| First Author | Greaves SA | Year | 2019 |
| Journal | J Exp Med | Volume | 216 |
| Issue | 5 | Pages | 1135-1153 |
| PubMed ID | 30948496 | Mgi Jnum | J:275059 |
| Mgi Id | MGI:6305902 | Doi | 10.1084/jem.20181652 |
| Citation | Greaves SA, et al. (2019) Active PI3K abrogates central tolerance in high-avidity autoreactive B cells. J Exp Med 216(5):1135-1153 |
| abstractText | Autoreactive B cells that bind self-antigen with high avidity in the bone marrow undergo mechanisms of central tolerance that prevent their entry into the peripheral B cell population. These mechanisms are breached in many autoimmune patients, increasing their risk of B cell-mediated autoimmune diseases. Resolving the molecular pathways that can break central B cell tolerance could therefore provide avenues to diminish autoimmunity. Here, we show that B cell-intrinsic expression of a constitutively active form of PI3K-P110alpha by high-avidity autoreactive B cells of mice completely abrogates central B cell tolerance and further promotes these cells to escape from the bone marrow, differentiate in peripheral tissue, and undergo activation in response to self-antigen. Upon stimulation with T cell help factors, these B cells secrete antibodies in vitro but remain unable to secrete autoantibodies in vivo. Overall, our data demonstrate that activation of the PI3K pathway leads high-avidity autoreactive B cells to breach central, but not late, stages of peripheral tolerance. |
