| Popis: |
Evolution is driven by a revolving process of mutation and natural selection during which the fittest individuals survive under harsh selective pressures in their environment. In a molecular recapitulation of this process, antibodies undergo a somatic evolution after antigen stimulation, resulting in a more protective defense of the host against the environment. Immunoglobulin genes undergo apparently random hypermutation of their rearranged variable regions followed by selection for the fittest (i.e., highest affinity) of the mutated antibodies. The first evidence of hypermutation and selection of immunoglobulin genes was the observation of increased mutations in the sequences of variable regions of heavy chains encoding anti-phosphorylcholine antibodies bearing IgG isotypes (Gearhart et al. 1981) and in their associated Vκ genes (Selsing and Storb 1981). Over the ensuing 16 years, we have delineated the pathway that B cells undergo to acquire somatic mutations in their rearranged immunoglobulin genes, in regards to the timing, location, and some extracellular requirements (Gearhart 1993). The advent of transgenic and polymerase chain reaction (PCR) technology brought especially powerful tools to cut and paste the immunoglobulin loci together to establish the minimal sequences required for targeting hypermutation, and gene targeting allows the targeting of proteins that may play a role in signaling the cell to begin mutating. |
