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Syk inhibition limits autoimmunity and abnormal B cell phenotype and function in mice with B cell-specific TRAF3 deficiency
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DOI：10.1093/jimmun/vkag049.png)
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Abstract
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Autoimmune disorders reduce quality of life and lifespan and can increase B cell lymphoma risk. The adaptor protein TRAF3 regulates B cell survival, activation, and differentiation by restraining signaling through Toll-like receptors, tumor necrosis factor (TNF) receptor superfamily members, and the B cell antigen receptor-pathways linked to autoimmunity and lymphoma. Mice lacking TRAF3 in B cells (B-Traf3-/-) develop both autoimmunity and B cell malignancies. TRAF3 negatively regulates activation of spleen tyrosine kinase (Syk), which is involved in multiple B cell signaling pathways. B-Traf3-/- mice treated with the Food and Drug Administration (FDA)-approved Syk inhibitor Fostamatinib, exhibited reduction in autoantibodies, gland inflammation, and expansion of autoimmune-associated B cell populations. Fostamatinib also corrected enhanced pro-survival proteins and aberrant B cell survival in Traf3-/- B cells, without inhibiting humoral responses to immunization. These findings identify elevated Syk activation as a key driver of B cell dysfunction and autoimmunity in B-Traf3-/- mice, suggesting therapeutic potential for Syk inhibitors in conditions linked to decreased B cell TRAF3 levels.
Keywords:
autoimmunity
B cells
signal transduction
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