Pathophysiology of multiple sclerosis – Wikipedia, the …

Multiple sclerosis (MS) is a condition where the CNS of a person present a special kind of distributed lesions (sclerosis) [1] whose pathophysiology is complex and still under investigation. It is considered a pathological entity by some authors[2] and a clinical entity by some others.[3] From a pathological point of view it can be classified as an encephalomyelitis, and sometimes is known as encephalomyelitis disseminata.

In MS, an unknown underlying condition causes damage in two phases. First some MRI-abnormal areas with hidden damage appear in the brain and spine (NAWM, NAGM, DAWM), followed later by leaks in the bloodbrain barrier where immune cells infiltrate causing the known demyelination[4] and axon destruction.[5] Some clusters of activated microglia, transection of axons and myelin degeneration is present before the BBB breaks down and the inmune attack begins[6][7][8]

MS is mainly a white matter disease, and lesions appear mainly in a peri-ventricular distribution (lesions clustered around the ventricles of the brain), but apart from the usually known white matter demyelination, also the cortex and deep gray matter (GM) nuclei are affected, together with diffuse injury of the normal-appearing white matter.[9] MS is active even during remission periods.[10] GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS[11]

At least five characteristics are present in CNS tissues of MS patients: Inflammation beyond classical white matter lesions, intrathecal Ig production with oligoclonal bands, an environment fostering immune cell persistence, Follicle-like aggregates in the meninges and a disruption of the bloodbrain barrier also outside of active lesions.[12] The scars that give the name to the condition are produced by the astrocyte cells healing old lesions.[13]

Damage occurs in two phases. First some MRI-abnormal areas with hidden damage appear in the brain and spine (NAWM, NAGM, DAWM), followed later by leaks in the bloodbrain barrier where immune cells infiltrate causing the known demyelination.[4]

According to the view of most researchers, a special subset of lymphocytes, called T helper cells, specifically Th1 and Th17,[14] play a key role in the development of the lesion. A protein called Interleukin 12 is responsible for the differentiation of naive T cells into inflammatory T cells. An over production of this protein is what causes the increased inflammation in MS patients.[15] Under normal circumstances, these lymphocytes can distinguish between self and non-self. However, in a person with MS, these cells recognize healthy parts of the central nervous system as foreign and attack them as if they were an invading virus, triggering inflammatory processes and stimulating other immune cells and soluble factors like cytokines and antibodies. Many of the myelin-recognizing T cells belong to a terminally differentiated subset called co-stimulation-independent effector-memory T cells.[16][17][18][19][20][21][22][23][24][25][26]

Recently other type of immune cells, B Cells, have been also implicated in the pathogenesis of MS[27] and in the degeneration of the axons.[28] and the oligodendrocytes.[29]

The axons themselves can also be damaged by the attacks.[30] Often, the brain is able to compensate for some of this damage, due to an ability called neuroplasticity. MS symptoms develop as the cumulative result of multiple lesions in the brain and spinal cord. This is why symptoms can vary greatly between different individuals, depending on where their lesions occur.

Repair processes, called remyelination, also play an important role in MS. Remyelination is one of the reasons why, especially in early phases of the disease, symptoms tend to decrease or disappear temporarily. Nevertheless, nerve damage and irreversible loss of neurons occur early in MS.

The oligodendrocytes that originally formed a myelin sheath cannot completely rebuild a destroyed myelin sheath. However, the central nervous system can recruit oligodendrocyte stem cells capable of proliferation and migration and differentiation into mature myelinating oligodendrocytes. The newly formed myelin sheaths are thinner and often not as effective as the original ones. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons. These scars are the so-called "scleroses" that define the condition. They are named glial scars because they are produced by glial cells, mainly astrocytes, and their presence prevents remyelination. Therefore there is research ongoing to prevent their formation.

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Pathophysiology of multiple sclerosis - Wikipedia, the ...