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Immunoglobulin A–specific deficiency induces spontaneous inflammation specifically in the ileum
  1. Takashi Nagaishi1,2,
  2. Taro Watabe1,
  3. Kunihiko Kotake3,4,
  4. Toshihiko Kumazawa3,4,
  5. Tomomi Aida5,
  6. Kohichi Tanaka5,
  7. Ryuichi Ono6,7,
  8. Fumitoshi Ishino6,
  9. Takako Usami8,
  10. Takamasa Miura9,
  11. Satomi Hirakata9,
  12. Hiroko Kawasaki9,
  13. Naoya Tsugawa1,
  14. Daiki Yamada1,
  15. Kazuhiro Hirayama10,
  16. Soichiro Yoshikawa11,12,
  17. Hajime Karasuyama11,13,
  18. Ryuichi Okamoto1,
  19. Mamoru Watanabe1,13,
  20. Richard S Blumberg14,
  21. Takahiro Adachi3,15
  1. 1Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan
  2. 2Department of Advanced Therapeutics for GI Diseases, Graduate School of Medical Science, TMDU, Bunkyo-ku, Tokyo, Japan
  3. 3Department of Immunology, Medical Research Institute, TMDU, Bunkyo-ku, Tokyo, Japan
  4. 4Research and Development Department, Ichibiki Co., Ltd, Nagoya, Aichi, Japan
  5. 5Department of Molecular Neuroscience, Medical Research Institute, TMDU, Bunkyo-ku, Tokyo, Japan
  6. 6Department of Epigenetics, Medical Research Institute, TMDU, Bunkyo-ku, Tokyo, Japan
  7. 7Current address: Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences (NIHS), Kawasaki, Kanagawa, Japan
  8. 8Laboratory of Recombinant Animals, Medical Research Institute, TMDU, Bunkyo-ku, Tokyo, Japan
  9. 9Biological Resource Center, National Institute of Technology and Evaluation (NITE), Shibuya-ku, Tokyo, Japan
  10. 10Laboratory of Veterinary Public Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
  11. 11Department of Immune Regulation, Graduate School of Medical Science, TMDU, Bunkyo-ku, Tokyo, Japan
  12. 12Current address: Department of Cellular Physiology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
  13. 13Advanced Research Institute, TMDU, Bunkyo-ku, Tokyo, Japan
  14. 14Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  15. 15Current address: Department of Precision Health, Medical Research Institute, TMDU, Chiyoda-ku, Tokyo, Japan
  1. Correspondence to Associate Professor Takahiro Adachi, Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan; tadachi.imm{at}mri.tmd.ac.jp; Associate Professor Takashi Nagaishi, Department of Advanced Therapeutics for GI Diseases, Graduate School of Medical Science, TMDU, Bunkyo-ku, Tokyo, Japan; tnagaishi.gast{at}tmd.ac.jp; Professor Richard S Blumberg, Gastroenterology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; rblumberg{at}bwh.harvard.edu

Abstract

Objective Although immunoglobulin A (IgA) is abundantly expressed in the gut and known to be an important component of mucosal barriers against luminal pathogens, its precise function remains unclear. Therefore, we tried to elucidate the effect of IgA on gut homeostasis maintenance and its mechanism.

Design We generated various IgA mutant mouse lines using the CRISPR/Cas9 genome editing system. Then, we evaluated the effect on the small intestinal homeostasis, pathology, intestinal microbiota, cytokine production, and immune cell activation using intravital imaging.

Results We obtained two lines, with one that contained a <50 base pair deletion in the cytoplasmic region of the IgA allele (IgA tail-mutant; IgAtm/tm) and the other that lacked the most constant region of the IgH α chain, which resulted in the deficiency of IgA production (IgA−/−). IgA−/− exhibited spontaneous inflammation in the ileum but not the other parts of the gastrointestinal tract. Associated with this, there were significantly increased lamina propria CD4+ T cells, elevated productions of IFN-γ and IL-17, increased ileal segmented filamentous bacteria and skewed intestinal microflora composition. Intravital imaging using Ca2+ biosensor showed that IgA−/− had elevated Ca2+ signalling in Peyer’s patch B cells. On the other hand, IgAtm/tm seemed to be normal, suggesting that the IgA cytoplasmic tail is dispensable for the prevention of the intestinal disorder.

Conclusion IgA plays an important role in the mucosal homeostasis associated with the regulation of intestinal microbiota and protection against mucosal inflammation especially in the ileum.

  • inflammation
  • intestinal bacteria
  • mucosal barrier
  • IgA
  • ileitis
  • small intestine

Data availability statement

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplemental information. DNA sequences were deposited in the DDBJ Sequence Read Archive under accession number DRA005447.

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Data availability statement

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as online supplemental information. DNA sequences were deposited in the DDBJ Sequence Read Archive under accession number DRA005447.

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Footnotes

  • TN and TW contributed equally.

  • Contributors TN: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; obtained funding. TW: acquisition of data; analysis and interpretation of data; statistical analysis; obtained funding. KK: acquisition of data; statistical analysis. TK: acquisition of data. TA: technical and material support. KT: technical and material support; ROno: technical support. FI: technical support. TU: material support. TM: acquisition of data; analysis and interpretation of data; statistical analysis. SH: acquisition of data; analysis and interpretation of data; statistical analysis. HK: acquisition of data; analysis and interpretation of data; statistical analysis. NT: acquisition of data. DY: acquisition of data. KH: analysis and interpretation of data; critical revision of the manuscript for important intellectual content. SY: obtained funding; technical support. HK: study concept and design. ROkamoto: study concept and design; study supervision. MW: study concept and design; obtained funding; study supervision. RSB: study supervision; critical revision of the manuscript for important intellectual content; drafting of the manuscript. TA: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; obtained funding. All authors reviewed the manuscript.

  • Funding This work was supported in part by Grants-in-Aid for Scientific Research on Innovative Area (MW, 22117508), Challenging Exploratory Research (TN, 15K15288), Scientific Research-S (MW, 26221307), Scientific Research-B (TN, 16H05286 and 20H03658) and Scientific Research-C (TA, 15K08526 and TW, 18K07997) from the Japanese Ministry of Education, Culture, Sports, Science and Technology, Practical Research Project for Rare/Intractable Disease (MW, 16eK0109047h0003) from Japan Agency for Medical Research and Development, RO1 Grants from the National Institutes of Health (RSB, DK088199, DK44319 and DK51362), Yamada Foundation (TA), Memorial Fund of Nihon University Medical Alumni Association (TN), Abbott Japan Allergy Research Award (TN), Foundation for Advancement of International Science (TN), Takeda Science Foundation (TN), Joint Usage/Research Programme of TMDU Medical Research Institute (SY, TN and TA), Japan Foundation for Applied Enzymology (TW), Nipponham Foundation for the Future of Food (TA), Tojuro Iijima Foundation for Food Science and Technology (TA), Mishima Kaiun Memorial Foundation (TA), and Naoki Tsuchida Memorial Research Grant (SY, TN and TA).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Open data DNA sequences of microbiota were deposited in the DDBJ Sequence Read Archive under accession number DRA005447.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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