| First Author | Zhang W | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 37 | Pages | 18550-18560 |
| PubMed ID | 31451659 | Mgi Jnum | J:279309 |
| Mgi Id | MGI:6360510 | Doi | 10.1073/pnas.1901340116 |
| Citation | Zhang W, et al. (2019) Excessive CD11c(+)Tbet(+) B cells promote aberrant TFH differentiation and affinity-based germinal center selection in lupus. Proc Natl Acad Sci U S A 116(37):18550-18560 |
| abstractText | Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response-a process critical for antibody affinity maturation-is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c(+)Tbet(+) age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipDeltaB) lupus mice, excessive CD11c(+)Tbet(+) ABCs induce deregulated follicular T-helper (TFH) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c(+)Tbet(+) ABCs and deregulated TFH cell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c(+)Tbet(+) ABC differentiation, and blocking CD11c(+)Tbet(+) ABC differentiation in ShipDeltaB mice by ablating MyD88 normalizes TFH cell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c(+)Tbet(+) ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus. |
