• Gary Birnbaum, MD

Why does MS vary in severity? A very important new clue!

The Genetic Basis of Multiple Sclerosis Severity

Suggests Central Nervous System Involvement

A. Harroud, on behalf of the International Multiple Sclerosis

Genetics Consortium

ECTRIMS 2021 -P927. Mult Scler J. 2021;27:756.


Paper S5.005; Session: S5: COVID and MS Basic Science

Annual Meeting of the American Academy of Neurology

April 3, 2022; Seattle, WA

Bottom Line:

What makes a person susceptible to MS and why are there such differences in the severity of disease among individuals? While much work has been done determining susceptibility, much less is known regarding severity issues. The as yet unpublished observations presented in the two meeting abstracts described above are among the first to examine the genetic basis of disease severity in MS. The results indicate that, unlike genes involved in susceptibility to MS, which mainly involve the immune system, genes associated with severity of disease are associated with central nervous system tissues. These data provide further evidence for the critical observation that there are intrinsic changes in the brains of persons with MS and that these changes affect the course of disease. These observations support previous ones that demonstrated abnormalities in MS central nervous system and further emphasize the need to greatly expand research in this area. Understanding the changes in the central nervous system of persons with MS is essential to understanding the disease process and could lead to the discovery of new treatments for this illness.

Key Points:

1. As noted in my previous blogs there are two theories regarding the cause of MS. One, the “inside-out” theory, hypothesizes that an abnormal central nervous system triggers an immune response that then attacks the brain. The other, the “outside-in” theory, hypothesizes that the primary cause of MS is an abnormal immune system that loses immune tolerance to brain tissue and attacks the brain. The two theories are not mutually exclusive, and the data presented in the above abstracts provide strong evidence that there are genetic changes in the central nervous system of persons with MS that contribute to disease severity.

2. There are at least three possible ways that this could occur. One is that the changes in MS central nervous system result in stimulation of the immune system, and that in persons with more severe disease these changes are able to stimulate the immune system more strongly. Put another way, the proteins expressed by the altered central nervous system are more antigenic. There are data to support this.

3. Another possibility is that the changes in MS central nervous system increase the likelihood of a cross-reactive immune response between the brain and a persistent viral infection such as Epstein-Barr virus. This in turn targets the central nervous system for an immune system attack.

4. The third possibility is that the changes in MS central nervous system result in less ability to heal and restore destroyed myelin. The presence of altered protein synthesis in myelin producing cells (oligodendrocytes) in MS has already been described.

5. New disease-modifying therapies directed toward modulating immune function have greatly reduced numbers of relapses in persons with MS but have had little effect on the chronic progressive phases of the disease. Indeed, chronic disease progression appears to result more from a degenerative process than an inflammatory one.

6. The above observations indicate the urgent need to define the changes present in the central nervous system in persons with MS in greater detail. Understanding these changes will not only provide more insight into the disease process but could result in the development of new disease-modifying therapies.


Much work has been done identifying factors involved in susceptibility to MS. These include genes involved with immune function (of which there are now more than two hundred), decreased levels of vitamin D and childhood obesity. Much less work has been done in defining factors involved in the severity of MS, a condition that varies greatly among individuals, even in members of the same family with this illness. Are such differences the result of differences in immune function, that is that immune function in persons with more severe MS is more abnormal or are there other possibilities? The data presented in the above two abstracts suggest that the picture is more complicated.

The data presented, in conjunction with previous observations of other researchers provide strong evidence that changes in the central nervous system of persons with MS contribute to, and may even be primary to, the development of MS. While defining the changes in immune function that make the immune systems of persons with MS susceptible to the disease are most important, equally critical is discovering what the nature of the central nervous system changes are, that determine disease severity and may also be involved in causation. Some changes in oligodendrocyte protein synthesis are described, but the identification of disease-specific genes related to brain and spinal cord function described by Dr. Harroud and associates, provides an even more exciting and potentially productive opportunity to reveal fundamental mechanisms of disease in MS, and increases the likelihood of finding new and possibly more effective therapies.

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