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  • Gary Birnbaum, MD

Inside-Out or Outside-In?

Aberrant oligodendroglial-vascular interactions disrupt the blood-brain barrier, triggering CNS inflammation.

Jianqin Niu, Hui-Hsin Tsai, Kimberly K. Hoi, Nanxin Huang, Guangdan Yu, Kicheol Kim, Sergio E. Baranzini, Lan Xiao, Jonah R. Chan and Stephen P. J. Fancy

Nat Neurosci. 2019 May;22(5):709-718. doi: 10.1038/s41593-019-0369-4.

Epub 2019 Apr 15

Key Points:

1. There are two theories regarding the cause of MS. They are referred to as the “outside-in” theory and the “inside-out” theory.

2. The “outside-in” theory states that the cause of MS is a failure of the immune system to remain “tolerant” of the central nervous system. That is, the immune system sees the central nervous system as a “foreign” tissue and attacks it.

3. The “inside-out” theory states that the central nervous system of persons with MS is not normal. That is it contains abnormal cells that die and release brain proteins into the circulation. These proteins than “turn on” or stimulate the immune system to attack the central nervous system.

4. There is evidence for both theories, and indeed, both theories may be important causes of MS.

5. The above paper provides additional evidence that the certain cells in the brains of persons with MS may not function normally and may be contributing to the disease process.

6. The authors noted clusters of cells around the edges of MS lesions that stuck to the lining of blood vessels. They identified these cells as immature myelin-producing cells called “oligodendrocyte precursor cells” or OPCs.

7. The brain is relatively protected from blood immune cells and antibodies by a barrier called the “blood brain barrier.” Cells lining the capillaries of the brain make up the blood brain barrier. They do so by forming tight junctions between them.

8. The clustered OPCs that stuck to the capillaries pushed themselves between the cells that make up the blood brain barrier (astrocytes and endothelial cells) and loosened the barrier. This resulted in a breakdown of the blood brain barrier, allowing immune cells to enter the brain.

9. Using a mouse model of myelin loss the authors also showed that the OPC clusters were unable to form new myelin, resulting in a loss of ability to heal demyelinated lesions.

10.As note in previous blogs, repair of lost myelin is deficient in most persons with MS. The reasons are not entirely known, but finding that immature myelin-producing cells are impaired and lose their ability to enter damaged areas in MS due to clustering on the surfaces of capillaries may be one important reason.

Great advances in treating MS have been made by suppressing, and even replacing, the immune system. However, until we understand how the brain itself contributes to the disease process, a true cure for MS may not be possible.

In a chronic illness such as MS two things must have happened. One is the triggering event that starts the disease. The other event is the process that continues or perpetuates the disease. The normal immune system is able to control itself. It does so in a multitude of ways involving regulatory cells and chemicals. However, in MS the immune system continues to be actives and contributes in a major way to brain injury. Even with elimination of the immune system and its replacement, the disease can still continue. In most other ways the immune system in persons with MS is normal, with intact ability to regulate itself. This suggests that the continued attack on the brain may result, not from a lack of regulation (the “outside-in” theory of MS), but from continued stimulation of the immune system by abnormal central nervous system tissue (the “inside-out” theory of MS). The above article provides evidence that immature myelin-producing cells (oligodendrocyte precursor cells or OPCs) in MS fail to function normally. They cluster at the surfaces of brain capillaries, lose their ability to migrate into areas of myelin loss, and disrupt the blood brain barrier, a critical site protecting the brain from the immune system. Work by other scientists also provided evidence that MS brain itself may be the trigger that starts the disease. If there is to be a cure for MS, we must know not only why the MS-immune system is unable to stop attacking the brain, but also what there is about the central nervous system in persons with MS that continues to stimulate the immune system.

An abstract of the article is available.