Cell Type-Specific Intralocus Interactions Reveal Oligodendrocyte Mechanisms in MS.
Factor DC, Barbeau AM, Allan KC, et al.
Cell. 2020;181:382-95 e21.
Bottom Line:
Genes both increase and decrease susceptibility to MS. Hundreds of susceptibility genes are described. However, these genes account for only about 48% of the risk for inheritance. Ninety percent of identified susceptibility genes don’t produce a protein. Rather these genes function as regulators of other genes. Almost all described susceptibility genes relate to the immune system. While the immune system clearly plays a major role in the disease, there are data that suggest there are changes to the myelin-producing cells (oligodendrocytes) of persons with MS that may precede the attack by the immune system.
The scientists in the above-cited paper studied genes called “outside variants.” These genes were not tightly associated with MS susceptibility, but interacted with high-susceptibility genes, and by interacting greatly increased the risk of developing MS. Using advanced molecular techniques the scientists identified 6 outside variants that contributed greatly to increased MS risk. These genes were specifically related to cells of the CNS, three of them to oligodendrocytes. As a result of these three “outside variant” gene interactions production of essential proteins were affected, preventing the maturation of immature oligodendrocytes (oligodendrocyte precursor cells) into mature oligodendrocytes, thus limiting their ability to remyelinate. These data show for the first time that there is a genetic susceptibility to the development of MS involving the central nervous system, in particular the prime target of immune cell attack, the oligodendrocyte. More work needs to be done to understand if and how these changes trigger the immune attack on the brain that is the hallmark of MS.
Key Points:
1. Data supporting a genetic susceptibility to MS is well established.
2. Genome Wide Association Studies (GWAS) have identified hundreds of genes associated with disease susceptibility.
3. Most of the genes relate to the immune system, but they account for only 49% of susceptibility risk and 90% of these genes are involved in the regulation of other genes rather than in the synthesis of new proteins.
4. Studies of central nervous system tissues from persons at the very earliest stages of MS showed a loss of myelin-producing cells, viz. oligodendrocytes. This occurred in the absence of any inflammation. These observations suggested that perhaps the start of MS was not an attack on the central nervous system by the immune system, but rather a loss of abnormal oligodendrocytes that subsequently triggered an immune response. In other words, MS may not result from an abnormal immune response, but rather from abnormal oligodendrocytes, that then trigger a destructive immune response.
5. A “proof of concept” series of experiments in support of this hypothesis was with a mouse model of MS in which mature oligodendrocytes were programmed to die. Shortly after the death of oligodendrocytes there was an immune attack on remaining oligodendrocytes and myelin, resulting in further tissue damage.
6. The scientists in the paper cited at the top looked at genes associated with a high risk of developing MS (“susceptibility genes”). They then looked at genes in their vicinity that also carried a risk of disease, but a much lower risk. These genes were called “outside variants.” One hundred twenty-six outside variants were found that interacted with high-susceptibility genes and affected their function. As a result of these interactions susceptibility was greatly increased.
7. Most of the outside variants related to cells of the immune system (T cells, B cells, macrophages, and monocytes). However, six variants were associated with cells of the central nervous system, three of them specific to oligodendrocytes.
8. The scientists next looked at what happened when “outside variants” interacted with high susceptibility genes. They discovered that such interactions resulted in a major interruption in the production of new proteins necessary for oligodendrocyte precursors to mature into myelin-producing oligodendrocytes.
9. Specifically, the outside variant interactions prevented the reading of the DNA code of oligodendrocytes by preventing a key enzyme, promoter-proximal RNA polymerase II (RNAPII), from functioning.
10. They did so by acting on so-called “pause release genes” necessary for the polymerase to “elongate” and prepare the essential messenger RNA (mRNA) needed for protein synthesis.
11. As a result, proteins necessary for the maturation of oligodendrocyte precursors to myelin-producing oligodendrocytes were blocked.
12. The scientists then studied oligodendrocytes in persons with primary progressive multiple sclerosis and secondary progressive MS, looking for the presence of proteins that blocked the functions of RNAPII.
13. Patients with primary progressive MS displayed a 6-fold increase in the numbers of cells that had such blocking proteins compared to normal controls. Similarly, secondary progressive MS patient lesions showed a 10-fold increase in polymerase-blocking proteins. These data were further evidence that oligodendrocytes in MS were not “normal” with changes that could prevent essential molecular processes needed to allow oligodendrocyte precursor cells to mature.
14. How these findings relate to the quality of myelin that is produced in persons with MS, whether the myelin is altered to the point of inducing an immune response, and how this relates to susceptibility genes in the immune system remains unknown. Nevertheless, these findings open a whole new area of study in the pathogenesis of MS.
Discussion:
As noted in one of my previous posting, there are two theories on the genesis of MS. One theory is the “outside-in” theory, that states an abnormality of the immune system, in particular a loss of immune tolerance to brain proteins is responsible for the development of MS. The other theory is the “inside-out” theory. This states that there is an intrinsic defect in the central nervous system of persons with MS, in particular in oligodendrocytes, that in turn triggers an immune response against such cells. Data in support of the latter theory are discussed above.
My personal inclination is that MS is the result of both processes, namely that there is an abnormality of oligodendrocytes in the central nervous system, and that in the setting of an easily dysregulated immune system, the immune system initiates its destructive attack on the brain.
The Australian neurologist, Dr. John Prineas, is a strong advocate of the theory that MS is a disease of dysfunctional oligodendrocytes based on his very careful analyses of brain tissues in persons with MS dying at the very onset of their illness. Additional evidence for oligodendrocyte dysfunction comes from two papers, one cited in by blog on May 19 2019, indicating an abnormality of oligodendrocyte-blood vessel interaction, the other demonstrating that oligodendrocyte death alone is enough to trigger an immune response against remaining myelin and oligodendrocytes.
The paper by Factor et al provides evidence for a genetic dysregulation in the synthesis of new proteins in oligodendrocyte precursors that prevent their maturation into myelin synthesizing oligodendrocytes. These exciting observations raise many new questions. Is the myelin produced by mature oligodendrocytes in persons with MS somehow altered in a fashion sufficient to induce an immune response against it? Alternatively, is the myelin altered in a way that now make it “immunologically” look like a viral protein, such that a normal immune response to a viral protein evokes a cross-reactive immune attack on the altered myelin? There are data in support of this conjecture. How do these observations relate to the functions of the “high-susceptibility” genes with which the outside variants interact? This paper engenders many more questions, but answers to them may provide important fundamental insights into the causes of MS.