New paper from MSUCOM student and dean explores how one gene may influence MS


Autoimmune diseases can be particularly difficult to study and treat, since they’re caused by a complex network of genetic and environmental factors. In a paper recently published in the Journal of Immunology, Andrea Amalfitano, Dean of MSU’s College of Osteopathic Medicine, and Patrick O’Connell, a seventh-year DO/PhD student, have started putting together the clues on how one gene in particular, ERAP1, may contribute to the development of multiple sclerosis (MS).

Amalfitano’s lab has studied several other immune-related conditions, including ankylosing spondylitis and colitis, and had previously worked with the ERAP1 gene and its relationship to autoimmune conditions. MS was a natural next step for further research since previous reports showed that people with ERAP1 gene mutations are more likely to develop MS.

“In the simplest context, MS is when your body’s immune system starts attacking your brain,,” O’Connell explained. “We don't know why and we don't fully understand it. But we do know that it's a complex disease, there are a lot of factors involved, and the human immune system is one of the major players.” By learning more about how the disease begins, O’Connell, Amalfitano, and the other researchers on the project hoped to gain insight into who might develop MS and which therapies might work best for them.

The team compared mice with and without the ERAP1 gene, since ERAP1 gene mutations can make the gene non-functional or function differently in humans. “Using this mouse model, we were able to tease apart how ERAP1 was affecting all the immune cells in the brain, and the mouse’s susceptibility to MS,” O’Connell said. “What we found is that not having functional ERAP1 affects a certain type of immune cell called B cells. And that is contributing, at least in our mice with MS, to them getting more severe MS symptoms.”

This is a very interesting finding, according to O’Connell, because over the past 15 years or so, B cells have emerged as a key part of the immune system driving MS. Some patients with MS seem to benefit from therapies that “knock out” their B cells. But these therapies don’t benefit all patients, and they come with the downside of making patients immunocompromised. “So we're trying to understand why depleting B cells helps with MS, and how exactly that works,” O’Connell said. “And can we develop better and more targeted therapies to target only certain types of B cells to help patients?”

That question is what Amalfitano’s lab plans to work on in the future. “Based upon the findings in this paper, we are now prepared to investigate how human genetic changes can predispose one to MS, in particular, how these specific gene changes might influence the function of an important subset of cells in the immune system, the B cells,” Amalfitano said. “With this knowledge, we can both potentially better identify the risks for MS to an individual (i.e. precision medicine) as well develop newer precision therapies targeting those B cell functions genetically susceptible in MS patients.”

For his part, O’Connell plans to do a residency in pediatrics and a fellowship in medical genetics, with the ultimate aim of becoming a pediatric geneticist, something his work in Amalfitano’s lab has prepared him for. “I wasn't really sure what I wanted to do when I started the DO/PhD program, but I was lucky that I sort of fell into Dean Amalfitano’s lab. Immunology is fascinating, and it’s broadly applicable to so many areas of medicine and research.”

As for his advice for other students interested in pursuing research during their education and afterwards, O’Connell said two things are key: “Keep an open mind, rotate through a lot of different labs, and see what you like. But the most important thing is to pick a mentor who’s a good match for how you work.”