IFN-alpha 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(-) 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.
Giordani
L
L
Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy.
Sanchez
M
M
Libri
I
I
Quaranta
M G
MG
Mattioli
B
B
Viora
M
M
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007136:Immunoglobulins / Q000378:metabolism; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D016898:Interferon-alpha / Q000378:metabolism* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010641:Phenotype; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
C513533:CpG ODN 2006; D016207:Cytokines; D007074:Immunoglobulin G; D007136:Immunoglobulins; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase