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Pro‐inflammatory immune complexes are sufficient to induce a lupus‐like phenotype in R4AxFcRIIb−/− BALB/c mice
Author(s) -
Jeganathan Venkatesh,
Kawabata Daisuke,
Xu Xiaonan,
Kim Sunjung,
Diamond Betty,
Grimaldi Christine
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.667.10
Subject(s) - antibody , immune system , microbiology and biotechnology , systemic lupus erythematosus , spleen , b cell activating factor , immunology , chemistry , plasma cell , biology , b cell , medicine , disease
FcRIIb, a low‐affinity inhibitory receptor for the Fc portion of IgG, is expressed on B cells and is required for the elimination of long‐lived plasma cells. FcRIIb−/− C57BL/6 mice spontaneously develop high titers of pathogenic IgG anti‐DNA antibodies and die prematurely of immune complex (IC)‐mediated renal failure, whereas BALB/c mice deficient in FcRIIb show no evidence of autoimmune disease. We have developed a mouse that is transgenic (Tg) for the heavy (H) chain of a nephritogenic anti‐DNA antibody (R4A‐γ2b) that maintains B cell tolerance when expressed on a non‐autoimmune background. Since the R4A H chain can generate pro‐inflammatory anti‐DNA antibodies, we hypothesized that the R4A Tg may be sufficient to break tolerance in FcRIIb−/− BALB/c mice. Young R4A Tg BALB/c FcRIIb−/− mice displayed negligible anti‐DNA titers; however by 6 months of age they developed elevated anti‐DNA antibodies, proteinuria and IC deposition in the kidney. An increase in the number of Tg‐expressing plasma cells was observed. In addition IFN‐α inducible genes, IFI202b and OASLE were upregulated in spleen consistent with the presence of pro‐inflammatory DNA‐containing ICs. Interestingly, splenic BAFF mRNA and serum BAFF protein levels were significantly increased. We propose that FcRIIb deficiency induces a feedback loop wherein the failure to eliminate plasma cells facilitate the generation of DNA‐containing pro‐inflammatory ICs, which induce BAFF, and enhance the maturation of high affinity anti‐DNA B cells.