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THU0379 Dichotomy in FC Gamma Receptor IIB Deficiency and Autoimmune-Prone Slam Haplotype Reveals the Role of Slam Haplotype in Monocytosis and the Significant Effect of FC Gamma Receptor IIB Deficiency in Yaa-Related Lupus Nephritis
  1. K. Nishikawa1,
  2. Q. Lin1,
  3. H. Tsurui1,
  4. S. Kawano2,
  5. K. Kojo2,
  6. H. Amano2,
  7. T. Shirai1,
  8. S. Hirose1
  1. 1Department of Pathology
  2. 2Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan

Abstract

Background The inhibitory FcγRIIb-deficient mice develop autoimmune diseases, such as lupus nephritis, rheumatoid arthritis, and vasculitis with inflammatory cell infiltration [1,2]; however, the incorporation of FcγRIIb-linked autoimmune-prone SLAM haplotype in these gene targeting mice makes it difficult to isolate the role of FcγRIIb deficiency from SLAM haplotype in these diseases.

Objectives In the present study, we genetically dissected the role of FcγRIIb deficiency and SLAM haplotype for these autoimmune diseases.

Methods By extensively backcrossing 129-based FcγRIIb-deficient mice to B6 mice, three congenic mouse strains were established, the first with FcγRIIb deficiency and 129-derive autoimmune-prone SLAM haplotype (KO1), the second with FcγRIIb deficiency and B6 SLAM haplotype (KO2), and the third with wild-type FcγRIIb and 129 SLAM haplotype (SLAM129).

Results Lupus nephritis did not develop in KO1, KO2, and SLAM129; however, KO1 and SLAM129 showed age-associated monocytosis and perivascular inflammatory cell infiltration. When introducing Yaa mutation, KO1.Yaa and KO2.Yaa mice developed severe nephritis. In contrast, SLAM129.Yaa mice developed mild form of lupus nephritis with the increased serum level of IgM, but not IgG, class autoantibodies.

Conclusions Monocytosis was shown to be one of the characteristic features in murine models of lupus nephritis [3]. Our study suggests that autoimmune-prone SLAM haplotype plays a pivotal role for monocytosis and resulting perivascular inflammatory cell infiltration; however, SLAM129 alone is not enough for the development of lupus nephritis. FcγRIIb deficiency alone was not enough for both monocytosis and lupus nephritis. In the presence of Yaa, FcγRIIb deficiency plays a significant role for the development of lupus nephritis with isotype switch of autoantibodies from IgM to pathogenic IgG class. Mild form of lupus nephritis in SLAM129.Yaa mice may be due to the deposition of IgM autoantibodies in glomeruli, which results in the up-regulation of chemokine production by activated mesangial cells and resultant inflammatory cell infiltration to glomeruli because of the high frequencies of monocytes in periphery.

References

  1. Bollans S. and Ravetch JV. Immunity 13:277-285, 2000.

  2. Sato-Hayashizaki A, et al. Arthritis Rheum. 63:2930-2938, 2011.

  3. Wofsy D, et al. J. Exp. Med. 159:629-634, 1984.

Disclosure of Interest None declared

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