shingo Hino, Koji Atarashi, Satoshi Onawa, Yumiko Fujimura, Trevor Lockett, Julie M. Clarke, David L. Topping, Masaru Tomita, Shohei Hori, Osamu Ohara, Tatsuya Morita, Haruhiko Koseki, Jun Kikuchi, Kenya Honda, Koji Hase, Hiroshi Ohno

Nature (Springer Science and Business Media LLC)  504 ( 7480 ) 446 - 450 2013.12

Accepted,  ISSN  0028-0836

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Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.

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AP-1B-Mediated Protein Sorting Regulates Polarity and Proliferation of Intestinal Epithelial Cells in Mice

Hase, Koji, Nakatsu, Fubito, Ohmae, Masumi, Sugihara, Kazushi, Shioda, Noriko, Takahashi, Daisuke, Obata, Yuuki, Furusawa, Yukihiro, Fujimura, Yumiko, Yamashita, Taisuke, Fukuda, Shinji, Okamoto, Hiroshi, Asano, Masahide, Yonemura, Shigenobu, Ohno, Hiroshi

GASTROENTEROLOGY 145 ( 3 ) 625 - 635 2013.09

Research paper (scientific journal), Accepted,  ISSN  0016-5085

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Background &amp
Aims In epithelial cells, protein sorting mechanisms regulate localization of plasma membrane proteins that generate and maintain cell polarity. The clathrin-adaptor protein (AP) complex AP-1B is expressed specifically in polarized epithelial cells, where it regulates basolateral sorting of membrane proteins. However, little is known about its physiological significance. Methods We analyzed the intestinal epithelia of mice deficient in Ap1m2 (Ap1m2-/- mice), which encodes the AP-1B μ1B subunit, and compared it with 129/B6/CD1 littermates (controls). Notch signaling was inhibited by intraperitoneal injection of dibenzazepine, and β-catenin signaling was inhibited by injection of IWR1. Intestinal tissue samples were collected and analyzed by immunofluorescence analysis. Results Ap1m2 -/- mice developed intestinal epithelial cell hyperplasia. The polarity of intestinal epithelial cells was disrupted, as indicated by the appearance of ectopic microvilli-like structures on the lateral plasma membrane and mislocalization of basolateral membrane proteins, including the low-density lipoprotein receptor and E-cadherin. The E-cadherin-β-catenin complex therefore was disrupted at the adherens junction, resulting in nuclear translocation of β-catenin. This resulted in up-regulation of genes regulated by β-catenin/transcription factor 4 (Tcf4) complex, and increased the proliferation of intestinal epithelial cells. Conclusions AP-1B is required for protein sorting and polarization of intestinal cells in mice. Loss of AP-1B in the intestinal epithelia results in mislocalization of E-cadherin, activation of β-catenin/Tcf4 complex, proliferation, and hyperplasia. © 2013 by the AGA Institute.

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Distinct Roles for CXCR6(+) and CXCR6(-) CD4(+) T Cells in the Pathogenesis of Chronic Colitis

Mandai, Yasushi, Takahashi, Daisuke, Hase, Koji, Obata, Yuuki, Furusawa, Yukihiro, Ebisawa, Masashi, Nakagawa, Tomoo, Sato, Toru, Katsuno, Tatsuro, Saito, Yasushi, Shimaoka, Takeshi, Yokosuka, Osamu, Yokote, Kotaro, Ohno, Hiroshi

