Pkc

ERK, JNK

FIGURE 7-19 Signal transduction by the BCR complex. Antigen-induced cross-linking of membrane Ig on B cells leads to clustering and activation of Src family tyrosine kinases and tyrosine phosphorylation of the ITAMs in the cytoplasmic tails of the Iga and IgP molecules. This leads to docking of Syk and subsequent tyrosine phosphorylation events as depicted. Several signaling cascades follow these events, as shown, leading to the activation of several transcription factors. These signal transduction pathways are similar to those described in T cells.

FIGURE 7-19 Signal transduction by the BCR complex. Antigen-induced cross-linking of membrane Ig on B cells leads to clustering and activation of Src family tyrosine kinases and tyrosine phosphorylation of the ITAMs in the cytoplasmic tails of the Iga and IgP molecules. This leads to docking of Syk and subsequent tyrosine phosphorylation events as depicted. Several signaling cascades follow these events, as shown, leading to the activation of several transcription factors. These signal transduction pathways are similar to those described in T cells.

Complement activation

Recognition by B cells

Signals from Ig and CR2 complex

FIGURE 7-20 Role of complement in B cell activation. B cells express a complex of the CR2 complement receptor, CD19, and CD81. Microbial antigens that have bound the complement fragment C3d can simultaneously engage both the CR2 molecule and the membrane Ig on the surface of a B cell. This leads to the initiation of signaling cascades from both the BCR complex and the CR2 complex, because of which the response to C3d-antigen complexes is greatly enhanced compared with the response to antigen alone.

FIGURE 7-20 Role of complement in B cell activation. B cells express a complex of the CR2 complement receptor, CD19, and CD81. Microbial antigens that have bound the complement fragment C3d can simultaneously engage both the CR2 molecule and the membrane Ig on the surface of a B cell. This leads to the initiation of signaling cascades from both the BCR complex and the CR2 complex, because of which the response to C3d-antigen complexes is greatly enhanced compared with the response to antigen alone.

B cell activation activated either by binding to antigen-complexed antibody molecules (the classical pathway) or by binding directly to some microbial surfaces and polysaccharides in the absence of antibodies (the alternative and lectin pathways) (see Chapters 4 and 12). Thus, polysaccha-rides and other microbial components may activate the complement system directly, during innate immune responses. Proteins and other antigens that do not activate complement directly may be bound by preexisting antibodies or by antibodies produced early in the response, and these antigen-antibody complexes activate complement by the classical pathway. Recall that complement activation results in the proteolytic cleavage of complement proteins. The key component of the system is a protein called C3, and its cleavage results in the production of a molecule called C3b that binds covalently to the microbe or antigen-antibody complex. C3b is further degraded into a fragment called C3d, which remains bound to the microbial surface or on the antigen-antibody complex. B lymphocytes express a receptor for C3d that is called the type 2 complement receptor (CR2, or CD21). The complex of C3d and antigen or C3d and antigen-antibody complex binds to B cells, with the membrane Ig recognizing antigen and CR2 recognizing the bound C3d (see Fig. 7-20).

CR2 is expressed on mature B cells as a complex with two other membrane proteins, CD19 and CD81 (also called TAPA-1). The CR2-CD19-CD81 complex is often called the B cell coreceptor complex because CR2 binds to antigens through attached C3d at the same time that membrane Ig binds directly to the antigen. Binding of C3d to the B cell complement receptor brings CD19 in proximity to BCR-associated kinases, and the cytoplasmic tail of CD19 rapidly becomes tyrosine phosphorylated. Phosphorylation of the tail of CD19 results in the efficient recruitment of Lyn, a Src family kinase, that can amplify BCR signaling by greatly enhancing the phosphorylation of ITAM tyrosines in Iga and IgP. Phosphorylated CD19 also activates other signaling pathways, notably one dependent on the enzyme PI3-kinase, which in turn further augment signaling initiated by antigen binding to membrane Ig. PI3-kinase is required for the activation of Btk and PLCy2 because these enzymes must bind to PIP3 on the inner leaflet of the plasma membrane to be fully activated, in a manner analogous to that shown in Figure 7-12. The net result of coreceptor activation is that the response of the antigen-stimulated B cell is greatly enhanced.

