• Gary Birnbaum, MD

Turning MS inside out!

Paper #1 - Axon-Myelin Unit Blistering as Early Event

in MS Normal Appearing White Matter

Antonio Luchicchi, PhD, Bert’t Hart, PhD, Irene Frigerio, MSc et al

ANN NEUROL 2021;00:1–15


Paper #2 - Functional characterization of the dural sinuses

as a neuroimmune interface

Justin Rustenhoven, Antoine Drieu, Tornike Mamuladze

Cell 184, 1000–1016 February 18, 2021


Bottom Line:

“MS-ologists” enjoy disputations. A favorite disputation revolves around the events causing MS. One proposal is that an abnormal, poorly regulated immune system loses its immune tolerance for brain tissue and begins to attack the brain as if it were a foreign tissue. This theory has been called the “outside-in” theory. Another proposal states that the brain itself is not normal in persons with MS, possibly because of a viral infection, and that in turn results in an immune response to the altered brain tissue. This has been called the “inside-out” theory of MS. A variant of the “inside-out” theory proposes that, as a result of a confluence of multiple genes, brain functions in persons with MS are fundamentally altered, resulting in a release of brain proteins into the spinal fluid and from there into the circulation, stimulating an immune response to proteins that are usually hidden or sequestered. There are data in support of each of these proposals, and they may not be mutually exclusive. Indeed, a poorly regulated immune system may respond more easily and more vigorously to certain brain proteins than a normally regulated immune system. Some of these issues were discussed in a previous posting on this blog (“Is there a brain susceptibility to MS”).

The above two papers address several important related issues. Paper #1 is on axon-myelin blistering and provides additional support for the concept that brain tissue in persons with MS is not normal, resulting in a release of proteins into the spinal fluid. These are then chemically altered in a way that allows them to more forcefully stimulate the immune system. Paper #2 deals with the important question, where and how do brain proteins in the spinal fluid, a relatively sheltered site, enter the circulation and stimulate an immune response. Details are discussed under “Key Points” below.

Key Points:

1. Paper #1: The observation that very early in the course of MS there is a loss of myelin-producing cells (oligodendrocytes) and loss of inside layers of myelin, in the absence of inflammation has been described by several authors. Most recently, genes have been described in oligodendrocytes from persons with MS that prevent proper maturation of oligodendrocytes. All these findings provide evidence that, while inflammation is a major part of the later phases of MS, non-immune changes may precede the development of an anti-brain immune response.

2. Paper #1 describes abnormalities in normal appearing white matter (NAWM) in the brains of persons with MS. Researchers stained the tissues with antibodies to myelin and myelin components and compared results from 17 persons with MS, most of whom had secondary progressive disease, with those from 17 controls, i.e., persons with no neurological illness, non-MS related inflammation such as encephalitis, and degenerative diseases such as Alzheimer’s disease.

3. Using sophisticated microscopic techniques, the researchers found that in normal appearing white matter in MS brains the myelin wrapped around nerve fibers (axons) showed blisters and blebs with swelling of the axons. In some cases, there also was nerve degeneration. All these changes were noted in areas with no evidence of inflammation. Similar changes were also observed in control brains, but numbers of such occurrences were significantly higher in MS brains, even when compared to inflamed encephalitis brains.

4. While myelin blebs and blisters were seen in both MS and control brains, the distribution or pattern of these changes was different than in control brains. NAWM close to MS lesions showed an increased frequency of such lesions. In addition, levels of certain fatty acids and levels of myelin proteins such as myelin associated glycoprotein (MAG) were lower. The membranes of axons lying between segments of myelin (nodes of Ranvier), also were altered.

5. Most importantly, the scientists found that fragments of proteins in both normal appearing white matter and on the surfaces of the brains from persons with MS had undergone a biochemical change called “citrullination.” Levels of citrullinated proteins were much higher in MS brains than in controls. Citrullination of a protein involves changing the amino acid arginine to citrulline. This greatly increases the ability of that protein to stimulate an immune response. Citrullinated proteins thus have the potential to precipitate an immune response that results in the invasion of the central nervous system by activated immune cells.

6. The myelin around axons nurtures axons and provides metabolic support. The presence of myelin blisters and blebs could impair axon metabolism, especially in energy-producing structures called mitochondria. This may result in a virtual loss of oxygen, a phenomenon called “hypoxia.” Prolonged hypoxia can result in the death of nerve cells with axon degeneration. This condition was discussed in detail in my January blog “Oxygen for MS?”.

7. Paper #2: The brain requires a great deal of blood to function normally. Indeed, at rest about one-fifth (15-20%) of the heart’s output goes to the brain. Despite this large requirement the brain is relatively sheltered from the circulation. This is due to the presence of tight junctions between blood vessel cells (endothelium) and brain cells (astrocytes), resulting in a blood-brain barrier (BBB). This BBB prevents easy access of immune cells and antibodies into normal brain. That being the case, how can proteins leave the central nervous system and stimulate an immune response? Paper #2 answers this question by providing an elegant, detailed analysis of where and how brain proteins leave the brain, enter the circulation and stimulate the immune system.

8. Under normal conditions “activated” T-cells (i.e., T-cells that have been stimulated by proteins outside the brain) are able to pass through the blood-brain barrier, enter brain tissues, and “patrol” if you will, brain tissues, looking for evidence of tissue damage or infection. If none is found, the immune cells leave the brain and return to the circulation.

