Control of IgE synthesis

IgE is distinguished from other antibody classes (IgM, IgD, IgG and IgA) by its e heavy chains. The heavy chain immunoglobulin gene cluster including the gene segments encoding the constant region of the e chain (Cf) are found on chromosome 12 in mouse and chromosome 14 in humans. The antigen specificity of a B cell clone is determined by the formation of a functional p. heavy chain gene, following the productive recombination of variable (VDJ) and C^ gene segments. Association with light chains then results in the expression of IgM (and IgD) in the cell. Upon appropriate stimulation of the B cell, the rearranged gene may then undergo further rearrangement within the heavy chain gene cluster, resulting in apposition of the same VDJ sequence to the C region encoding an antibody of a class other than IgM. Heavy chain switching may be directed to Cy (for IgG), to C, (for IgE) or to C(< (for IgA), which all lie downstream of C^, and is a necessary step in the expression of the new antibody class, with its characteristic effector functions. IgG, IgE and IgA are recognized by class-specific Fc receptors on different types of cells, which have different tissue distributions and distinct functions in immunity.

The mechanism of heavy chain gene switching is partially understood. Upstream of each of the C cassettes are two important sequences, the so-called I exon and the switch or S region. The selection of C^, Ce or C,v is determined by the exposure of the B cell to particular cytokines: interferon y for three of the four IgG subclasses, IL-4 or IL-13 for IgE and the fourth IgG subclass (IgGl in mouse, IgG4 in humans), and transforming growth factor (3 for IgA. These cytokines act by inducing the expression of germline gene transcripts, initiated upstream of S and terminating beyond the C cassette. The germline gene transcript is spliced to form a transcript with a germline exon, I, and the exons in the C cassette. This transcript cannot be translated because it contains multiple stop codons in the I exon. This exon is looped out and lost when VDJ recombines with C to form the switched gene.

The direction of heavy chain switching is determined by the microenvironment of the B cell. IL-4 is produced by activated TH2 cells and mast cells. When B cells present antigen to TH2 cells, they induce IL-4 secretion and expression of CD40-ligand (CD40L), which provides the second signal required for heavy chain switching. This process occurs in lymphoid tissue, and also elsewhere (even in vitro) if B cells, IL-4 and a CD40L, such as an antibody to CD40, are present in the medium. Figure 3 shows how the release of IL-4 upon the degranulation of mast cells might stimulate a TH2 response. The differentiation of Th0 cells to Th2 cells is stimulated by IL-4, first from an exogenous source, in this case mast cells, and later in an autocrine fashion. Antigen presentation to T cells via MHC II (major histocompatibility complex class II), following internalization of antigen-IgE complexes, bound to FceR.II/CD23, activates the T cells to secrete IL-4 and express

CD40L, thus stimulating heavy chain switching to IgE in the B cell. Antigen stimulation of B cells, soluble fragments of FceRII/CD23 and IL-6 are perhaps further required for differentiation of the B cells into plasma cells which secrete IgE.

Several factors are known to stimulate the growth and differentiation of B cells in an IgE class-specific manner. Three of these (EBV, soluble fragments of FceRII/CD23, and anti-CD21) are ligands for CD21, expressed on the surface of B cells. The original name of this protein, complement receptor 2, reflects the function of CD21 as the receptor for the activated products of the third component of complement, C3. These have the effect of lowering the threshold antigen concentration for clonal selection of B cells. FceRII/CD23 apparently stimulates IgE synthesis by a mechanism analogous to that by which C3 stimulates the synthesis of specific antibodies; this involves upregulation of the 'survival gene' Bcl-2 in the cell nucleus. Accordingly, both C3 and FceRII/CD23 may effect clonal selection by preventing apoptosis (cell death) and so permit cell proliferation. Interestingly, while C3 promotes specific antibody synthesis, FceRIl/CD23 stimulates IgE synthesis, regardless of the specificity of the antigen receptor.

Figure 3 illustrates how IgE is switched on, but it does not reveal how this positive feedback mechanism is controlled to set an upper limit to the concentration of IgE. The properties of the FceRII/CI)23 knockout mouse demonstrate that FceRII/CD23 is important in the downregulation of IgE synthesis, though it does not exclude an additional upregula-tory function, as explained below. In vivo inhibitory mechanisms should operate at IgE concentrations above the K0 for the IgE-FceRI interaction; the relatively low affinity of FceRII/CD23 for IgE (compared with FceRI) may thus be inseparable from this function. IgE synthesis is inhibited by the binding of IgE, or, better, antigen-IgE complexes, to FceRII/CD23 in the B cell membrane. Presumably, the greater efficacy of the antigen-IgE complexes results from their ability to crosslink FceRII/CD23 molecules in the B cell membrane, and thereby deliver a negative signal to the cell. An analogous mechanism for feedback inhibition by IgG, involving a low-affinity IgG receptor, has been studied in greater detail with regard to the signal transduction pathway.

The activity of FceRlI/CD23 in both upregularing and downregulating IgE synthesis may be explained by the fact that it is cleaved at the cell membrane by endogenous proteases into fragments that stimulate IgE synthesis by binding to CD21, as described above. But IgE binding to FceRII/CD23 inhibits proteolysis, and thereby prevents the release of the stimulatory fragments. Moreover, crosslinking of igE

Switching and differentiation

Figure 3 Synthesis of IgE. Simplified diagram of the mechanisms and key molecules involved in B cells switching to IgE after exposure to allergen. On binding to allergen, IgE interacts with its high-affinity receptor on mast cells, causing the cells to degranulate and release histamine, lipid mediators and IL-4. The IL-4 stimulates TH0 cells to become TH2 cells expressing IL-4. In addition, IgE— allergen complexes bind and crosslink CD23 (FceRII) on B cells expressing surface IgM. The allergen is then internalized, processed and presented on the cell surface by class II MHC. The MHC-allergen complex is then recognized by the TCR on the TH2 cells, and this cell-cell contact induces the expression of CD40L on the TH2 cells, which then binds to CD40 on the B cell. This signal, in conjunction with the IL-4 produced by the TH2 cells, induces switching and differentiation of the B cell, ultimately into either a memory B cell or a plasma cell secreting IgE.

Figure 3 Synthesis of IgE. Simplified diagram of the mechanisms and key molecules involved in B cells switching to IgE after exposure to allergen. On binding to allergen, IgE interacts with its high-affinity receptor on mast cells, causing the cells to degranulate and release histamine, lipid mediators and IL-4. The IL-4 stimulates TH0 cells to become TH2 cells expressing IL-4. In addition, IgE— allergen complexes bind and crosslink CD23 (FceRII) on B cells expressing surface IgM. The allergen is then internalized, processed and presented on the cell surface by class II MHC. The MHC-allergen complex is then recognized by the TCR on the TH2 cells, and this cell-cell contact induces the expression of CD40L on the TH2 cells, which then binds to CD40 on the B cell. This signal, in conjunction with the IL-4 produced by the TH2 cells, induces switching and differentiation of the B cell, ultimately into either a memory B cell or a plasma cell secreting IgE.

FceRII/CD23 by antigen-IgE complexes delivers a negative signal to the cell. Therefore, FceRII/CD23 stimulates IgE synthesis at low IgE concentrations and inhibits IgE synthesis at high IgE concentration: it is pivotal in the regulation of IgE.

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