Regulatory Roles of the Tumor Necrosis Factor Receptor BCMA

Abstract

B cell maturation antigen (BCMA) is a tumor necrosis family receptor (TNFR) member that is predominantly expressed on terminally differentiated B cells and, upon binding to its ligands B cell activator of the TNF family (BAFF) and a proliferation inducing ligand (APRIL), delivers pro-survival cell signals. Thus, BCMA is most known for its functional activity in mediating the survival of plasma cells that maintain long-term humoral immunity. The expression of BCMA has been also linked to a number of cancers, autoimmune disorders, and infectious diseases that suggest additional roles for BCMA activity. Despite the recent advances in our understanding of the roles for the related TNFR members BAFF-R and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), the signaling pathway used by BCMA for mediating plasma cell survival as well as its putative function in certain disease states are not well understood. By examining the expression, regulation, and signaling targets of BCMA we may gain further insight into this receptor and how it operates within cells in both health and disease. This information is important for identifying new therapeutic targets that may be relevant in treating diseases that involve the BAFF/APRIL cytokine network.

Replacing mouse BAFF with human BAFF does not improve B-cell maturation in hematopoietic humanized mice

“…21,[35][36][37] Based on this, we also anticipated observing increased numbers of these effector B-cell populations in hBAFFKI hu-mice, a hypothesis supported by studies in which injection of hBAFF in hu-PBL and hu-mice improved thymusindependent antibody responses to the Pneumovax vaccine. 19,20 Our linear regression analyses comparing naive B cells and memory B cells or plasmablasts in hu-mice indicated a correlation between effector and naive cell populations.…”

“…21,[35][36][37] To determine whether expression of hBAFF impacted the distribution of these effector B cells in hu-mice, we used flow cytometry to quantify cells with this phenotype (Figure 5A-C …”

The role of BAFF in the progression of rheumatoid arthritis

“…Thus, it seems that both APRIL and BAFF can act as agonists in vivo for membrane-bound BCMA. Coquery and Erickson [43] detected no BCMA on the surface of normal mature murine B cells, and the levels on the surface of plasma cells were modest. RNase protection assays showed that BCMA mRNA is expressed predominantly in terminally differentiating and immunoglobulin secreting B cell lines [43].…”

A proliferation-inducing ligand sustains the proliferation of human naïve (CD27−) B cells and mediates their differentiation into long-lived plasma cells in vitro via transmembrane activator and calcium modulator and cyclophilin ligand interactor and B-cell mature antigen

“…APRIL and BAFF bind to TACI with equal affinity, and APRIL binds BCMA with higher affinity than BAFF [28][29][30][31][32][33][34][35]. Bone marrow PCs from Bcm-knockout mice have a lower survival rate compared with those from wild-type mice, indicating that signal transduction through BCMA is related to the long-term survival of PCs [3,11,36]. The pattern of temporal expression of BAFF suggests that it acts during earlier stages of B-cell differentiation than APRIL.…”

“…APRIL signaling through its receptors, which are the members of the TNF receptor family, B-cell maturation antigen (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), mediates the late stage of B cell development [5][6][7][8][9][10][11]. In a mouse model, APRIL deficiency decreases the ability of the bone marrow to support plasma cell (PC) survival [12].…”