Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies, leading to multiple organ dysfunction. SH3BP2 (Src homology domain 3 binding protein 2) is an adaptor protein, which is dominantly expressed in immune cells and regulates intracellular signaling pathways such as Syk and PLCγ. We have previously reported that SH3BP2 deficiency suppresses autoantibody production and subsequent arthritis induction in a murine collagen-induced arthritis model (Mukai T, et al. Arthritis Rheumatol 2015). To further investigate the role of SH3BP2 in autoimmune inflammatory diseases, we here examine the effect of SH3BP2 gain-of-function in a murine SLE model. We hypothesized that the SH3BP2 gain-of-function exacerbates autoantibody production and organ damage in lupus-prone mice, contrasting the phenotype observed in the SH3BP2 deficient arthritis model.

Methods: SH3BP2 gain-of-function mutant (P416R knock-in; SH3BP2^KI/+) mice and lupus-prone (B6.MRL-Fas^lpr/j) mice were crossed to yield the double mutant (SH3BP2^KI/+/Fas^lpr/lpr) mice. Body weight and proteinuria were assessed until 12 months of age. At the end of the observation, mice were euthanized, and serum and organs were collected. Anti-double-stranded DNA (anti-dsDNA) antibody levels in sera were measured by ELISA. Organ involvement was assessed histologically. B-cell and T-cell subsets were analyzed by flow cytometry. To determine the role of SH3BP2 in B cells to mediate proliferation following cross-linking of the B-cell receptor (BCR), resting splenic B cells were isolated from wild-type and SH3BP2^KI/+ mice and stimulated with either anti-IgM antibody, anti-IgM antibody plus anti-CD40 antibody or LPS.

Results: Unexpectedly, we found that SH3BP2 gain-of-function mutation suppressed the development of renal disease. According to the amelioration of disease, SH3BP2^KI/+/Fas^lpr/lpr mice had lower titers of anti-dsDNA antibodies than Fas^lpr/lpr mice. The B220⁺CD4^–CD8^– (double-negative) T cell population characteristic of Fas^lpr/lpr mice in the lymph nodes was decreased in the SH3BP2^KI/+/Fas^lpr/lpr mice. In vitro experiments, B-cell proliferation in response to BCR cross-linking with anti-IgM antibody was comparable between wild-type and SH3BP2^KI/+ cells, suggesting that the mechanism of suppression of disease was not B cell mediated.

Conclusion: Contrary to our initial hypothesis, SH3BP2 gain-of-function mutation ameliorated clinical and immunological phenotypes of the lupus-prone mice. Further analyses are required to reveal the immunoregulatory role of SH3BP2 in the autoimmune disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sh3bp2-gain-of-function-mutation-ameliorates-lupus-in-b6-mrl-faslpr-mice/