Autoreactive B cells are censored by multiple mechanisms of tolerance induction, including clonal deletion, anergy (non-responsiveness) or antigen receptor editing. It is generally believed that these processes are imposed to bone marrow (BM) immature and peripheral transitional B-cells through coordinated signaling of B-cell antigen receptor (BCR) and cytokine receptors. However, the intracellular signaling machinery that controls these processes has not been fully characterized.
The aim of this proposal is to elucidate the mechanisms by which the Cbl family of E3-ubiquitin ligases regulates B-cell tolerance. This research goal roots in the following findings: 1) Cbl proteins negatively regulate BCR signaling through inhibiting tyrosine kinase cascades. 2) Inactivation of both c-Cbl and Cbl-b in B cells alters development of transitional B-cells. 3) B-cell specific c-Cbl and Cbl-b double knock-out (dKO) mice develop systemic lupus erythematosus (SLE)-like disease. These results together demonstrate a critical regulatory role of Cbl proteins in B-cell tolerance induction. We propose that Cbl proteins regulate B-cell tolerance by facilitating clonal deletion, anergy, and/or BCR editing; they may do so through promoting ubiquitination of key signaling components that control the development and survival of transitional B-cells that are susceptible to tolerance induction. We will study: 1) Whether Cbl proteins control B-cell tolerance through clonal deletion, anergy or BCR editing. 2) Whether Cbl proteins regulate B-cell tolerance at developmental checkpoints of transitional B-cells. 3) Whether Cbl-mediated ubiquitination controls BCR-proximal signaling and transitional B-cell development. Completion of this work will bring insight into cellular and molecular mechanisms by which Cbl proteins control B-cell tolerance and autoimmune diseases. It might also provide tool for clinic therapy. ? ?
| Kitaura, Yasuyuki; Jang, Ihn Kyung; Wang, Yan et al. (2007) Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b. Immunity 26:567-78 |
