Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis
Front Immunol. 2019 Jan 10;9:3116. doi: 10.3389/fimmu.2018.03116. eCollection 2018
1. The initial pattern of MS in most individuals is one of attacks (exacerbations) followed by varying degrees of recovery (remissions).
2. Over many years, even decades, this pattern of MS (the relapsing form of multiple sclerosis) can slowly change to one where attacks no longer happen but are replaced by a gradual progression of disability (secondary progressive MS).
3. A small percentage of individuals presents only with a gradual progressive disability, without relapses. Such a course is called primary progressive multiple sclerosis.
4. This paper describes differences in immune responses in the central nervous system between relapsing MS and progressive MS.
5. A major point of the paper is that the changes of progressive MS are present from the very onset of relapsing MS, but are overshadowed by the frequent bouts of new or acute inflammation that characterize relapsing disease.
6. In relapsing MS there are bursts of massive invasions of the central nervous system by immune cells circulating in the blood. These cells go mainly to white matter, i.e. regions of the brain composed of nerve fibers (axons) surrounded by fatty insulation (myelin). Such bursts are associated with clinical relapses and new lesions on MRIs. Since these cells circulate in the blood they are especially susceptible to the effects of disease-modifying therapies.
7. At the same time there is a more gradual, ongoing invasion of the central nervous system by other immune cells that slowly enter the brain, going to normal appearing white matter, but also around the surfaces of the brain, namely the cortex, where most nerve cells are located, and under the brain’s coverings (the meninges).
8. The cells associated with progressive MS remain in the brain, relatively isolated from the rest of the body, without multiplying, but persisting in their particular “compartments” for long periods of time. As a result they are resistant to the usual disease-modifying therapies that function mainly on circulating and multiplying immune cells.
9. The cells associated with progressive MS slowly release toxic substances[https://www.ncbi.nlm.nih.gov/pubmed/22458983] that also stimulate brain cells such as microglia and astrocytes to become destructive, resulting in nerve cell death and gradual shrinkage, or atrophy, of the cerebral cortex and spinal cord. Atrophy of the cerebral cortex is often associated with altered cognition or thinking.
10.The change from relapsing to progressive MS is very gradual, with no clear boundary between the two. Thus, there are persons with MS who experience gradual progression of their disease without relapses, yet continue to have evidence of active inflammation on central nervous system MRIs.
11.This overlap of progressive and acute disease is important in understanding how the three disease-modifying therapies approved for progressive MS (ocrelizumab, cladribine, and siponimod) work.
12.There is a relationship between the immune responses of relapsing MS and those of progressive MS. Reducing disease activity in relapsing MS reduces the risk of developing progressive MS. This was discussed in a previous blog (“Can progressive MS be prevented?”).
13. Ocrelizumab and siponimod both reduce disease activity in relapsing MS. They do so by different mechanisms. Ocrelizumab reduces numbers of circulating B-cells in the blood. Siponimod traps immune cells in lymph nodes.
14.The beneficial effects of these drugs in progressive MS were almost exclusively noted in individuals that continued to have evidence of acute inflammation. In other words, these individuals had not fully transitioned from relapsing to progressive disease. Indeed, little if any benefit was noted in those individuals that had fully transitioned, and had no evidence of acute inflammation.
For a drug to be truly effective in preventing progressive disease, that is when there no longer is acute inflammation, it will be necessary to understand what starts and continues to stimulate the cells involved in progressive MS. New evidence in this regard is presented in the blog “What triggers progressive MS?”.
The above article provides an excellent summary of the cascade of events that develop during the courses of relapsing and progressive MS. The key observations are that two different patterns of immune response occur at the same time. One predominates in early relapsing MS. The other becomes dominant in progressive MS.
The pattern in relapsing MS is one of recurring bouts of active inflammation, with large numbers of immune cells bursting into the brain from the blood. These cells mainly enter the white matter (regions of nerve fibers and myelin), where they continue to multiply, causing destruction of myelin and the cells that produce myelin (oligodendrocytes). Eventually nerve fibers (axons) are also destroyed. These bursts of immune system activation are associated with disease relapses and new lesions on central nervous system MRIs. Since these cells continue to enter the brain from the blood, disease-modifying therapies that affect the blood immune system are effective in the treatment of relapsing multiple sclerosis.
At the same time, different cells of the immune system also enter the brain, releasing chemicals distinct from those produced by cells involved in acute disease. Their entry into the brain is gradual and continuous, and involves different brain regions, mainly normal appearing white matter, the areas under the covering of the brain (meninges), as well as gray matter (regions of the brain containing mainly nerve cells or neurons). These cells gradually accumulate; releasing toxins that activate cells already in the brain, such as microglia and astrocytes, that too begin to contribute to brain degeneration. As a result there is both nerve cell death and loss of myelin, with gradual shrinkage or atrophy of the brain. Once these immune cells enter the brain they don’t multiply and become isolated from the blood, forming compartments of cells that are resistant to standard disease-modifying therapies.
Recent observations show an interaction between relapsing and progressive immune responses (see the blog entitled “Can progressive MS be prevented?”). Yet it is clear that the underlying causes of the two responses must differ. There now are two FDA approved disease-modifying therapies, ocrelizumab and siponimod, for persons with “active” progressive MS, each with a different mechanism of action. The drugs’ benefits in delaying progressive disability were almost exclusively noted in persons that showed evidence of both acute inflammation and progressive disease. Progression continued without treatment benefit in persons with no evidence of acute inflammation.
To truly prevent disease progression, it will be necessary to know what triggers the progressive pattern of immune response and what continues to drive it as acute inflammation subsides. In my blog “What triggers progressive MS?”, I review an article that offers a clue.
The abstract of the article is available.