Somatic mutations occur in the form of gene rearrangement. Diversification is achieved by three methods:
â€¢ Somatic Hypermutation
â€¢ Affinity maturation
â€¢ Class switching
â€¢ Gene conversion
Somatic hypermutation increases the BCR by bringing about point mutations in the V regions of both chains. The somatic mutations is brought about by an enzyme AID which is activation induced cytidine deaminase and this is expressed in B cells but do not occur in TCR genes. AID is active only in activated B cells and these increase DNA damage thereby leading to a mutation. Somatic hypermutation occurs only when DNA is acted by AID and generated by UNG. A high density of single strand nicks which flanks C region genes and is thought to generate double stranded breaks needed for class switch. Somatic hypermutation occurs in periphery of B cells. This further brings about point mutations and this gene gives rise to mutant B cell recptor on the surface of B cells. Affinity maturation occurs when there is continuous mutation of the genes. Mutations increase the affinity of a B cell receptor for antigen. Cells that stop this are selected. B cell expresses new receptors after every mutation. If favourable then it undergoes another round of mutation. This way the specificity of B cells are refined and this occurs in germinal centres. This is called as affinity maturation. Diversity in TCRs is generated during gene rearrangement and all the somatic hypermutation of rearranged V regions does not occur in T cells as it happens in B cells. Diversity is seen more in CDR3 regions. Hypermutation is an adaptive specialisation for B cells to make high affinity secreted antibody that carry out effector functions. Changes in receptor binding in T cells are damaging in comparison to B cells hence T cells do not have somatic hypermutation happening. Proliferation of B cells occurs rapidly and there is diversification which is seen and this is gene conversion.
In Gene conversion there are short sequences of the V region and these are replaced by sequences from the upstream region of V chain. Gene conversion is associated to the somatic hypermutation as it requires AID. When there is early differentiation of bone marrow the VH regions exons expressed by BCR are modified and no V(D)J recombination occurs.
Sometimes there is IgM and IgD which is expressed later. The V region might express IgG, IgA or IgE antibody after an immune response in comparison to one during a response where IgM is expressed. This is called class switching or isotype switching. Switching from IgM to other immunoglobulin classes happens only after B cells have been produced by antigen. This is done via a switch recombination which is a type of non homologous DNA recombination and this is guided by stretches of repetitive DNA called switch regions. These regions lie in the intron between the IH gene segments and CÂµ gene and at equivalent sites upstream of the genes. The switch sequences lie in introns and hence cannot cause frameshift mutations.
TCR: The diversity of the receptors is mainly due to assembly of functional genes by V(D)J rearrangement (recombination). In the T cell receptors as well as the BCR the fragments are separated by variable (V), diversity (D) and joining (J) regions all of these are linked to the constant (C) region. VDJ recombination occurs in Recombination signal sequences (RSSs).
The RSSs are not tightly conserved. In TCRs the RSSs are usually arranged so that the joined coding remains in chromosome and joined RSS are removed on a circular DNA. The RAG genes are the ones recognising the RSSs. RAG genes include RAG1 and RAG2 proteins which help in the first step of V(D)J rearrangement. Naturally occurring RAG1 N terminal truncation supports rearrangement of TCR but not Ig genes. CDR3s of the T cell receptor alpha and beta chains form the centre of the antigen binding site of a T cell receptor. The borders of this consists of CDR1 and CDR2 loops which are present in the germline V gene segments for the Î± and Î² chains. More variable loops of TCR bind to unique compartments on the other hand less variable loops of TCR bind to less variable MHC compartments. The Î³Î´ receptors of the TCR are a distinct lineage of T cells.
SOME OF THE STRIKING SIMILARITIES BETWEEN MHC, ANTIBODY/TCR GENES
Gene conversion is a common factor between MHC and antibody.
Balancing selection is seen both in MHC and antibody.
Pathogen selection of alleles in MHC, antibody and TCR is a common factor.
In both TCR and BCR there is presence of P- and N- nucleotides.
DIFFERENCES BETWEEN MHC, ANTIBODY AND TCR
The main difference found between the three are that in MHC there is polygeny which occurs, in antibody there is genetic diversity by V(D)J rearrangement, affinity maturation and class switch and finally in TCR there is diversity only by V(D)J rearrangement.
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