TY - JOUR
T1 - Obesity-Associated Autoantibody Production Requires AIM to Retain the Immunoglobulin M Immune Complex on Follicular Dendritic Cells
AU - Arai, Satoko
AU - Maehara, Natsumi
AU - Iwamura, Yoshihiro
AU - Honda, Shin ichiro
AU - Nakashima, Katsuhiko
AU - Kai, Toshihiro
AU - Ogishi, Masato
AU - Morita, Kumiko
AU - Kurokawa, Jun
AU - Mori, Mayumi
AU - Motoi, Yuji
AU - Miyake, Kensuke
AU - Matsuhashi, Nobuyuki
AU - Yamamura, Ken ichi
AU - Ohara, Osamu
AU - Shibuya, Akira
AU - Wakeland, Edward K.
AU - Li, Quan Zhen
AU - Miyazaki, Toru
N1 - Funding Information:
We thank T. Tokuhisa (Chiba), N. Minato (Kyoto), S. Izui (Geneva), M. Ohba (Tokyo), A. Nishijima (Tokyo), K. Ohkubo (Genostaff, Tokyo) for useful advice and technical assistance, and M. Miyamoto and Y. Inoue for preparing the manuscript. This work was supported by the Global COE Research Program, Health and Labor Sciences Research Grants (Ministry of Health, Labor and Welfare of Japan), Mitsubishi Pharma Research Foundation, Natto Research Foundation (to T.M.), Grants-in-Aid for Scientific Research (B), Kanae Foundation for the Promotion of Medical Science, Astellas Foundation for Research on Metabolic Disorders, Ono Medical Research Foundation, and Banyu Foundation (research grant to S.A.).
PY - 2013/4/25
Y1 - 2013/4/25
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2013.03.006
DO - 10.1016/j.celrep.2013.03.006
M3 - Article
C2 - 23562157
AN - SCOPUS:84877004146
SN - 2211-1247
VL - 3
SP - 1187
EP - 1198
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -