Background/Purpose: B cells play a pivotal role in pathological processes of autoimmune diseases. Spleen tyrosine kinase (Syk) functions as a key molecule in B-cell receptor (BCR)-mediated signaling. However, the underlying mechanisms of Syk in autoimmune diseases such as RA and SLE remain unclear.

Methods: Purified naïve (CD27^–) and memory (CD27^–) B cells from healthy donor were stimulated with BCR cross-linking, soluble CD40L, and CpG-ODN2006. The role of Syk was evaluated with a specific Syk inhibitor: BAY61-3606. B cell line (Raji) and PBMCs from RA and SLE patients were utilized to assess the detailed molecular mechanism of activated B cells and involvement in the pathology of RA and SLE.

Results: BCR-crosslinking, in conjunction with CD40 and TLR-9 stimulations, efficiently activate B cells and induced various functions such as proliferation and differentiation especially in memory B cells, while specific Syk inhibitors completely abrogated them to background levels. It is noteworthy that BCR-crosslinking markedly induced expression of TNF receptor-associated factor (TRAF)-6 but not TRAF-2,-3 and -5. Additional CD40 and TLR9 stimulations further induced expression of TRAF-6 and phosphorylation of NF-κB, while a Syk inhibitor again significantly inhibited them. Strong phosphorylation of Syk were observed in B cells from RA (n=62) and SLE patients(n=58) compared with healthy donors (n=27). Levels of Syk phosphorylation were higher in SLE patients positive for anti-dsDNA antibodies than those negative for them and also well correlated with the disease activity score such as SLEDAI. On the other hand, Syk phosphorylation were higher in RA patients most positive for anti-CCP antibodies than those negative for them, however, not correlated with the disease activity score such as DAS28, CDAI and SDAI.

Conclusion: Syk-mediated BCR-signaling is prerequisite for optimal induction of TRAF-6, thereby allowing efficient propagation of TLR9-signaling critical for proliferation and differentiation of human memory B cells. Moreover, we suggest that Syk-mediated signaling on B cells is involved in pathological process in autoimmune diseases via producing autoantibody, however, more dominantly in pathology of SLE compared with RA.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-syk-in-human-b-cell-activation-and-its-relevance-to-autoimmune-diseases/