class-switch recombination

Class-switch recombination involves isotype switching between immunoglobulin classes and isotypes.

Small resting B lymphocytes initially producing IgM antibodies. The diverse antibody repertoire achieved early in B-lymphocyte development results from VDJ recombination of gene segments to produce unique heavy- and light-chain variable (V) Ig regions. The variable regions encode the antigen binding sites of antibody receptors expressed on the surface of naïve B lymphocytes and their clonal progeny. The low affinity of naïve VDJ generated antibodies is compensated for by the high affinity of secreted IgM, in which the prototypical four-chain Ig structure is combined into pentamers or hexamers. Following encounter with antigen, B cells become activated to isotype switch from IgM to other Ig classes, including high-affinity IgG and IgA antibodies required to inactivate toxins, neutralize viruses, and promote the clearance of microorganisms.

Ligation of antigen by cognate B lymphocytes accompanied by costimulation by helper T lymphocytes, activates B lymphocytes, which enter the germinal centers of peripheral lymphoid organs to become centroblast B cells. Within the germinal center, secondary antibody diversification is brought about through somatic hypermutation (SHM) and/or gene conversion (GC) of the V region to generate high-affinity antigen binding sites. (SHM is the predominant mechanism in mice and humans, whereas GC occurs in chickens and some other species.)

Within a particular centroblast B cell in the germinal center, the heavy-chain variable (V) regions encoding the antigen binding sites are rearranged down the chromosome through class-switch recombination (CSR). Then they can be expressed with one of the constant (C) region genes to perform many different effector functions having been released into the circulation.

This isotype class switch distributes a particular variable region to different constant immunoglobulin regions. Each constant region mediates a specialized effector function, and switching permits adaptive guidance of antibodies. Creating a new heavy chain requires loop-out and deletion of DNA between switch regions, employing transcription of the switch regions. Requisite switching factors include activation-induced cytidine deaminase and components of general DNA repair, including base excision repair (UNG2), mismatch repair, and double-strand break repair.[r1]

'Individuals, such as those with hyper-IgM syndrome (HIGM), who lack the ability to make such high-affinity IgG and IgA antibodies, are unable to combat bacterial and viral infections and usually die at a young age.[s]

Tables  Fc receptors  Immune Cytokines  Immunoglobulins

[r1] DNA acrobats of the Ig class switch. Wang CL, Wabl M. J Immunol. 2004 May 15;172(10):5815-21. [Free Full Text Article]

[s] The generation of antibody diversity through somatic hypermutation and class switch recombination. Li Z, Woo CJ, Iglesias-Ussel MD, Ronai D, Scharff MD. Genes Dev. 2004 Jan 1;18(1):1-11. [Free Full Text Article]

tags [Immunology][recombination]