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Activating Fc Receptors Participate in the Development of Autoimmune Diabetes in NOD Mice¹

Yoshihiro Inoue^*, Tomonori Kaifu^*, Akiko Sugahara-Tobinai^*, Akira Nakamura^*, Jun-Ichi Miyazaki and Toshiyuki Takai^2,*

^* Department of Experimental Immunology, and the Core Research for Evolutional, Science and Technology Program of the Japan Science and Technology Agency, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; and Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Osaka, Japan

Type 1 diabetes mellitus (T1D) in humans is an organ-specific autoimmune disease in which pancreatic islet cells are ruptured by autoreactive T cells. NOD mice, the most commonly used animal model of T1D, show early infiltration of leukocytes in the islets (insulitis), resulting in islet destruction and diabetes later. NOD mice produce various islet cell-specific autoantibodies, although it remains a subject of debate regarding whether these autoantibodies contribute to the development of T1D. FcRs are multipotent molecules that play important roles in Ab-mediated regulatory as well as effector functions in autoimmune diseases. To investigate the possible role of FcRs in NOD mice, we generated several FcR-less NOD lines, namely FcR common -chain (FcR)-deficient (NOD.^–/–), FcRIII-deficient (NOD.III^–/–), FcRIIB-deficient (NOD.IIB^–/–), and both FcR and FcRIIB-deficient NOD (NOD.null) mice. In this study, we show significant protection from diabetes in NOD.^–/–, NOD.III^–/–, and NOD.null, but not in NOD.IIB^–/– mice even with grossly comparable production of autoantibodies among them. Insulitis in NOD.^–/– mice was also alleviated. Adoptive transfer of bone marrow-derived dendritic cells or NK cells from NOD mice rendered NOD.^–/– animals more susceptible to diabetes, suggesting a possible scenario in which activating FcRs on dendritic cells enhance autoantigen presentation leading to the activation of autoreactive T cells, and FcRIII on NK cells trigger Ab-dependent effector functions and inflammation. These findings highlight the critical roles of activating FcRs in the development of T1D, and indicate that FcRs are novel targets for therapies for T1D.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the Core Research for Evolutional, Science and Technology Program of the Japan Science and Technology Agency, a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a grant from the 21st-century Center of Excellence program "Center for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases."

² Address correspondence and reprint requests to Dr. Toshiyuki Takai, Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo 4–1, Sendai, Japan. E-mail address: tostakai{at}idac.tohoku.ac.jp

³ Abbreviations used in this paper: T1D, type 1 diabetes mellitus; ADCC, Ab-dependent cell-mediated cytotoxicity; DC, dendritic cell; FcR, Fc receptor common subunit; GAD, glutamic acid decarboxylase; IVIg, intravenous gamma globulin; NOD.^–/–, FcR common -chain-deficient NOD; NOD.IIB^–/–, FcRIIB-deficient NOD; NOD.III^–/–, FcRIII-deficient NOD; NOD.null, FcR common -chain and FcRIIB double-deficient NOD; ITP, immune thrombocytopenic purpura.