Blockade of Bruton's tyrosine kinase suppresses B cell activation and antibody secretion in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with unsatisfactory clinical outcomes. The abnormal B cell activation and pathogenic antibodies secretion are important in the pathogenesis of SLE. Bruton's tyrosine kinase (Btk) plays vital roles in B cell activation, development and differentiation. In this study, we investigated the inhibitory effect and mechanism of blocking Btk signaling in B cells as well as the therapeutic effect on SLE in mice. Btk gene knockout and its inhibitor ibrutinib were used to block Btk signaling. In vitro assays were conducted to explore the effects of blocking Btk expression on B cell responses. A mouse model of SLE was established, and the therapeutic effect of blocking Btk signaling on SLE was investigated. In vitro B Cell Culture and stimulation experiments demonstrated that blocking Btk signaling inhibited B cell activation, proliferation, differentiation, and antibody secretion. In vivo experiments revealed that blocking Btk significantly alleviates SLE and lupus nephritis. Furthermore, blocking Btk signaling reduced the levels of B, plasma, germinal center B, IgG-producing, and IgM-producing cells, and inhibited B cell development in SLE mice, as well as decreased the levels of pathogenic antibodies. Mechanistically, blocking Btk signaling inhibited B cell responses through suppressing PLCγ2 phosphorylation and its downstream pathways MYC, NFAT, and NF-κB. In conclusion, we demonstrated that Blocking Btk signaling inhibits B cell responses and antibody production, thereby alleviating SLE and lupus nephritis. Thus, Btk inhibitors are expected to be clinically used for treating SLE.

Antibody; B cells; Bruton's tyrosine kinase; Ibrutinib; Systemic lupus erythematosus.