SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

Tomoyuki Mukai¹, Kyoko Kawahara¹, Masanori Iseki², Akiko Nagasu¹, Hajime Nagasu³, Takahiko Akagi¹, Shoko Tsuji¹, Yasuyoshi Ueki⁴, Katsuhiko Ishihara², Naoki Kashihara³ and Yoshitaka Morita¹, ¹Department of Rheumatology, Kawasaki Medical School, Kurashiki, Okayama, Japan, ²Department of Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki, Okayama, Japan, ³Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan, ⁴Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN

Meeting: ACR Convergence 2020

Keywords: Animal Model, Systemic lupus erythematosus (SLE)

Session Information

Date: Saturday, November 7, 2020

Title: SLE – Animal Models Poster

Session Type: Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: The adaptor protein, Src homology 3 domain-binding protein 2 (SH3BP2), is widely expressed in immune cells, such as myeloid cells, B cells, and T cells. It controls intracellular signaling pathways such as Syk and Src. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model and to explore differential phenotypes in immune cell sub-populations isolated from SH3BP2-deficient mice.

Methods: For the lupus model, we used Fas^lpr mice (C57BL/6 background). Clinical and immunological phenotypes were compared between Fas^lpr and SH3BP2-deficient Fas^lpr mice. Splenomegaly and renal involvement were assessed in 35-week-old mice. Serum levels of anti-dsDNA antibody and rheumatoid factor were determined using ELISA. Lymphocyte subsets in spleen and lymph nodes were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were generated and analyzed; differentiation of bone marrow-derived dendritic cell and activation of T cells and macrophages were determined in vitro.

Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, such as splenomegaly, renal involvement, elevated serum dsDNA antibody and rheumatoid factor, and increased splenic B220⁺CD4^–CD8^– T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells but it did not affect the functions of T cells and macrophages in vitro.

Conclusion: SH3BP2 deficiency ameliorated clinical and immunological manifestations in lupus-prone mice, possibly via targeting dendritic cells differentiation. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

Disclosure: T. Mukai, Chugai Pharmaceutical Co., 2, AYUMI Pharmaceutical Co., 2; K. Kawahara, Chugai Pharmaceutical Co., 2, AYUMI Pharmaceutical Co., 2; M. Iseki, None; A. Nagasu, Chugai Pharmaceutical Co., 2, AYUMI Pharmaceutical Co., 2; H. Nagasu, None; T. Akagi, Chugai Pharmaceutical Co., 2, AYUMI Pharmaceutical Co., 2; S. Tsuji, Chugai Pharmaceutical Co., 2, AYUMI Pharmaceutical Co., 2; Y. Ueki, None; K. Ishihara, None; N. Kashihara, None; Y. Morita, Chugai Pharmaceutical Co., 2, AYUMI Pharmaceutical Co., 2.

To cite this abstract in AMA style:

Mukai T, Kawahara K, Iseki M, Nagasu A, Nagasu H, Akagi T, Tsuji S, Ueki Y, Ishihara K, Kashihara N, Morita Y. SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/sh3bp2-deficiency-ameliorates-murine-systemic-lupus-erythematosus/. Accessed .

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