PLOS ONE (PUBLIC LIBRARY SCIENCE)  8 ( 6 )  2013.06

Research paper (scientific journal), Accepted,  ISSN  1932-6203

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CD4(+) T cells play a central role in the development of inflammatory bowel disease (IBD) via high-level production of effector cytokines such as IFN-gamma and TNF-alpha. To better characterize the colitogenic CD4(+) T cells, we examined their expression of CXCR6, a chemokine receptor that is expressed by T cells upon activation and is upregulated in several inflammatory diseases. We found that 80% of colonic lamina propria CD4(+) T cells expressed CXCR6 in the CD45RB(high) T cell-transferred colitis model. CXCR6 expression was similarly upregulated in inflamed mucosa of patients with Crohn's disease. Although surface marker analysis demonstrated that both CXCR6(+) and CXCR6(-) CD4(+) T-cell subsets consist of the cells with effector and effector-memory cells, the more cells in the CXCR6(+) subset produced IFN-gamma and TNF-alpha compared to CXCR6(-) subset, and only the CXCR6(+) subset produced IL-17A. Nevertheless, adoptive retransfer of lamina propria CXCR6(+) T cells into Rag1(-/-) recipients failed to induce the disease due to limited expansion of the transferred cells. By contrast, retransfer of CXCR6(-) cells evoked colitis similar to that observed in CD4(+)CD45RB(high) T cell-transferred mice, and resulted in their conversion into CXCR6(+) cells. Collectively, these observations suggest that the CXCR6(+) CD4(+) T-cell subset consists of terminally differentiated effector cells that serve as the major source of effector cytokines in the inflamed tissue, whereas CXCR6(-)CD4(+) T-cell subset serves as a colitogenic memory compartment that retains the ability to proliferate and differentiate into CXCR6(+)CD4(+) T cells.

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The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells

Kanaya, Takashi, Hase, Koji, Takahashi, Daisuke, Fukuda, Shinji, Hoshino, Katsuaki, Sasaki, Izumi, Hemmi, Hiroaki, Knoop, Kathryn A., Kumar, Nachiket, Sato, Mayuko, Katsuno, Tatsuro, Yokosuka, Osamu, Toyooka, Kiminori, Nakai, Kumiko, Sakamoto, Ayako, Kitahara, Yuuki, Jinnohara, Toshi, McSorley, Stephen J., Kaisho, Tsuneyasu, Williams, Ifor R., Ohno, Hiroshi

NATURE IMMUNOLOGY 13 ( 8 ) 729 - + 2012.08

Research paper (scientific journal), Accepted,  ISSN  1529-2908

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Intestinal microfold cells (M cells) are an enigmatic lineage of intestinal epithelial cells that initiate mucosal immune responses through the uptake and transcytosis of luminal antigens. The mechanisms of M-cell differentiation are poorly understood, as the rarity of these cells has hampered analysis. Exogenous administration of the cytokine RANKL can synchronously activate M-cell differentiation in mice. Here we show the Ets transcription factor Spi-B was induced early during M-cell differentiation. Absence of Spi-B silenced the expression of various M-cell markers and prevented the differentiation of M cells in mice. The activation of T cells via an oral route was substantially impaired in the intestine of Spi-B-deficient (Spib(-/-)) mice. Our study demonstrates that commitment to the intestinal M-cell lineage requires Spi-B as a candidate master regulator.

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Epithelial Cell-Intrinsic Notch Signaling Plays an Essential Role in the Maintenance of Gut Immune Homeostasis

Obata, Yuuki, Takahashi, Daisuke, Ebisawa, Masashi, Kakiguchi, Kisa, Yonemura, Shigenobu, Jinnohara, Toshi, Kanaya, Takashi, Fujimura, Yumiko, Ohmae, Masumi, Hase, Koji, Ohno, Hiroshi

JOURNAL OF IMMUNOLOGY 188 ( 5 ) 2427 - 2436 2012.03

Research paper (scientific journal), Accepted,  ISSN  0022-1767

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Intestinal epithelial cells (IECs) have important functions as the first line of defense against diverse microorganisms on the luminal surface. Impaired integrity of IEC has been implicated in increasing the risk for inflammatory disorders in the gut. Notch signaling plays a critical role in the maintenance of epithelial integrity by regulating the balance of secretory and absorptive cell lineages, and also by facilitating epithelial cell proliferation. We show in this article that mice harboring IEC-specific deletion of Rbpj (RBP-J ΔIEC), a transcription factor that mediates signaling through Notch receptors, spontaneously develop chronic colitis characterized by the accumulation of Th17 cells in colonic lamina propria. Intestinal bacteria are responsible for the development of colitis, because their depletion with antibiotics prevented the development of colitis in RBP-J ΔIEC mice. Furthermore, bacterial translocation was evident in the colonic mucosa of RBP-J ΔIEC mice before the onset of colitis, suggesting attenuated epithelial barrier functions in these mice. Indeed, RBP-J ΔIEC mice displayed increase in intestinal permeability after rectal administration of FITC-dextran. In addition to the defect in physical barrier, loss of Notch signaling led to arrest of epithelial cell turnover caused by downregulation of Hes1, a transcriptional repressor of p27 Kip1 and p57 Kip2. Thus, epithelial cell-intrinsic Notch signaling ensures integrity and homeostasis of IEC, and this mechanism is required for containment of intestinal inflammation. Copyright © 2012 by The American Association of Immunologists, Inc.

