Chapter 10 - Structure and Signaling Function of the B-Cell Antigen Receptor and Its Coreceptors

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The B-cell antigen receptor (BCR) plays a central role in the clonal selection of B cells and the generation of humoral immunity. In addition from inducing a specific immune response, the expression of the BCR also is required for the proper development and maintenance of the B-cell pool in the periphery. Each mature B cell carries roughly 120,000 BCR complexes on the cell surface with identical antigen binding sites. Because of the highly variable immunoglobulin (Ig) gene rearrangement program, B cells differ from each other in the antigen-binding specificity of their BCR. It has been estimated that most of the 1011 B cells of the human immune system differ from each other in their exact binding specificity. The enormous binding variability of their antigen receptors are characteristic of both B and T cells. However, unlike T cells, whose antigen receptors are restricted in binding to a defined antigen structure, namely the major histocompatibility complex (MHC)/peptide complex, B cells can be activated by a large group of structurally highly diverse molecules. In this respect, the BCR is quite different from most other receptors on the cell surface that have only one or a few specific ligands. Any model of B-cell activation should take into account these unique properties of the BCR. In this chapter we describe the basic structure of the BCR and several proposed models for its activation. We also discuss the interaction of the BCR with signal-transducing kinases, with a focus on the Src-family kinase Lyn and the spleen tyrosine kinase (Syk). We then address the structure and function of the B-cell coreceptors that either amplify (CD19) or inhibit (CD22) BCR signaling. Once B cells are activated, signals from BCR are processed through several signaling pathways. In our discussion of these processes, we focus on the phospholipase (PL) C-γ2 calcium release machinery and the phosphoinositide 3-kinase (PI3K) signaling pathway controlling proliferation and survival of B cells. Together, these pathways drive the clonal expansion of B cells and their differentiation into antibody-producing plasma cells.