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. 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. If these activated B cells encounter specific signaling molecules via their
CD40 and cytokine 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 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). In humans, the order of the heavy chain
exons is as follows: • μ -
IgM • δ -
IgD • γ3 -
IgG3 • γ1 - IgG1 • α1 -
IgA1 • γ2 - IgG2 • γ4 - IgG4 • ε -
IgE • α2 - IgA2 Class switching occurs by a mechanism called class switch recombination (CSR) binding. Class switch recombination is a biological mechanism that allows the class of
antibody produced by an activated
B cell to change during a process known as isotype or class switching. During CSR, portions of the antibody heavy chain
locus are removed from the
chromosome and the gene segments surrounding the deleted portion are rejoined to retain a functional antibody gene that produces antibody of a different
isotype. Double-stranded breaks are generated in DNA at conserved
nucleotide motifs, called switch (S) regions, which are upstream from
gene segments that encode the constant regions of antibody
heavy chains; these occur adjacent to all heavy chain constant region genes with the exception of 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. 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. The intervening DNA between the S-regions is subsequently deleted from the chromosome, removing unwanted μ or δ heavy chain constant region
exons and allowing substitution of a γ, α or ε constant region gene segment. 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 antibody heavy chain. In the absence of non-homologous end joining, free ends of DNA may be rejoined by an alternative pathway biased toward microhomology joins. 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. == Cytokines responsible for class switching ==