Antigen receptor-derived signals in B cells: Comparative biology of malignant and non-malignant CD5+ B cells and implications for malignant pathogenesis.

摘要

B-1 cells produce polyspecific immunoglobulins (Ig) and constitute a central element in the innate humoral response. These cells are defined in part by their expression of CD5, and by their manufacture of Ig with affinity for both foreign and autologous structures. While constituting the majority of B cells in the neonate, B-1 cells represent a minority of B lymphocytes in adults. Development and persistence of the CD5+ B cell population involves signals generated through multiple cell surface receptors such as CD40 and the IL-4 receptor. We hypothesized that engagement of the B cell receptor (BCR) for antigen would provide survival signals to CD5+ B cells resulting in inhibition of apoptosis.; In this work, we analyzed the consequences of BCR crosslinking in malignant CD5+ B cells isolated from the peripheral blood of chronic lymphocytic leukemia (CLL) patients, and non-malignant CD5+ B cells from human cord blood samples. We observed that upon antigen receptor engagement apoptosis inhibition occurs in both the malignant and non-malignant human CD5+ B cell. Expression of known anti-apoptotic factors such as bfl-1, mcl-1, bcl-2, and inhibitors of apoptosis (IAPs) increased upon BCR engagement as assessed by RNAse protection assays and immunoblot. In human CD5+ B cells stimulated through the BCR, there was augmented NF-κB activity, as detected by electrophoretic mobility shift assay (EMSA). Upon application of the NF-κB inhibitor BAY11-7082, there was reduced expression of VIA, TRAF1, TRAF2, and cIAP in CLL cells. We also established that PI-3 kinase is activated upon BCR engagement, and is inhibited by application of LY294002. Whereas PI-3 kinase inhibition had little effect on bcl-2, VIA, and cIAPs, there was a clear requirement for PI-3 kinase activity in expression of mcl-1 in CD5+ B cells upon IgM engagement.; From these investigations it is evident that survival of CD5+ B cells can be affected by signals generated through the BCR. The implication of our work is that antigen for which malignant CD5+ B cells have affinity could promote persistence of the cells in vivo. Inhibition of surface immunoglobulin (slg)-derived survival signals might be utilized in future therapies for CLL, which is currently incurable.