| First Author | Jackson SW | Year | 2016 |
| Journal | J Exp Med | Volume | 213 |
| Issue | 5 | Pages | 733-50 |
| PubMed ID | 27069113 | Mgi Jnum | J:233318 |
| Mgi Id | MGI:5781254 | Doi | 10.1084/jem.20151724 |
| Citation | Jackson SW, et al. (2016) B cell IFN-gamma receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6. J Exp Med 213(5):733-50 |
| abstractText | Dysregulated germinal center (GC) responses are implicated in the pathogenesis of human autoimmune diseases, including systemic lupus erythematosus (SLE). Although both type 1 and type 2 interferons (IFNs) are involved in lupus pathogenesis, their respective impacts on the establishment of autoimmune GCs has not been addressed. In this study, using a chimeric model of B cell-driven autoimmunity, we demonstrate that B cell type 1 IFN receptor signals accelerate, but are not required for, lupus development. In contrast, B cells functioning as antigen-presenting cells initiate CD4(+) T cell activation and IFN-gamma production, and strikingly, B cell-intrinsic deletion of the IFN-gamma receptor (IFN-gammaR) abrogates autoimmune GCs, class-switched autoantibodies (auto-Abs), and systemic autoimmunity. Mechanistically, although IFN-gammaR signals increase B cell T-bet expression, B cell-intrinsic deletion of T-bet exerts an isolated impact on class-switch recombination to pathogenic auto-Ab subclasses without impacting GC development. Rather, in both mouse and human B cells, IFN-gamma synergized with B cell receptor, toll-like receptor, and/or CD40 activation signals to promote cell-intrinsic expression of the GC master transcription factor, B cell lymphoma 6 protein. Our combined findings identify a novel B cell-intrinsic mechanism whereby IFN signals promote lupus pathogenesis, implicating this pathway as a potential therapeutic target in SLE. |
