Immunoglobulin class switching

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Mechanism of class-switch recombination that allows isotype switching in activated B cells.

Immunoglobulin class switching, also known as isotype switching, isotypic commutation or class-switch recombination (CSR), is a biological mechanism that changes a

affinity for the same antigens, but can interact with different effector
molecules.

Mechanism

Class switching occurs after activation of a mature

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.[2]

Naïve mature B cells produce both

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 etc.).[3]

In humans, the order of the heavy chain

exons
is as follows:

  1. μ -
    IgM
  2. δ -
    IgD
  3. γ3 - IgG3
  4. γ1 - IgG1
  5. α1 -
    IgA
    1
  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 of

apyrimidic/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 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.[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]

Cytokines responsible for class switching

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

Table 1. Class switching in mice
T cells Cytokines Immunoglobulin classes
IgG1 IgG2a IgG2b IgG3 IgG4 IgE
Th2 IL-4 ↑ ↓ ↓ ↓ ↓ ↑
IL-5 ↑
Th1 IFNγ ↓ ↑ ↓ ↑ ↓ ↓
Treg
 TGFβ ↑ ↓ ↑
IL-10[14] ↑
Table 2. Class switching in humans
T cells Cytokines Immunoglobulin classes
IgG1 IgG2 IgG3 IgG4 IgA IgE
Th2 IL-4 ↑ ↓ ↑ ↑
IL-5 ↑
Th1 IFNγ ↓ ↑ ↓
Treg
 TGFβ ↓ ↑
IL-10[15][16] ↑ ↑

Gene regulatory sequences responsible for class switching

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 defines locus suicide recombination (LSR).[18]

See also

References

  1. PMID 32633840
    .
  2. PLoS Biology
    1(1): e16.
  3. PMID 15522624
    .
  4. ^ Parham, Peter (2015). The Immune System (4th ed.). Garland Science.
  5. S2CID 32059768
    .
  6. PMID 15496946
    .
  7. PMID 18370922
    .
  8. PMID 16793349
    .
  9. S2CID 4341381
    .
  10. PMID 15879114
    .
  11. PMID 24848929
    .
  12. ISBN 978-0-8153-3642-6. (via NCBI Bookshelf)
    .
  13. ISBN 978-0-323-03399-2
    (pbk.)
  14. PMID 8671667
    .
  15. PMID 8294883
    .
  16. PMID 8642297
    .
  17. PMID 21762815
    .
  18. S2CID 1513560
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Immunoglobulin_class_switching&oldid=1207658556"