Closer and Closer to the Cause of Multiple Sclerosis

September 11, 2014

At the ACTRIMS/ECTRIMS conference, one has the impression that the science of multiple sclerosis is moving forward at an unprecedented rapid rate. Live from the floor . . .

This year’s joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Boston (September 10-13, 2014) boasts approximately 9,000 attendees from 89 countries. Hallway conversations feature many languages, and the auditorium has been consistently packed with attendees.


Today’s plenary session by David Hafler, MD, MSc, Yale University School of Medicine, New Haven, CT, definitively answered one of the lingering questions about MS: Is it really an autoimmune disease? His answer, supported by an elegant summary of current genetic and environmental research, was a resounding yes. This confirmation of MS as an autoimmune disease is important, as there are still those who doubt the etiology--witness the misplaced enthusiasm for the recent failed theory of CCSVI (chronic cerebrospinal venous insufficiency).

Genetics and Environment

It is has long been known that genetics influences the development of MS. For example, while the risk of MS in the general population is 0.1%, the sibling risk is 2% to 4% and the identical twin risk is 30%. However, Dr Hafler explained that recent genome-wide association studies (GWAS) have revealed over 150 genetic variants that contribute to the development of MS under the proper environmental stimulus (stimuli). He speculated that as many as 400 genetic variants may eventually be identified. He stressed that these are not abnormal mutations, but common allelic variants “that everyone shows.” Each one by itself has a small effect on disease risk. “It is not bad genes or a bad environment: It is the bad interaction between genes and environment,” Dr Hafler stated.

Environmental risk factors include cigarette smoking, decreased vitamin D, increased body mass index, Epstein-barr virus (EBV) infection, and possibly increased salt intake.

Inside or Outside?

Dr Hafler also clarified another important point that has vexed researchers and clinicians for years. Does the pathology of MS start inside or outside the brain?

According to Dr Hafler, MS is a “…genetically mediated autoimmune disease initiated by infiltrating T cells and then recruiting B cells and macrophages into the central nervous system.” The pathogenic T cells begin in the periphery, enter the choroid plexus, and then progress into the cerebrospinal fluid. In a second wave, there is massive recruitment of Th17 and Th1 cells into the brain parenchyma. Although both T and B cells are involved, it is the T cells that are the major drivers of inflammation.

Dr Hafler observed, “We’ve reached a stage in MS research that we have some fundamental understanding.” However, he reassured young investigators that there was still much to do. In particular, it is not clear why a therapy that is effective in one autoimmune disease might exacerbate another autoimmune disease. For example, anti-IL17 works in psoriasis, but makes Crohn’s disease worse. It is also unclear whether there is one key environmental factor, as yet unidentified, that triggers autoreactive T cells. Another area of interest is how the microbiome influences the myelin reactive T cell repertoire.


The ACTRIMS/ECTRIMS meeting is a bit overwhelming as there are many overlapping sessions and hundreds of presentations. One has the impression that the science of MS is moving forward at an unprecedented rapid rate. The definitive ascertainment that MS is one of many autoimmune diseases will further propel the development of effective therapies that promise to improve the lives of people with MS.