Immunoglobulins can exist as membrane proteins, expressed at the surface of B cells. When B cells differentiate in the bone marrow from the initial hematopoietic stem cells, they reach a stage, called immature B lymphocytes, that is characterized by the presence of IgM at the cell surface (Fig. 1). This IgM, which is a basic m2k2 or m2l2 monomer, is anchored into the membrane bilayer by an extra portion at the COOH-terminus of the heavy chains that is not present in the soluble form. Differences in length result simply from the alternative splicing of membrane exons (see Introns, Exons) present in the germline. The transmembrane region is terminated by only three amino acid residues located in the cytoplasm of the B cell.
Figure 1. Schematic representation of the B-cell receptor (BCR). The BCR is composed of one antigen binding module, the surface IgM, connected to the signaling module, a heterodimer containing the Iga and Igb, encoded by the MB-1 and B-29 genes, respectively. Note the Ig domain organization of the ectodomains of the Iga and Igb chains that contain in their cytoplasmic part the ITAM (immunoreceptor tyrosine-based activation motif) motifs that play a central role in signaling by contacting intracellular protein tyrosine kinases.
Because the surface Ig clearly acts as a B-cell receptor (BCR) upon triggering by the antigen, the necessity of a signaling module, similar to CD3 in T cells, is apparent. This was indeed the case. The BCR-activating module is a heterodimer composed of one Iga and one Igb chain (also designated as CD79 a and b), each of which has an external Ig-like domain, a transmembrane portion, and an cytoplasmic region that contains several signaling motifs, called immunoreceptor tyrosine-based activation motif (ITAM). ITAM were first described on polypeptide chains of CD3 and consist of two Tyr—X—X—Leu/Ile sequences separated by a stretch of seven amino acid residues. They are found in a number of signal transduction modules associated with most crucial receptors of the immune system, such as the T-cell receptor (TCR), BCR, and FcR. Upon stimulation of BCR with cross-linking antigens, ITAM interact with protein tyrosine kinases of the src family (p59fyn, p53lyn, p56lyn, p55lck), leading to the translocation of p72syk to the membrane and activation of the ras pathway and phospholipase Cg2. As a consequence, the BCR is internalized, which is the first step of processing of antigens by B cells. Full activation of B cells require other signals, involving molecules other than the BCR.