Signaling Pathways Downstream of the B Cell Receptor

After antigen binding to the BCR, Syk and other tyrosine kinases activate numerous downstream signaling pathways that are regulated by adaptor proteins (see Fig. 7-19). The cross-linking of the BCR or the activation of the BCR by a coreceptor-dependent mechanism results in ITAM phosphorylation and recruitment of Syk to the ITAM, followed by the activation of this dual SH2 domain-containing kinase. Activated Syk phosphorylates critical tyrosine residues on adaptor proteins such as SLP-65 (SH2-binding leukocyte phosphoprotein of 65 kD, also called BLNK, B cell linker protein). This facilitates the recruitment to these adaptor proteins of other SH2 domain- and phosphotyrosine-binding (PTB) domain-containing enzymes, including guanine nucleo-tide exchange proteins that can separately activate Ras and Rac, PLCy2, and the Btk tyrosine kinase, among others. Recruitment facilitates the activation of these downstream effectors, each generally contributing to the activation of a distinct signaling pathway.

• The Ras-MAP kinase pathway is activated in antigen-stimulated B cells. The GTP/GDP exchange factor SOS is recruited to BLNK through the binding of the Grb-2 adaptor protein; Ras is then converted by this exchange factor from an inactive GDP-bound form to an active GTP-bound form. Activated Ras contributes to the activation of the ERK MAP kinase pathway discussed earlier in the context of T cell signaling. In a parallel fashion, the activation of the Rac small GTP protein may contribute to the activation of the JNK MAP kinase pathway.

• A specific phosphatidylinositol-specific phospholipase C (PLC) is activated in response to BCR signaling, and this in turn facilitates the activation of downstream signaling pathways. In B cells, the dominant isoform of PLC is the y2 isoform, whereas T cells express the related y1 isoform of the enzyme. PLCy2 becomes active when it binds to BLNK and is phosphorylated by Syk and Btk. As described in the context of TCR signaling, active PLC breaks down membrane PIP2 to yield soluble IP3 and leaves DAG in the plasma membrane. IP3 mobilizes calcium from intracellular stores, leading to a rapid elevation of cytoplasmic calcium, which is subsequently augmented by an influx of calcium from the extracellular milieu. In the presence of calcium, DAG activates some isoforms of protein kinase C (mainly PKC-P in B cells), which phos-phorylate downstream proteins on serine/threonine residues.

• PKC-fi activation downstream of the BCR contributes to the activation of NF-kB in antigen-stimulated B cells. This process is similar to that in T cells triggered by PKC-9, the PKC isoform present in T cells, and the pathway of NF-kB activation downstream of PKCs is described later in this chapter.

These signaling cascades ultimately lead to the activation of a number of transcription factors that induce the expression of genes whose products are required for functional responses of B cells. Some of the transcription factors that are activated by antigen receptor-mediated signal transduction in B cells are Fos (downstream of Ras and ERK activation), JunB (downstream of Rac and JNK activation), and NF-kB (downstream of Btk, PLCy2, and

PKC-P activation). These were discussed earlier when we described T cell signaling pathways. These and other transcription factors, many not mentioned here, are involved in stimulating proliferation and differentiation of B cells (see Chapter 11).

As in T cells, our knowledge of antigen-induced signaling pathways in B cells and their links with subsequent functional responses is incomplete. We have described some of these pathways to illustrate the main features, but others may play important roles in B cell activation. The same signaling pathways are used by membrane IgM and IgD on naive B cells and by IgG, IgA, and IgE on B cells that have undergone isotype switching because all these membrane isotypes associate with Iga and IgP.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment