Immunoglobulin class switching

  Immunoglobulin class switching (or isotype switching or Isotypic Commutation) is a biological mechanism that changes an antibody from one class to another, for example, from an isotype called IgM to an isotype called IgG. During this process, the constant region portion of the antibody heavy chain is changed, but the variable region of the heavy chain stays the same. Since the variable region does not change, class switching does not affect the antigens that are bound by the antibody. Instead, the antibody retains affinity for the same antigens, but can interact with different effector molecules.

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Mechanism

Class switching occurs after activation of a mature B cell via its membrane-bound antibody molecule (or B cell receptor) to generate the different classes of antibody, all with the same variable domains as the original antibody generated in the immature B cell during the process of V(D)J recombination, but possessing distinct constant domains in their heavy chains.^[1]

Naïve mature B cells produce both IgM and IgD, which are the first two heavy chain segments in the immunoglobulin locus. After activation by antigen, these B cells proliferate and begin to produce high levels of these antibodies. If these activated B cells are also activated via their CD40 and IL-4 receptors (both modulated by T helper cells), they undergo antibody class switching to produce IgG, IgA or IgE antibodies. During class switching, the constant region of the immunoglobulin heavy chain changes but the variable regions, and therefore antigen specificity, stay the same. This allows different daughter cells from the same activated B cell to produce antibodies of different isotypes or subtypes (e.g. IgG1, IgG2 etc.).^[2]

The order of the heavy chain exons are as follows:

• μ - IgM
• δ - IgD
• γ3 - IgG3
• γ1 - IgG1
• pseudogene similar to ε gene that is not used
• α1 - IgA1
• γ2 - IgG2
• γ4 - IgG4
• ε - IgE
• α2 - IgA2

Class switching occurs by a mechanism called class switch recombination (CSR)binding. This process uses conserved nucleotide motifs, called switch (S) regions, found in DNA upstream from each of the antibody heavy chain constant region genes, except the δ-chain. DNA is nicked and broken at two selected S-regions by the activity of a series of enzymes, including Activation-Induced (Cytidine) Deaminase (AID), uracil DNA glycosylase and apyrimidic/apurinic (AP)-endonucleases.^[3][4] The intervening DNA between the S-regions is subsequently deleted from the chromosome, removing the unwanted μ or δ heavy chain constant region genes and possibly some of the γ, α or ε constant region genes. The free ends of the DNA are rejoined by a process called non-homologous end joining (NHEJ) to link the variable domain exon to the desired downstream constant domain exon of the immunoglobulin heavy chain.^[5] Class switching can occur more than once, but it can only switch to heavy chain segments that are downstream (in the immunoglobulin locus) from the previous heavy chain exon. With the exception of the μ and δ genes, only one antibody class is expressed by a B cell at any point in time.

See also

• immunogenetics
• antibody

References

1. ^ Eleonora Market, F. Nina Papavasiliou (2003) V(D)J Recombination and the Evolution of the Adaptive Immune System PLoS Biology1(1): e16.
2. ^ Stavnezer J, Amemiya CT (2004). "Evolution of isotype switching". Semin. Immunol. 16 (4): 257-75. PMID 15522624.
3. ^ Durandy A (2003). "Activation-induced cytidine deaminase: a dual role in class-switch recombination and somatic hypermutation". Eur. J. Immunol. 33 (8): 2069-73. PMID 12884279.
4. ^ Casali P, Zan H (2004). "Class switching and Myc translocation: how does DNA break?". Nat. Immunol. 5 (11): 1101-3. PMID 15496946.
5. ^ Lieber MR, Yu K, Raghavan SC (2006). "Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations". DNA Repair (Amst.) 5 (9-10): 1234-45. PMID 16793349.