Toll-like receptor engagement stimulates anti-snRNP autoreactive B cells for activation.
Autoreactive B cells are the source of pathogenic autoantibodies (autoAb) in systemic lupus erythematosus (SLE). Previous studies have demonstrated that anti-small nuclear ribonucleoprotein particles (snRNP) B cells from normal background mice tolerize T cells in the periphery and do not secrete autoAb. In this study, we examined whether these anti-snRNP B cells can be activated for autoAb production by the engagement of Toll-like receptors (TLR). Anti-snRNP B cells proliferated vigorously and secreted abundant anti-snRNP autoAb upon exposure to CpG or polyriboinosinic polyribocytidylic acid [poly (I:C)] in vitro. In addition, the costimulatory molecules CD80 and CD86 were up-regulated. While both anti-snRNP B cells and wild-type B cells produced similar levels of IL-6 and IL-10, anti-snRNP B cells secreted predominately IFN-gamma in response to CpG or poly (I:C) stimulation. Furthermore, we showed that in vivo engagement of TLR stimulated immature anti-snRNP B cells to further differentiate and produce autoAb and form germinal centers. The activated anti-snRNP B cells became expanded and migrated into the T-B cell interface. Moreover, TLR engagement directly or indirectly activated autoreactive B cells via a CD4 T cell-independent manner. These results provide in vitro and in vivo evidence that BCR/TLR co-engagement promotes the activation of anti-snRNP B cells for autoAb production.
Ding
Chuanlin
C
James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Wang
Li
L
Al-Ghawi
Hayma
H
Marroquin
Jose
J
Mamula
Mark
M
Yan
Jun
J
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011070:Poly I-C / Q000494:pharmacology; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology* / Q000378:metabolism*
D001323:Autoantibodies; D016207:Cytokines; D008024:Ligands; D017411:Ribonucleoproteins, Small Nuclear; D051193:Toll-Like Receptors; D011070:Poly I-C