B cells orchestrate mutations on cue. The procedure for antibody development requires a second take to get the performance right.
According to the World Health Organization (WHO), we are living 6 years longer now than in 1990. And to continue improvements in global life expectancy, we need vaccines. Smallpox has been eradicated, polio and measles are declining, and we may even catch up with diseases like hepatitis and some forms of cancer. For all of this to happen, we must continue with scientific research to unearth pertinent knowledge that fuels advancements.
Designing vaccines is dependent on deciphering how antibodies are generated. We inherit V, D, and J genes (antibody genes) which undergo rearrangements inside B cells to generate diverse combinations of receptors capable of picking up different proteins. Ensuing B cells that react with “self” proteins are eliminated, and B cells with the potential to pick up foreign proteins (antigens) persist. As a result, a baby is born with an antibody repertoire of varied V, D, and J gene combinations. This arms the individual with low affinity immunoglobin (Ig) M antibodies that circulate in blood.
When the immune system encounters a new antigen (bacteria/virus/vaccine), B cells are charged with the task of replacing the low affinity IgM antibodies with those that have an increased affinity for that antigen. Consecutive exposures to the same antigen result in faster response times and with antibodies of higher affinity – the principle behind vaccinations. High-affinity IgG and IgA antibodies are required to inactivate toxins, neutralize viruses, and promote the clearance of microorganisms. This process of “affinity maturation” by B cells to produce antibodies of greater affinity is driven by “somatic hypermutation” or “SHM”.
SHM is targeted to the Ig genes where mutations are orchestrated on cue for the purpose of generating high affinity antibodies. In recent years we have been unravelling the mechanisms inside B cells that contribute to SHM. The discovery of activation-induced cytidine deaminase (AID) and the demonstration that it is required for SHM and other processes have triggered several advances in the immunology and vaccine fields.
A team of scientists from Anaptysbio Inc. and the Scripps Research Institute recently published their findings on affinity maturation of antibodies. They generated 53 distinct antibodies against 21 antigens, and compared this to the in vivo antibody repertoire. Their scrutiny into insertion and deletion mutations, SHM, and AID provide insights into affinity maturation that will contribute towards future vaccine development. HemaCare is proud to have supplied peripheral blood mononuclear cells (PBMC) from 61 volunteers . HemaCare is also a supplier of B cells.
1: Bowers PM, Verdino P, Wang Z, da Silva Correia J, Chhoa M, Macondray G, Do M, Neben TY, Horlick RA, Stanfield RL, Wilson IA, King DJ. Nucleotide insertions and deletions complement point mutations to massively expand the diversity created by somatic hypermutation of antibodies. J Biol Chem. 2014 Oct 15. PubMed PMID: 25320089.