Antigen-induced clustering of membrane Ig receptors triggers biochemical signals that activate B cells (Fig. 1). The process of B lymphocyte activation is, in principle, similar to the activation of T cells . In B cells, antigen receptor–mediated signal trans duction requires the bringing together (cross-linking) of two or more membrane Ig molecules. Antigen receptor cross-linking occurs when two or more antigen molecules in an aggregate, or repeating epitopes of one antigen molecule, bind to adjacent membrane Ig molecules of a B cell. Polysaccharides, lipids, and other nonprotein antigens often contain multiple identical epitopes in each molecule and are therefore able to bind to numerous Ig receptors on a B cell at the same time. Even protein antigens may be expressed in an array on the surface of microbes and are thus able to cross-link antigen receptors of a B cell.

Fig1. Antigen receptor–mediated signal transduction in B lymphocytes. Cross-linking of antigen receptors on B cells by antigen triggers biochemical signals that are transduced by the immunoglobulin (Ig)-associated proteins Igα and Igβ. These signals induce early tyrosine phosphorylation events, activation of various biochemical intermediates and enzymes, and activation of transcription factors. Similar signaling events are seen in T cells after antigen recognition. Note that maximal signaling requires cross-linking of at least two Ig receptors by antigens. AP-1, Activating protein 1; GDP, guanosine diphosphate; GTP, guanosine triphosphate; ITAM, immunoreceptor tyrosine-based activation motif; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor κB; PKC, protein kinase C; PLC, phospholipase C.

Signals initiated by antigen receptor cross-linking are transduced by receptor-associated proteins. Membrane IgM and IgD, the antigen receptors of naive B lymphocytes, have highly variable extracellular antigen-binding regions . However, these membrane receptors have short cytoplasmic tails, so although they recognize antigens, they do not themselves transduce signals. The receptors are noncovalently associated with two proteins, called Igα and Igβ, to form the B cell receptor (BCR) complex, analogous to the T cell receptor (TCR) complex of T lymphocytes. The cytoplasmic domains of Igα and Igβ each contain a conserved immunoreceptor tyrosine-based activation motif (ITAM), similar to those found in signaling subunits of many other activating receptors in the immune system (e.g., CD3 and ζ proteins of the TCR complex; see Chapter 5). When two or more antigen receptors of a B cell are brought together by antigen-induced cross-linking, the tyrosines in the ITAMs of Igα and Igβ are phosphorylated by tyrosine kinases associated with the BCR complex. These phosphotyrosines recruit the Syk tyrosine kinase (equivalent to ZAP-70 in T cells), which is activated and in turn phosphorylates tyrosine residues on adaptor proteins. These phosphorylated proteins then recruit and activate a number of downstream molecules, mainly enzymes that initiate signaling cascades that activate transcription factors.

The net result of receptor-induced signaling in B cells is the activation of transcription factors that switch on the expression of genes whose protein products are involved in B cell proliferation and differentiation. Some of the important proteins are described below.