IFN-α amplifies human naive B cell TLR-9-mediated activation and Ig production

TLRs are a family of molecules that function as sensors for the detection of pathogens. TLR-9, expressed on B cells and pDCs, recognizes CpG motifs of unmethylated bacterial DNA and plays a role in the development of autoimmunity. The present study was designed to investigate the effects of IFN-alpha in combination with CpG ODN on the activation of CD27-naive B cells and on Ig production. We provide evidence that CpG ODN not only induces a total and T-dependent, specific IgM response by naive B cells but also their phenotypic differentiation in plasma cells, as demonstrated by the upregulation of CD38 expression. We found that TLR-9 stimulation with CpG ODN induces IL-1 beta, TNF-alpha, IL-10, and IL-6 production. Interestingly, we also found that CpG ODN induces naive B cell maturation into memory cells, as demonstrated by the induction of CD27, AID mRNA expression, and IgG production. More importantly, our results demonstrate that IFN-alpha amplifies the inductive effect of CpG ODN on naive B activation and on Ig production through a mechanism involving TLR-9/MyD88-dependent signaling. Moreover, we found that IFN-alpha enhances the frequency of CpG ODN-induced memory B cells. Our results may contribute to clarify the events promoting IFN-alpha-induced amplification of naive B cell activation via TLR-9 for a better understanding of the pathogenesis of autoimmune disorders and may guide treatments targeting this pathway within B cells. J. Leukoc. Biol. 86: 261-271; 2009.