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The Epithelia-Specific Membrane Trafficking Factor AP-1B Controls Gut Immune Homeostasis in Mice

Takahashi, Daisuke, Hase, Koji, Kimura, Shunsuke, Nakatsu, Fubito, Ohmae, Masumi, Mandai, Yasushi, Sato, Toru, Date, Yasuhiro, Ebisawa, Masashi, Kato, Tamotsu, Obata, Yuuki, Fukuda, Shinji, Kawamura, Yuki I., Dohi, Taeko, Katsuno, Tatsuro, Yokosuka, Osamu, Waguri, Satoshi, Ohno, Hiroshi

GASTROENTEROLOGY 141 ( 2 ) 621 - 632 2011.08

Research paper (scientific journal), Accepted,  ISSN  0016-5085

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Background &amp
Aims: Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized
this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1Bmediated protein sorting in the maintenance of gastrointestinal immune homeostasis. Methods: The role of AP-1B in intestinal immunity was examined in AP-1Bdeficient mice (Ap1m2-/-) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1Bmediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2-/- mice. Results: Ap1m2-/- mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17Aproducing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease. Conclusions: AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1Bmediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation. © 2011 AGA Institute.

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CCR6(hi)CD11c(int) B cells promote M-cell differentiation in Peyer's patch

Ebisawa, Masashi, Hase, Koji, Takahashi, Daisuke, Kitamura, Hiroshi, Knoop, Kathryn A., Williams, Ifor R., Ohno, Hiroshi

INTERNATIONAL IMMUNOLOGY (Oxford University Press (OUP))  23 ( 4 ) 261 - 269 2011.04

Research paper (scientific journal), Accepted,  ISSN  0953-8178

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Liposomal glycosphingolipids activate natural killer T cell-mediated immune responses through the endosomal pathway

Inoue, Joe, Ideue, Ryuichi, Takahashi, Daisuke, Kubota, Masahiro, Kumazawa, Yoshio

JOURNAL OF CONTROLLED RELEASE 133 ( 1 ) 18 - 23 2009.01

Research paper (scientific journal),  ISSN  0168-3659

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Activation-Induced Cytidine Deaminase Deficiency Causes Organ-Specific Autoimmune Disease

Hase, Koji, Takahashi, Daisuke, Ebisawa, Masashi, Kawano, Sayaka, Itoh, Kikuji, Ohno, Hiroshi

PLOS ONE (PUBLIC LIBRARY SCIENCE)  3 ( 8 )  2008.08

Research paper (scientific journal), Accepted,  ISSN  1932-6203

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Activation-induced cytidine deaminase (AID) expressed by germinal center B cells is a central regulator of somatic hypermutation (SHM) and class switch recombination (CSR). Humans with AID mutations develop not only the autosomal recessive form of hyper-IgM syndrome (HIGM2) associated with B cell hyperplasia, but also autoimmune disorders by unknown mechanisms. We report here that AID(-/-) mice spontaneously develop tertiary lymphoid organs (TLOs) in non-lymphoid tissues including the stomach at around 6 months of age. At a later stage, AID(-/-) mice develop a severe gastritis characterized by loss of gastric glands and epithelial hyperplasia. The disease development was not attenuated even under germ-free (GF) conditions. Gastric autoantigen -specific serum IgM was elevated in AID(-/-) mice, and the serum levels correlated with the gastritis pathological score. Adoptive transfer experiments suggest that autoimmune CD4(+) T cells mediate gastritis development as terminal effector cells. These results suggest that abnormal B-cell expansion due to AID deficiency can drive B-cell autoimmunity, and in turn promote TLO formation, which ultimately leads to the propagation of organ-specific autoimmune effector CD4(+) T cells. Thus, AID plays an important role in the containment of autoimmune diseases by negative regulation of autoreactive B cells.

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