title: Obesity-associated autoantibody production requires AIM to retain the immunoglobulin M immune complex on follicular dendritic cells.
abstract: 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.
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. sarai@m.u-tokyo.ac.jp
authors.forename: Satoko
authors.initials: S
authors.lastname: Arai
authors.forename: Natsumi
authors.initials: N
authors.lastname: Maehara
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Iwamura
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Honda
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nakashima
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kai
authors.forename: Masato
authors.initials: M
authors.lastname: Ogishi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Morita
authors.forename: Jun
authors.initials: J
authors.lastname: Kurokawa
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mori
authors.forename: Yuji
authors.initials: Y
authors.lastname: Motoi
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matsuhashi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamamura
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Akira
authors.initials: A
authors.lastname: Shibuya
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wakeland
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.forename: Toru
authors.initials: T
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000097:blood; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001323:Autoantibodies / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000378:metabolism / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D020566:Dendritic Cells, Follicular / Q000276:immunology / Q000378:metabolism*; D059305:Diet, High-Fat; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D010950:Plasma Cells / Q000378:metabolism; D011485:Protein Binding; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000936:Antigen-Antibody Complex; D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; C117272:Cd5l protein, mouse; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011961:Receptors, Fc; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D051197:Toll-Like Receptor 4; C024242:polymeric IgM