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

Abstract

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(-) naïve B cells and on Ig production. We provide evidence that CpG ODN not only induces a total and T-dependent, specific IgM response by naïve B cells but also their phenotypic differentiation in plasma cells, as demonstrated by the up-regulation of CD38 expression. We found that TLR-9 stimulation with CpG ODN induces IL-1beta, TNF-alpha, IL-10, and IL-6 production. Interestingly, we also found that CpG ODN induces naïve 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 naïve 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 naïve 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.

Negative regulation of inflammatory responses by immunoglobulin A receptor (FcαRI) inhibits the development of Toll-like receptor-9 signalling-accelerated glomerulonephritis

“…Such nucleic acid-containing immunocomplexes were shown to activate autoreactive B cells and autoantibody production. TLR-9-active sequence transgenic mice produce large amounts of anti-RNA, -DNA and -nucleosome antibodies of the IgG2a and IgG2b isotype that cause nephritis [27]. B cells can promptly detect and mount responses to antigen after immunization.…”

Toll‐like receptors on B‐CLL cells: expression and functional consequences of their stimulation

“…40 Recent report has described CD38 upregulation and differentiation of B cells in plasma cells after stimulation with CpG ODN. 41 We show that the expression of CD38 on B-CLL cells could be induced by 2 mechanisms. Either by the direct stimulation of B-CLL cells by agonists of TLR-7 and TLR-9, receptors expressed on B-CLL cells.…”

Idiopathic Inflammatory Myopathies: A Review of Immunopathological Features and Current Models of Pathogenesis

“…Immunohistochemical and molecular studies have shown that transcriptionally active CD138+ plasma cells -that have undergone affinity maturation and switched their isotype from IgM to IgG or IgA -are abundant in PM muscle (Greenberg, 2007a;Salajegheh et al, 2010b;Cappelletti et al, 2011). In view of the recently demonstrated ability of TLR9 to induce B cells to mature to plasma cell in vitro (Giordani et al, 2009), together with the observed upregulation of TLR9 in this form of myopathy , it is reasonable to hypothesize a role for this receptor in immunoglobulin production in PM.…”