Junctional region diversity
Imprecise recombination involving V(D)J region DNA enhances the number of possible different antibody molecule polypeptides due to loss or gain of additional nucleotides during the recombination event. The resulting V(D)J product may be functional, i.e. generate antibody molecules, or, if the reading frame is lost, non-functional. Whether functional or not, the CDR3 remains a unique marker for the malignant clone.
TdT inserts N region nucleotides into the CDR3
N region nucleotide insertion is seen at the boundary of V, D
or J coding segments and is template-independent. These N regions contain between one and 12 nucleotides and are more often guanine or cytosine rather than adenine or thymidine, reflecting the role played by the enzyme TdT in this process.
The TCR molecules are dimeric proteins, usually a + P (TCR a:P), although 5% of circulating T-cells bear the y:§ TCR. The random combination of subunits in the TCR dimers further enhances the generation of diversity. The recombination events on one chromosome leading to the production of a functional molecule, such as TCR a:P, result in the inhibition of recombination at that locus on the other chromosome. This so-called allelic exclusion ensures that any given lymphocyte will express only one type of receptor molecule.
This describes the random introduction of mutations within the V, D and J segments and is well documented in Ig genes but does not contribute to diversity in the TCR genes. Rearranged V region sequences in B cells have been analyzed and found to differ from those of the germline V sequences from which they were generated. Most of these mutated V regions are found in the secondary immune response on rechallenge of B cells with antigen. During this process the antibody of the primary response (IgM) is switched to IgG or IgA. The somatic mutation rate has been estimated to be as high as 10-3 per base pair per cell generation, and the process occurs predominantly in variable regions of the molecule. The presence of somatic mutation can be useful in determining the stage of lineage in B-cell malignancies. In CLL it has been shown that cells either do or do not have mutated Ig genes. This has important prognostic significance since those cases that have undergone somatic hypermutation have a better prognosis than those cases that have no mutations.
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