| First Author | Manni M | Year | 2018 |
| Journal | Nat Immunol | Volume | 19 |
| Issue | 4 | Pages | 407-419 |
| PubMed ID | 29483597 | Mgi Jnum | J:281492 |
| Mgi Id | MGI:6376450 | Doi | 10.1038/s41590-018-0056-8 |
| Citation | Manni M, et al. (2018) Regulation of age-associated B cells by IRF5 in systemic autoimmunity. Nat Immunol 19(4):407-419 |
| abstractText | Age-associated B cells (ABCs) are a subset of B cells dependent on the transcription factor T-bet that accumulate prematurely in autoimmune settings. The pathways that regulate ABCs in autoimmunity are largely unknown. SWAP-70 and DEF6 (also known as IBP or SLAT) are the only two members of the SWEF family, a unique family of Rho GTPase-regulatory proteins that control both cytoskeletal dynamics and the activity of the transcription factor IRF4. Notably, DEF6 is a newly identified human risk variant for systemic lupus erythematosus. Here we found that the lupus syndrome that developed in SWEF-deficient mice was accompanied by the accumulation of ABCs that produced autoantibodies after stimulation. ABCs from SWEF-deficient mice exhibited a distinctive transcriptome and a unique chromatin landscape characterized by enrichment for motifs bound by transcription factors of the IRF and AP-1 families and the transcription factor T-bet. Enhanced ABC formation in SWEF-deficient mice was controlled by the cytokine IL-21 and IRF5, whose variants are strongly associated with lupus. The lack of SWEF proteins led to dysregulated activity of IRF5 in response to stimulation with IL-21. These studies thus elucidate a previously unknown signaling pathway that controls ABCs in autoimmunity. |
