Researchers at Children's Hospital Boston have begun unraveling the mystery of how B lymphocytes - key infection-fighting cells in the body - are able to create many different kinds of specialized antibodies through selective gene mutations, while being protected from random mutations that could give rise to cancers.
The findings, reported in the Aug. 26 issue of the journal Nature, will help scientists better understand two things: how the body is able to mount a strong immune defense against foreign attackers, and how cancers, particularly lymphomas, develop and might be prevented.
B lymphocytes, or B cells, are the immune-system cells responsible for producing antibodies – proteins that recognize, bind to, and neutralize viruses and other harmful pathogens. Since there is a huge diversity of pathogens in the environment – more than our genomes could possibly anticipate and encode for -- the antibody response has to be very fluid and adaptable. The human immune system handles antibody diversification through selective mutations to specific stretches of DNA in B cells that encode immunoglobulins, the proteins from which antibodies are made. Mutations in these gene segments – to the so-called variable regions -- give our B cells the ability to make unique, specialized antibodies with high affinity for a specific invader.
This mutation process, known as somatic hypermutation, is known to require an enzyme called activation-induced cytidine deaminase (AID). But how AID targets the variable region of the immunoglobulin genes -- while leaving the rest of the genetic material in the B cell untouched -- has been a mystery.
In the biochemical study reported in Nature, the Children's Hospital Boston researchers discovered that another protein, known as replication protein A (RPA), interacts with AID, attaches to it, and directs AID to the specific segment of the B cell's DNA required for a tailored immune response. The study details the process by which AID is biochemically modified to promote its interaction with RPA.
"Such a targeting mechanism for AID is essential for our immune system," says Dr. Frederick W. Alt, a Howard Hughes Medical Institute researcher at the Children's Department of Molecular Medicine and senior investigator on the study. "Without it, we'd be immunodeficient, unable to diversify our antibody repertoire."
The Children's study also has implications for the prevention of lymphomas, notes Dr. Jayanta Chaudhuri, first author on the study and a postdoctoral fellow in Alt's laboratory.