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.
"The AID-RPA interaction must be regulated to bring about the specificity of the mutation," Chaudhuri says. "If this regulation is impaired for some reason, then the B cell would incur a lot of random mutations and that might lead to tumors."
The next step, then, is to figure out what sometimes goes wrong and allows the AID-RPA complex to go to the wrong regions, potentially leading to activation of cancer genes.
"Now that we've learned how AID gets access to the variable regions, we can ask how the process goes awry to cause mutations of genes that could lead to cancer," says Alt.
RPA is found throughout the body, and is known to be involved in repairing damaged DNA, but until now, it hadn't been known to have a role in the immune system.
"We've discovered a new function for it," says Alt. "It's generating quite a bit of excitement in the immunology field and promises to teach us more about the immune response."
Alt has spent his career exploring the immune system's ability to defend against a vast array of antigens through genetic rearrangements, as well as the mechanisms the body uses to suppress genomic instability, an increased tendency toward gene mutation that can lead to cancer. In recent years, these two lines of investigation--immunology and cancer -- have intersected and informed each other.