Activating Fcγ receptors participate in the development of autoimmune diabetes in NOD mice

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

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

Abstract

Type 1 diabetes mellitus (T1D) in humans is an organ-specific autoimmune disease in which pancreatic islet β 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 β cell-specific autoantibodies, although it remains a subject of debate regarding whether these autoantibodies contribute to the development of T1D. FcγRs 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 FcγRs in NOD mice, we generated several FcγR-less NOD lines, namely FcR common γ-chain (FcRγ)-deficient (NOD·γ -/-), FcγRIII-deficient (NOD.III-/-), FcγRIIB-deficient (NOD.IIB-/-), and both FcRγ and FcγRIIB-deficient NOD (NOD.null) mice. In this study, we show significant protection from diabetes in NOD.γ-/-, NOD.III-/-, and NOD.null, but not in NOD.IIB-/- mice even with grossly comparable production of autoantibodies among them. Insulitis in NOD.γ-/- mice was also alleviated. Adoptive transfer of bone marrow-derived dendritic cells or NK cells from NOD mice rendered NOD.γ-/- animals more susceptible to diabetes, suggesting a possible scenario in which activating FcγRs on dendritic cells enhance autoantigen presentation leading to the activation of autoreactive T cells, and FcγRIII on NK cells trigger Ab-dependent effector functions and inflammation. These findings highlight the critical roles of activating FcγRs in the development of T1D, and indicate that FcγRs are novel targets for therapies for T1D.

Original languageEnglish
Pages (from-to)764-774
Number of pages11
JournalJournal of Immunology
Volume179
Issue number2
DOIs
Publication statusPublished - 2007 Jul 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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