Somatic hypermutation (SHM) is a critical enzymatic process utilized by B cells to generate antibodies. The human immune system is highly adapted to generate an enormous diversity of antibodies against foreign pathogens using a limited set of genes within the genome. SHM has been highly conserved through mammalian biology and is the key process responsible for generating antibody diversity within B cells.
Antibodies are encoded within the human genome as distinct immunoglobulin genes, named the variable (V), diversity (D) and joining (J) genes, which are joined together through the process of recombination and displayed on the surface of B cells. On encountering a foreign pathogen, antigen-specific B cells displaying recombined antibodies are stimulated to initiate the process of SHM which results in an enormous number of variants of the recombined antibodies from which high specificity, high affinity variants are selected and produced to fight pathogens.
The biochemistry responsible for SHM was poorly understood until seminal work by two key antibody experts, Dr. Matthew Scharff and Dr. Michael Neuberger, demonstrated that hypermutation is triggered by activation-induced cytidine deaminase (AID), an enzyme which acts directly and specifically on specific motifs contained within the variable region of antibody-encoding DNA. The human immune system has also evolved to tolerate the specific nonrandom mutations mediated by AID, such that SHM-derived antibodies appear more natural to the human body as compared to randomly mutated sequences.