New wind in the sails of rheumatoid arthritis research
In 1987, Peter Gregersen was part of a big breakthrough in the field of rheumatoid arthritis (RA) research. By comparing versions of a particular gene in patients with RA to those without the disease, Peter and his colleagues found a telltale stretch of amino acids – the building blocks of proteins – that seemed to distinguish those who had RA from those who did not. From these observations, they developed a hypothesis that this string of five amino acids within a region of the genome known as the major histocompatibility complex (MHC) was critical to rheumatoid arthritis susceptibility. Known as the “shared epitope,” this string of amino acids was responsible for a person’s risk of developing RA.
For twenty years, this hypothesis remained immutable. But there were always hints that something else – additional genetic risk factors in the MHC – might be at play, but no one could pinpoint them in this difficult-to-study region. Despite many efforts, Peter’s 1987 discovery remained one of the few major advances in the search for the cause of RA and the hunt for more effective ways to treat it.
A few years ago, another group of researchers set its sights on the same region of the genome – the MHC – because of interest in a very different disease: HIV. Broad associate member Paul de Bakker and his colleagues at the Broad Institute, Ragon Institute, and elsewhere developed a strategy to examine the genome with great resolution – known as fine-mapping – and looked across the MHC region in thousands of people infected with HIV, some of whom followed a typical course after infection and some of whom were able to keep the virus in check (read more here). Their approach would prove to be useful in the hunt for risk factors for other diseases, too.
“It just so happened that my colleague, Soumya Raychaudhuri, at the time was pursuing genetic risk factors associated with rheumatoid arthritis,” recalls Paul, who is also an assistant professor at Brigham and Women’s Hospital and Harvard Medical School. “He too was very interested in fine-mapping disease loci.” Teaming up to apply the same strategy to look for RA risk factors in the MHC seemed like the logical next step.
The results of that collaborative effort appeared in a recently published paper in Nature Genetics. The new work validates but also expands in important ways Peter’s 1987 discovery.
“This works breaks a 20-year log jam in the field,” says Soumya, first author of the paper. He is the primary investigator of a laboratory studying the genetics of autoimmune diseases at Brigham and Women’s Hospital and Harvard Medical School; he is also an affiliate of the Broad Institute. “Many of these MHC [signals] have been around forever, but we’re using this fine-mapping approach to figure out where the key positions are that modulate risk.”
Soumya also cautions that very little is generally known about RA. For other autoimmune disorders, such as celiac disease, the trigger – or “autoantigen” – that causes the immune system to attack the self is known. For celiac disease, that trigger is gluten, something that a person with the disorder can avoid.
“For rheumatoid arthritis, we don’t have a convincing autoantigen,” says Soumya. “This is one small step to get at the autoantigen in RA.”
Using Paul’s fine-mapping strategy, the research team looked at genetic information from 20,000 people, comparing the versions of genes in the MHC from individuals who have RA to genes from those who do not. This technique pinpointed positions in two of the amino acids from Peter’s “shared epitope” but also pointed to two additional amino acids that may play a role in RA risk.
These two new amino acids were particularly exciting to the researchers because of where they sit within key immune system proteins, known as HLA proteins. They sit at the base of what is known as the peptide-binding groove – the part of the protein that should be able to detect and bind foreign bodies.
“That’s a very important finding in my view because it implies a mechanism,” says Peter, who is now an investigator at the Feinstein Institute for Medical Research.
The researchers hope to use this information to figure out what molecule is binding within this groove or cleft – an important step toward understanding and detecting RA’s equivalent of gluten.
“Now, with these results, we’ll be in a position to figure out what antigen binds these molecules well and what does not,” says Soumya. “It’ll give us the ability to test candidate antigens that are out there in the literature.”
Knowing the antigen could lead to the development of new interventions. It’s not clear if lifestyle changes – such as a gluten-free diet for patients with celiac disease – will help prevent RA symptoms, but understanding the underlying cause of the disease could help the scientific community develop better treatment strategies.
The researchers are also interested in looking beyond RA. They may be able to apply the same approach to other autoimmune diseases, narrowing in on new genetic risk factors and propelling forward the search for the underlying causes of these illnesses.