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FIGURE 11-14 Ig heavy chain isotype switching. B cells activated by helper T cell signals (CD40L, cytokines) undergo switching to different Ig isotypes, which mediate distinct effector functions. Selected examples of switched isotypes are shown. The role of IFN-y in directing specific isotype switching events has been established only in rodents.

FIGURE 11-14 Ig heavy chain isotype switching. B cells activated by helper T cell signals (CD40L, cytokines) undergo switching to different Ig isotypes, which mediate distinct effector functions. Selected examples of switched isotypes are shown. The role of IFN-y in directing specific isotype switching events has been established only in rodents.

Isotype switching in response to different types of microbes is regulated by cytokines produced by the helper T cells that are activated by these microbes. For instance, the major protective humoral immune response to bacteria with polysaccharide-rich capsules consists of IgM antibodies, which bind to the bacteria, activate the complement system, and induce phagocytosis of the opso-nized bacteria. Polysaccharide antigens, which do not elicit T cell help, stimulate mainly IgM antibodies, with little if any isotype switching to some IgG subclasses. The response to many viruses and bacteria involves production of IgG antibodies, which block entry of the microbes into host cells and also promote phagocytosis by macrophages. Viruses and many bacteria activate helper T cells of the Th1 subset, which produce the cytokine IFN-y. In mice, IFN-y is the main inducer of B cell switching to opsonizing and complement-fixing IgG subclasses; it is still not clear which cytokines serve this role in humans. The antibody response to many helminthic parasites is mainly IgE, which participates in eosinophil- and mast cell-mediated elimination of the helminths (see Chapters 12 and 15); IgE antibodies also mediate immediate hypersensitivity (allergic) reactions (see Chapter 19). Helminths activate the TH2 subset of helper T cells, which produces IL-4, the cytokine that induces switching to IgE. In the germinal center reaction, these cytokines might be produced not by classical TH1 and TH2 effector cells (which tend to migrate to peripheral sites of infection and inflammation) but by TFH cells that retain the capacity to produce TH1 or TH2 cytokines. In addition, B cells in different anatomic sites switch to different isotypes. Specifically, B cells in mucosal tissues switch to IgA, which is the antibody class that is most efficiently transported through epithelia into mucosal secretions, where it defends against microbes that try to enter through the epithelia (see Chapter 13). Switching to IgA is stimulated by transforming growth factor-P (TGF-P), which is produced by many cell types, including helper T cells, in mucosal and other tissues. Cytokines of the TNF family, BAFF and APRIL, also stimulate switching to IgA. Because these cytokines are produced by myeloid cells, they can stimulate IgA responses in the absence of T cell help. Some individuals who inherit mutant versions of the TACI gene, which encodes a receptor for these cyto-kines, have a selective deficiency of IgA production (see Chapter 20).

CD40 signals work together with cytokines to induce isotype switching. CD40 engagement induces the enzyme activation-induced deaminase (AID), which, as we shall see later, is crucial for both isotype switching and somatic mutation. The requirement for CD40 signaling and AID to promote isotype switching in B cells is well documented by analysis of mice and humans lacking CD40, its ligand, or AID. In all these cases, the antibody response to protein antigens is dominated by IgM antibodies, and there is limited switching to other isotypes. Cytokines, as described later, identify the specific Ig heavy chain loci that will participate in the switching process.

The molecular mechanism of isotype switching is a process called switch recombination, in which the rearranged VDJ exon that encodes an Ig heavy chain V domain recombines with a downstream C region gene and the intervening DNA is deleted. An overview of the process is provided in Figure 11-15. These DNA

recombination events involve nucleotide sequences called switch regions, which are located in the introns between the J and C segments at the 5' ends of each CH locus. Switch regions are 1 to 10 kilobases long, contain numerous tandem repeats of GC-rich DNA sequences, and are found upstream of every heavy chain gene. Upstream of each switch region is a small exon called the I exon (for initiator of transcription) preceded by an I region promoter. Signals from cytokines and CD40 induce transcription from a particular I region promoter reading through the I exon, switch region, and adjacent CH exons. These transcripts are known as germline transcripts. They do not encode specific proteins but are required for

Rearranged DNA in IgM-producing cells

Naive B cell

Microbial ^¡J^p antigen

Naive B cell

FIGURE 11-15 Mechanisms of heavy chain isotype switching. In the absence of helper T cell signals, B cells produce IgM. When antigen-activated B cells encounter helper T cell signals (CD40L and, in this example, IL-4), the B cells undergo switching to other Ig isotypes (in this example, IgE). These stimuli initiate germline transcription through the Ie-Se-Ce locus. The proximal Ch genes are deleted in a circle of DNA, leading to recombination of the VDJ exon with the CE gene. Switch regions are indicated by circles labeled S^ or SY. Although a switch region is not shown for the 8 gene, in humans a switch-like region upstream of the 8 gene is functional. I^ and Ie represent initiation site for germline transcription. (Note that there are multiple Cy genes located between C8 and CE, but these are not shown.)

Transcription through e locus

Recombination of Sn with Se; deletion of intervening C genes

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