9. When the brain is inflamed, as occurs in MS, there is a breakdown of the BBB, with leakage of proteins into the circulation and ready access of circulating immune cells into central nervous system tissues. What is not known is what starts this process, and can brain proteins enter the circulation when the brain is not inflamed?

10. In contrast to the blood-brain barrier found in brain the blood vessels of the membranes covering the brain, the dural meninges, in particular the dura mater, have no blood-brain barrier. The authors of Paper #2 found that proteins released from brain cells flow into the cerebrospinal fluid (CSF) and from there flow to specific patches of the dura called “hubs.” These hubs occur in drainage areas or channels in the dura called “dural sinuses.” The dural sinuses are large “tubes” that drain the large amount of blood entering the brain from that organ, back into the circulation.

11. Cells in the dural hubs have on their surfaces specialized proteins that allow T cells to stick to, and adhere, to the sinus walls. This results in a diverse population of T cells that are “trapped” at the hubs. In addition, and most importantly, there also are other cells such as macrophages and microglia. These cells, called “antigen presenting cells,” have the ability to partially digest brain proteins and “present” them to T cells in such a way that T cells are able to recognize the protein fragments (peptides), interact with them, and become activated. Such stimulated cells then can enter the brain and secrete potentially harmful chemicals, such as cytokines.

12. As noted above, the populations of “trapped” or adherent T cells present at the dural sinus hubs are diverse. Some cells are “pro-inflammatory,” secreting cytokines that increase inflammation; others are “anti-inflammatory,” with the ability to control or reduce inflammation.

13. Since all components necessary to allow T cells to recognize brain-derived proteins are present at dural hubs, two possible pathways of response could occur. One pattern of response would be to stimulate T cells recognizing myelin proteins to attack the brain, releasing toxic cytokines. The other possibility is that the immune cells recognizing brain proteins become tolerant or non-responsive to the proteins, thus maintaining a non-destructive immune environment.

14. Which pattern of immune response evolves is almost certainly determined by multiple factors. Genetically defined patterns of immune response are almost certainly involved as are a combination of metabolic factors (vitamin D levels?), and environmental factors (exposure to viruses?). Identifying these factors in greater detail and understanding their interactions should lead to fundamental insights into the cause(s) of MS and potentially important new therapies.


What triggers MS? Is it the brain? Is it the immune system? Is it a little of both? These are several of the many questions nagging the brains of “MS-ologists.” Most of the work over the past several decades dealing with disease mechanisms in MS involved studies of the immune system. The obvious reason for this is the easy accessibility of the immune system to study (just puncture a vein) and the fact that MS is an inflammatory disease in which the immune system plays a pivotal role. However, over the past decade an increasing number of articles were published suggesting that, while the immune system clearly is critical in the MS disease process, it may be a “secondary” phenomenon. In other words, in the setting of a genetically defined pattern of immune response, the immune system in persons with MS is triggered to respond to changes in brain tissue that are genetically altered and/or altered due to an environmental agent such as a virus.

Paper #1 describes changes in MS brains that occur in the absence of inflammation and that result in myelin damage and the release of myelin proteins into the spinal fluid. Most importantly, these proteins subsequently become altered biochemically, that is they have a change in their amino acids, losing the amino acid arginine and having it replaced with the amino acid citrulline. Proteins, or protein fragments (peptides) that are so “citrullinated” have increased capacity to stimulate the immune system and are implicated in causing another immune-mediated disease, rheumatoid arthritis. Paper #1 is thus another in a series of research findings suggesting that the central nervous system in persons with MS is different than that of persons without MS. Subsequent immune responses are thus a “secondary” phenomenon, perhaps providing a reason why even such radical treatments as autologous bone marrow transplant, which replaces a person’s immune system, does not prevent subsequent atrophy or loss of brain tissue.

Paper #2 addresses the basic question, “once proteins are released from brain tissue into the spinal fluid, how can they enter the circulation and affect the immune system?” In a sophisticated, elegant series of experiments, albeit in mice, the researchers showed that there are portions of the blood-draining structures of the covering of the brain (the dural sinuses) that have specialized properties. These regions, called “hubs,” not only lack the tight junctions of blood vessel cells that result in the blood-brain barrier, but also have cells that express on their surfaces proteins that allow immune cells, mainly T cells, to stick or adhere and become “trapped” there. The final noteworthy feature of these hubs is the presence of cells that can process brain proteins into smaller peptides and present them, with all the necessary accessory signaling, to T cells, resulting in activation and stimulation of the cells.

If “hubs” are normal features of dural sinuses, that is, all brains have the potential to stimulate immune responses, what triggers the destructive immune response in MS? The answer is not known, but most likely there are multiple factors. One major factor could be a genetically defined pattern of immune responses peculiar to brain proteins that results in an aggressive versus a tolerant response to such proteins. Another factor could be that the immune system in persons with MS is responding to a genetically and/or environmentally altered central nervous system. In any case, whether you espouse the “inside-out” theory of brain dysfunction in MS or the “outside-in” theory where the fundamental event is an abnormal immune system, understanding the cascade of events initiating MS could lead to important new treatments, possibly even disease prevention.

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