The B Lymphocyte Antigen Receptor Complex

The B lymphocyte antigen receptor is a transmembrane form of an antibody molecule associated with two signaling chains. The structure of antibodies was described in detail in Chapter 5. Here we will focus on some salient features of the membrane forms of Ig and their associated proteins and discuss how they deliver signals to B cells. Because the signaling pathways are similar to those in T cells, we will summarize these without much detail. However, there are both similarities and significant differences between B and T cell antigen receptors (see Table 7-1).

Structure of the B Cell Receptor for Antigen

Membrane IgM and IgD, the antigen receptors of naive B cells, have short cytoplasmic tails consisting of only three amino acids (lysine, valine, and lysine). These tails are too small to transduce signals generated after the recognition of antigen. Ig-mediated signals are transduced by two other molecules, called Iga and IgP, that are disulfide linked to one another and are expressed in B cells noncovalently associated with membrane Ig (Fig. 7-18). These proteins each contain an ITAM motif in their cytoplasmic tails, are required for the transport of membrane Ig molecules to the cell surface, and together with membrane Ig form the B cell receptor (BCR) complex. B cell receptor complexes in class-switched B cells, including memory B cells, contain membrane immunoglobulins that may be of the IgG, IgA, or IgE classes (see Chapter 11).

Signal Initiation by the B Cell Receptor

Signal initiation by antigens occurs by cross-linking of the BCR and is facilitated by the coreceptor for the BCR. It is thought that cross-linking of membrane Ig by multivalent antigens brings Src family kinases together and, by

Extracellular space

Plasma membrane

Plasma membrane

Extracellular space

Cytoplasm

FIGURE 7-18 B cell antigen receptor complex. Membrane IgM (and IgD) on the surface of mature B cells is associated with the invariant IgP and Iga molecules, which contain ITAMs in their cytoplasmic tails that mediate signaling functions. Note the similarity to the TCR complex.

Cytoplasm

Immunoreceptor tyrosine-based activation motif (ITAM)

FIGURE 7-18 B cell antigen receptor complex. Membrane IgM (and IgD) on the surface of mature B cells is associated with the invariant IgP and Iga molecules, which contain ITAMs in their cytoplasmic tails that mediate signaling functions. Note the similarity to the TCR complex.

promoting their physical interaction, fully activates these enzymes, enabling them then to phosphorylate the tyrosine residues on the ITAMs of Iga and IgP. It is also possible that as in T cells, antigen binding facilitates a conformational change in BCR-associated ITAMs, making them accessible to already active Src family kinases that modify ITAM tyrosines, but there is at present no firm evidence to support such a model. The phosphorylation of ITAM tyrosine residues triggers all subsequent signaling events downstream of the BCR (Fig. 7-19). Cross-linked Ig receptors enter lipid rafts, where many adaptor proteins and signaling molecules are concentrated. Iga and IgP are loosely connected to Src family tyrosine kinases such as Lyn, Fyn, and Blk, and these enzymes are also linked by lipid anchors to the inside of the plasma membrane. The phosphorylation of the tyrosine residues in the ITAMs of Iga and IgP provides a docking site for the tandem SH2 domains of the Syk tyrosine kinase. Syk is activated when it associates with phosphorylated tyro-sines of ITAMs and may itself be phosphorylated on specific tyrosine residues by BCR-associated Src family kinases, leading to further activation. If the antigen is monovalent and incapable of cross-linking multiple Ig molecules, some signaling may nevertheless occur, but additional activation by helper T cells may be necessary to fully activate B cells, as discussed in Chapter 11.

Role of the CR2/CD21 Complement Receptor as a Coreceptor for B Cells

The activation of B cells is enhanced by signals that are provided by complement proteins and the CD21 coreceptor complex, which link innate immunity to the adaptive humoral immune response (Fig. 7-20). The complement system consists of a collection of plasma proteins that are

Cross-linking of membrane Ig by antigen

Tyrosine phosphorylation events

s Activated Src family kinases (e.g. Lyn, Fyn, Blk)

Biochemical intermediates

Active enzymes

Transcription factors s Activated Src family kinases (e.g. Lyn, Fyn, Blk)

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