Immunoglobulin class switching, also known asisotype switching,isotypic commutation orclass-switch recombination (CSR), is a biological mechanism that changes aB cell's production ofimmunoglobulin from one type to another, such as from theisotypeIgM to the isotypeIgG.^[1] During this process, the constant-region portion of the antibodyheavy chain is changed, but the variable region of the heavy chain stays the same (the termsvariable andconstant refer to changes or lack thereof between antibodies that target differentepitopes). Since the variable region does not change, class switching does not affect antigen specificity. Instead, the antibody retainsaffinity for the same antigens, but can interact with differenteffector molecules.

Class switching occurs after activation of a matureB cell via its membrane-bound antibody molecule (orB 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 ofV(D)J recombination, but possessing distinct constant domains in theirheavy chains.^[2]

Naïve mature B cells produce bothIgM andIgD, which are the first two heavy chain segments in the immunoglobulinlocus. After activation by antigen, these B cells proliferate. If these activated B cells encounter specific signaling molecules via theirCD40 and cytokine receptors (both modulated byT 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 do not, and therefore antigenic specificity remains 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).^[3]

In humans, the order of the heavy chainexons is as follows:

1. μ -IgM
2. δ -IgD
3. γ₃ -IgG3
4. γ₁ - IgG1
5. α₁ -IgA1
6. γ₂ - IgG2
7. γ₄ - IgG4
8. ε -IgE
9. α₂ - IgA2^[4]

Class switching occurs by a mechanism called class switch recombination (CSR) binding. Class switch recombination is a biological mechanism that allows the class ofantibody produced by an activatedB cell to change during a process known as isotype or class switching. During CSR, portions of the antibody heavy chainlocus are removed from thechromosome and the gene segments surrounding the deleted portion are rejoined to retain a functional antibody gene that produces antibody of a differentisotype. Double-stranded breaks are generated in DNA at conservednucleotide motifs, called switch (S) regions, which are upstream fromgene segments that encode the constant regions of antibodyheavy chains; these occur adjacent to all heavy chain constant region genes with the exception of the δ-chain. DNA isnicked and broken at two selected S-regions by the activity of a series ofenzymes, includingactivation-induced (cytidine) deaminase (AID),uracilDNA glycosylase, andapyrimidic/apurinic (AP)-endonucleases.^[5][6] AID begins the process of class switching by deaminating (removing an amino group from) cytosines within the S regions, converting the original C bases into deoxyuridine and allowing the uracil glycosylase to excise the base. This allows AP-endonucleases to cut the newly-formed abasic site, creating the initial SSBs that spontaneously form DSBs.^[7] The intervening DNA between the S-regions is subsequently deleted from the chromosome, removing unwanted μ or δ heavy chain constant regionexons and allowing substitution of a γ, α or ε constant region gene segment. The free ends of the DNA are rejoined by a process callednon-homologous end joining (NHEJ) to link the variable domainexon to the desired downstream constant domain exon of the antibody heavy chain.^[8] In the absence of non-homologous end joining, free ends of DNA may be rejoined by an alternative pathway biased toward microhomology joins.^[9] With the exception of the μ and δ genes, only one antibody class is expressed by a B cell at any point in time. While class switch recombination is mostly a deletional process, rearranging a chromosome in "cis", it can also occur (in 10 to 20% of cases, depending upon the Ig class) as an inter-chromosomal translocation mixing immunoglobulin heavy chain genes from both alleles.^[10][11]

T cell cytokines modulate class switching in mice (Table 1) and humans (Table 2).^[12][13] These cytokines may have suppressive effect on production of IgM.

In addition to the highly repetitive structure of the target S regions, the process of class switching needs S regions to be first transcribed and spliced out of the immunoglobulin heavy chain transcripts (where they lie within introns). Chromatin remodeling, accessibility to transcription and to AID, and synapsis of broken S regions are under the control of a large super-enhancer, located downstream the more distal Calpha gene, the 3' regulatory region (3'RR).^[17] In some occasions, the 3'RR super-enhancer can itself be targeted by AID and undergo DNA breaks and junction with Sμ, which then deletes the Ig heavy chain locus and defineslocus suicide recombination (LSR).^[18]

• Antibody
• Genetic recombination
• Immune checkpoint
• Immunogenetics

• Immunoglobulin+class+switching at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

• Immune system
• Biological processes
• Immune system process
• Immunology

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• Short description is different from Wikidata