Possible cause of MS? How a gene variant can combine with environmental factors to cause MS

By Steve Cimino

The distinct way immune cells respond to viruses like Epstein-Barr in people with the HLA-DR15 gene variant plays a significant role in the development of multiple sclerosis (MS), according to new research into what causes the autoimmune disease. “Fitness to cope with dangerous pathogens in the context of certain HLA molecules comes at the price of misguided immune responses,” Jian Wang, PhD, a postdoctoral researcher in the neurology clinic at the University Hospital Zürich, and colleagues wrote in Cell.

To determine how exactly HLA-DR15 contributes to the genesis of MS, the researchers launched an interdisciplinary international study on the HLA gene complex.

“The association of MS with the HLA-DR15 haplotype was actually known since the early 1970s,” said study coauthor Roland Martin, MD, of the department of neurology at the University Hospital Zürich, in an interview. “It was, to my knowledge, the first discovered association of an HLA molecule with a human autoimmune disease. But until recently, it was not known functionally how it translates into disease susceptibility and disease onset.”

It was also known that carriers of HLA-DR15 who come down with the Epstein-Barr virus (EBV) along with infectious mononucleosis have a 15-fold greater risk of MS, but the underlying mechanisms were not fully understood.

Dr. Roland Martin
“Late EBV infection means a greater risk of MS, but it’s still very difficult to say if EBV is an absolute requirement or if people with MS then also activate this virus,” Dr. Martin said. “It’s fair to say that MS without EBV doesn’t exist. But 25% of the healthy population is DR15 positive, and in MS it’s approximately 50%. Many people are DR15 positive and they don’t get MS.”

“We wanted to figure out, on a functional level, how HLA molecules contribute to MS,” he added.

We wanted to figure out, on a functional level, how HLA molecules contribute to MS.

Determining altered behaviors

Patients with MS who were age 18 years or older from a single outpatient neurology clinic were recruited for the study between July 2018 and February 2019. Receiving treatments through participation in a clinical trial (which thereby eases financial burden) was among the exclusion criteria.

Participants who were included in the analysis (n = 243) filled out a paper survey that took about 15 minutes to complete. Among the assessment tools was the modified Comprehensive Score for Financial Toxicity Patient-Reported Outcome (COST) instrument, which was previously validated to assess cancer patients.

The survey also assessed HRQOL and alterations in lifestyle to compensate for financial lack, such as decreased spending on food, clothing, or leisure; withdrawal from savings accounts; and increased use of credit cards. Care-altering coping behaviors also were assessed and defined as foregoing imaging tests and nonadherence to medications because of the costs. For patients who received their MS diagnosis more than 3 months before study entrance, information on disease severity and disease type (i.e., relapsing remitting, primary or secondary progressive) was obtained. Patients were also asked about demographics, health insurance, financial self-efficacy as measured by the Financial Self-Efficacy Scale, and health literacy.

As HLA-DR15 molecules often can be found on the surface of white blood cells, where they present various protein fragments to T cells, the study began by investigating which fragments are presented. In the thymus, where immune cells are trained, they found that the HLA-DR15 molecules also presented fragments of themselves.

As those trained T cells then migrate into the blood, they come into contact with viruses or bacteria that they are tuned to recognize – at a cost.

“When the cells are activated by, for example, EBV infections, they become memory cells and more sensitive to antigenic stimulus,” Dr. Martin said. “Then, if the autoantigen that is involved in the MS itself and expressed in the brain also becomes available, the cells are more strongly activated, we assume that they can then go to the brain and cause damage.”

Beyond EBV, the researchers also confirmed a distinct reaction to the intestinal bacterium Akkermansia muciniphila, which is observed at relatively higher numbers in the gut of MS patients.

Top image credit: nobeastsofierce/Shutterstock
Image credit: CNRI / Science Source

Why these two environmental factors? Dr. Martin believes that the carriers of this common gene have adapted to new surroundings, which leaves them unexpectedly prone to MS.

“The way I envision it,” he said, “is that, in certain geographic areas of the world, where people have migrated over the last several thousand years, they are encountering certain pathogens. In Africa, it’s more parasites and certain distinct infections. In Europe and North America, we are confronted with viruses and also bacterial infections. The HLA background that we have has adapted to that, endowing people in those areas to cope with those infections efficiently.”

“The downside of being able to recognize certain infectious agents very well,” he added, “is that similarities between antigens from the virus or from the bacterium with certain self-antigens can lead to autoimmune diseases like MS.”

In terms of research next steps, Dr. Martin expressed optimism that their findings could lead to novel treatment approaches that go beyond MS.

“In many autoimmune diseases, there is a very strong HLA association,” he said. “Rheumatoid arthritis, diabetes, celiac disease, psoriasis. All of these have an association with different HLA molecules. What we’ve described here, in principle, could play a role in other autoimmune diseases as well.

The downside of being able to recognize certain infectious agents very well is that similarities between antigens from the virus or from the bacterium with certain self-antigens can lead to autoimmune diseases like MS.

“What’s already been shown, in diabetes and also in an MS model, is that if you take small molecules that block the HLA binding pocket, you can block T-cell activity against antigens of the pancreas in models of diabetes or MS. And treat the disease, so to speak,” Dr. Martin said.

He also emphasized that, in the long run, their work would hopefully contribute to a better understanding of MS’s origins.

“Our study primarily shows how we educate an immune system, if we are DR15 positive, in a way that sets you up for developing this brain- and spinal cord–specific autoimmune disease,” he said. “But what is at the very beginning? What starts the MS process? This is still not known.”

The study was supported by a European Research Council grant and the Clinical Research Priority Program MS at the University of Zürich. Three of the authors reported being cofounders and co-owners of Cellerys, a company that is developing cell therapies for MS. Dr. Martin reported receiving grants and lecture fees from various pharmaceutical companies.