Obesity-Associated Autoantibody Production Requires AIM to Retain the Immunoglobulin M Immune Complex on Follicular Dendritic Cells
Satoko Arai,
Natsumi Maehara,
Yoshihiro Iwamura,
Shin-ichiro Honda,
Katsuhiko Nakashima,
Toshihiro Kai,
Masato Ogishi,
Kumiko Morita,
Jun Kurokawa,
Mayumi Mori,
Yuji Motoi,
Kensuke Miyake,
Nobuyuki Matsuhashi,
Ken-ichi Yamamura,
Osamu Ohara,
Akira Shibuya,
Edward K. Wakeland,
Quan-Zhen Li,
Toru Miyazaki
Affiliations
Satoko Arai
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Natsumi Maehara
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Yoshihiro Iwamura
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Shin-ichiro Honda
Department of Immunology, Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki 305-8575, Japan
Katsuhiko Nakashima
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Toshihiro Kai
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Masato Ogishi
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Kumiko Morita
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Jun Kurokawa
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Mayumi Mori
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Yuji Motoi
Division of Infectious Genetics, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Kensuke Miyake
Division of Infectious Genetics, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
Nobuyuki Matsuhashi
Department of Gastroenterology, NTT Medical Center Tokyo, Tokyo 141-8625, Japan
Ken-ichi Yamamura
Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan
Osamu Ohara
Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan
Akira Shibuya
Department of Immunology, Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki 305-8575, Japan
Edward K. Wakeland
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093, USA
Quan-Zhen Li
Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8814, USA
Toru Miyazaki
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Natural immunoglobulin M (IgM) is reactive to autoantigens and is believed to be important for autoimmunity. Blood pentameric IgM loaded with antigens forms a large immune complex (IC) that contains various elements, including apoptosis inhibitor of macrophage (AIM). Here we demonstrate that this IgM-AIM association contributes to autoantibody production under obese conditions. In mice fed a high-fat diet, natural IgM increased through B cell TLR4 stimulation. AIM associated with IgM and protected AIM from renal excretion, increasing blood AIM levels along with the obesity-induced IgM augmentation. Meanwhile, the AIM association inhibited IgM binding to the Fcα/μ receptor on splenic follicular dendritic cells, thereby protecting the IgM IC from Fcα/μ receptor-mediated internalization. This supported IgM-dependent autoantigen presentation to B cells, stimulating IgG autoantibody production. Accordingly, in obese AIM-deficient (AIM−/−) mice, the increase of multiple IgG autoantibodies observed in obese wild-type mice was abrogated. Thus, the AIM-IgM association plays a critical role in the obesity-associated autoimmune process.
