Genetic predisposition to Multiple Sclerosis mapped throughout immune system

There is an extensive overlap of immune cell types and genes 
associated with MS. Figure 1 from the group's paper

Multiple Sclerosis (MS) is the most common immune-mediated disorder, with 2.3 million people diagnosed worldwide. A detailed gene map of the illness takes us a step closer to understanding the mystery of how MS develops.

The cause of MS is still unknown, but some studies have indicated that the complex interaction between environmental factors and variations in genes may be what leads to MS risk or susceptibility.

Professor Helmut Butzkueven, based in the Department of Neuroscience in the Central Clinical School at Monash University, is a clinician-researcher who has been investigating MS for many years. His team is grappling with the big picture of MS. His and colleagues’ latest research is the culmination of nine years of work. Their results suggest that both the adaptive (targeted) and innate (non-specific) arms of the immune system are involved, not just the adaptive immune response as was previously thought.
In MS, the myelin sheath that surrounds the nerve cell axons is attacked by the body’s own immune cells. But which immune cell types contribute to the development of MS? Most studies have focused on T cells - those originating in the thymus gland, hence ‘T’ - as the major contributor.

Professor Butzkueven draws a more complex picture by showing multiple types of immune cells are involved. “This paper is a step rather than a solution, concentrating on what we know of the genetic signals regulating immune system function, or dysfunction in the case of MS.”

The study looked at multiple immune cell types obtained from patients with MS who were untreated (cases) and healthy volunteers (controls) to explore genes that might be involved and in which their expression regulates MS risk.

First author Dr Melissa Gresle said,“We found that there were 129 distinct genes whose function could be directly involved in MS risk, suggesting that a big network of genes is involved in MS risk. It’s a complex intersection of genes, environment, and the regulation of expression of genes involving more than one type of immune response cell in autoimmunity."

Professor Butzkueven added, “Currently, we are looking at how this gene expression network interacts with environmental factors, which could be modified to stop the development of MS. For example, MS is much more common in the lower latitudes of Australia, being 7 times more common in Victoria than in North Queensland. This strongly suggests that the genetic functions we have mapped interact with the environment. One of the lead candidates is sunlight and Vitamin D.”

Dr Wei Yeh, a PhD student in Dr Gresle and Professor Butzkueven’s research group, recently reviewed what is currently known about vitamin D and multiple sclerosis. He said, “We know that being deficient in vitamin D is associated with increased risk of developing multiple sclerosis. However, the specific mechanisms by which vitamin D deficiency leads to this are not well understood. We hope to understand this further by investigating how vitamin D changes gene expression levels in different immune cells, and whether there might be differences in this response between people with and without MS.” 

Professor Butzkueven concluded, “We are now concentrating on linking our 'gene function map' with vitamin D biology and exposure data to climb the next rung of knowledge.  At the end of this mysterious ladder is the big answer all our patients ask when they are diagnosed: 'What causes MS and why did I get it'?”

References

Gresle MM, Jordan MA, Stankovich J, et al. Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells. Life Sci Alliance. 2020;3(7):e202000650. doi:10.26508/lsa.202000650

Yeh WZ, Gresle M, Jokubaitis V, Stankovich J, van der Walt A, Butzkueven H. Immunoregulatory effects and therapeutic potential of Vitamin D in multiple sclerosis. Br J Pharmacol. 2020;10.1111/bph.15201. doi:10.1111/bph.15201