affinity maturation

Affinity maturation is a process of affinity-selected differentiation of activated B cells. Repeated exposures to the same antigen provokes greater antibody ligating affinity in the antibody secreted by successive generations of plasma cells.

The mechanisms by which affinity maturation is achieved are somatic hypermutation and clonal selection. Somatic hypermutation (SHM) is a diversity generating, regulated cellular mechanism through which antibodies are produced against an enormous variety of different potential antigens. The binding affinities of the variable regions of immunoglobulins are altered by AID-enzyme-promoted mutations during antigen-stimulated proliferation of B cells. These somatic hypermutations are transcribed and translated into thousands of slightly different immunoglobulins coded by the hypermutated V regions. The complementarity determining regions of these antibodies possess different affinities for the encountered antigen, and clonal selection will favor cells equipped with highest affinity antibodies because these B cells are favoured in terms of activation and co-operation with T cells.

Clonal selection is the phenomenon whereby a previously unencountered cognate antigen (epitope) can stimulate naïve B lymphocytes to proliferate and differentiate into clones of memory B cells and plasma cells that produce antibodies with the highest affinity for the antigen. Those B cells that have highest affinity BCR against the encountered antigen will be selected for proliferation, antibody production, and committment to an antigen-specific memory lineage.

Thus, SHM prepares a spectrum of antibodies with different affinities for the antigen, while clonal selection ensures that the immune system will react increasingly effectively (highest affinity) to an encountered antigen and will be ready for rapid response to subsequent encounters with the antigen.

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tags [Immunology] [affinity maturation]

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somatic hypermutation

Somatic mutation, or somatic hypermutation (SHM) is a diversity generating, regulated cellular mechanism displayed by the adaptive immune response.

▼ activation B cells : activation-induced (cytidine) deaminase : affinity maturation : AID : antibody diversification : antibody production : base excision repair : BCR : BER : C to U : class-switch recombination : CSR : deoxycytidine, deoxyuracil : deletions : DNA polymerase : GC : gene-conversion : hypermutation : immunoglobulins : indels : insertions : memory B cells : plasma cells : secondary antibody diversification : single nucleotide polymorphism : somatic hypermutation, somatic mutation : SNP : transmission : uracil-DNA glycosylase : V region ▼

AID-generated somatic hypermutations affect the variable (V) regions of genes encoding immunoglobulins. Somatic (hyper)mutation affects only individual cells of the immune system, so the programmed mutations that it generates are transmitted only within the particular cell line (somatic) and are not transmitted to the organism's offspring.

Following activation of naïve B cells and during the subsequent antigen-stimulated proliferation of B cells, the gene locus for the Ig-BCR experiences a highly accelerated rate of somatic mutation (increased by a factor of 10^5 to 10^6). That is, mutation rate is roughly 1 per 1,000 for each V gene base pair per cell division compared to 1 per 1,000,000 for each base pair per cell division for 'regular' DNA. This acceleration is attributable to the enzyme activation-induced (cytidine) deaminase (AID), which extracts the amino group from a deoxycytidine base in DNA, converting deoxycytidine to deoxyuracil. Deoxycytidine is a nucleoside formed through attachment of the nucleobase cytosine to a deoxyribose ring via a β-N1-glycosidic bond, and deamination of cytosine generates uracil []im C to U[].

AID is currently considered the master regulator of secondary antibody diversification because it is involved in the initiation of three distinct immunoglobulin diversification processes: somatic hypermutation (SHM), class-switch recombination (CSR), and gene-conversion (GC).

AID-catalyzed deamination of deoxycytidine creates a single nucleotide polymorphism (SNP) in the DNA strand by generating a uracil:guanine mismatch. The nucleobases that normally occur in DNA are adenine paired with thymine, and cytosine paired with guanine. Uracil is normally found only in RNA, where it is paired with adenine.

A high-fidelity DNA repair enzyme, uracil-DNA glycosylase (UNG2), excises the alien uracil nucleobase, then error-prone DNA polymerases complete the base-excision repair process. During this base-excision repair, incorrect nucleobases may be substituted at or adjacent to the original C to U mutation site. Mispairing mutations are susceptible to indels - insertions and deletions. Such mutation vulnerable areas in the genome are termed 'hotspots', and they have played a significant role in biological evolution.

When the B cell proliferates, AID-generated somatic hypermutations are transcribed and translated into thousands of slightly different immunoglobulins coded by the hypermutated V regions. Ultimately, those B cells that express Ig-antibodies (BCRs) with greatest affinity for encountered antigen will differentiate into memory B cells plus plasma cells that produce affinity-specified antibodies against the cognate, stimulating antigen. Affinity maturation ensures that repeated encounter with the same antigen will induce production of antibody with greater affinity.

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