Pathophysiology of multiple sclerosis

Multiple sclerosis is an inflammatory demyelinating disease of the CNS in which activated immune cells invade the central nervous system and cause inflammation, neurodegeneration, and tissue damage. The underlying cause is currently unknown. Current research in neuropathology, neuroimmunology, neurobiology, and neuroimaging, together with clinical neurology, provide support for the notion that MS is not a single disease but rather a spectrum. There are three clinical phenotypes: relapsing remitting MS (RRMS), characterized by periods of neurological worsening following by remissions; secondary progressive MS (SPMS), in which there is gradual progression of neurological dysfunction with fewer or no relapses; and primary progressive MS (MS), in which neurological deterioration is observed from onset. Pathophysiology is a convergence of pathology with physiology. Pathology is the medical discipline that describes conditions typically observed during a disease state; whereas physiology is the biological discipline that describes processes or mechanisms operating within an organism. Referring to MS, the physiology refers to the different processes that lead to the development of the lesions and the pathology refers to the condition associated with the lesions.

Follicle like aggregates in the meninges are formed only in secondary progressive MS. and correlate with the degree of subpial cortical demyelination and brain atrophy, suggesting that they might contribute to cortical pathology in SPMS

In multiple sclerosis, inflammation, demyelination, and neurodegeneration are observed together. Some clinical trials have shown that the inflammation produces both the relapses and the demyelination, and that neurodegeneration (axonal transection) is independent from inflammation, produces the accumulative disability, and advances even when inflammation and demyelination are delayed. It seems that neurodegeneration is produced by damaged mitochondria, which in turn comes from activated microglia. Currently it is unknown what the primary cause of MS is; if MS is a heterogeneous disease, the lesion development process would not be unique. In particular, some PPMS patients having a special clinical course named rapidly progressive multiple sclerosis could have a special genetic cause and a different development process. Several types of damage appear in the brain: normal appearing white matter (NAWM) and characteristic lesions. Changes in NAWM include axonal injury without demyelination, low grade inflammation, and microglial and astrocytic activation

MS lesions develop inside NAWM areas. Their shape is influenced by their activity

The most accepted sequence of events is first NAWM appearance, then the so called pre active lesions, with activated microglia, and finally the BBB (blood brain barrier) breakdown, which enables the entry of T cells to the CNS. This marks the beginning of an autoimmune attack which destroys myelin in active lesions. When the attack is resolved, a characteristic glial scar is formed by astrocytes. Current models can be divided into two categories: inside out and outside in. In the former, it is hypothesized that a problem in CNS cells produces an immune response that destroys myelin and subsequently breaks the BBB. In latter, an external factor produces BBB leaks, enters the CNS, and destroys myelin and axons. Whatever the underlying condition for MS is, it appears that damage is triggered by an unknown soluble factor in the CSF, potentially produced in meningeal areas; this factor can diffuse into the cortical parenchyma and destroy myelin either directly or indirectly through microglia activation. Some authors report active lesion formation before BBB breakdown; others point to adipsin as a factor of the breakdown. MS lesions are driven mainly by T cells. It has been found recently that B cells are also involved.

The blood–brain barrier (BBB) is a protective barrier that denies the entrance of foreign material into the nervous system. BBB disruption is the moment in which penetration of the barrier by lymphocytes occur and has been considered one of the early problems in MS lesions. The BBB is composed of endothelial cells which line the blood vessel walls of the central nervous system. Compared to normal endothelial cells, the cells lining the BBB are connected by occludin and claudin which form tight junctions in order to create a barrier to keep out larger molecules such as proteins. In order to pass through, molecules must be taken in by transport proteins or an alteration in the BBB permeability must occur, such as interactions with associated adaptor proteins like ZO 1, ZO 2 and ZO 3. The BBB is compromised due to active recruitment of lymphocytes and monocytes and their migration across the barrier. Release of chemokines allow for the activation of adhesion molecules on the lymphocytes and monocytes, resulting in an interaction with the endothelial cells of the BBB which then activate the expression of matrix metalloproteinases to degrade the barrier. After barrier breakdown symptoms may appear, such as swelling. Activation of macrophages and lymphocytes and their migration across the barrier may result in direct attacks on myelin sheaths within the central nervous system, leading to the characteristic demyelination event observed in MS. After demyelination has occurred, the degraded myelin sheath components, such as myelin basic proteins and Myelin oligodendrocyte glycoproteins, are then used as identifying factors to facilitate further immune activity upon myelin sheaths. Further activation of cytokines is also induced by macrophage and lymphocyte activity, promoting inflammatory activity as well continued activation of proteins such as matrix metalloproteinases, which have detrimental effect on BBB integrity. Recently it has been found that BBB damage happens even in non enhancing lesions. MS has an important vascular component.

Postmortem studies of the BBB, especially the vascular endothelium, show immunological abnormalities. Microvessels in periplaque areas coexpressed HLA DR and VCAM 1, some others HLA DR and urokinase plasminogen activator receptor, and others HLA DR and ICAM 1.

The damaged white matter is known as "Normal appearing white matter" (NAWM) and is where lesions appear. BBB can be broken centripetally (the most normal) or centrifugally. Several possible biochemical disrupters were proposed. Some hypotheses about how the BBB is compromised revolve around the presence of compounds in the blood that could interact with vessels only in the NAWM areas. The permeability of two cytokines, Interleukin 15 and LPS, may be involved in BBB breakdown. Breakdown is responsible for monocyte infiltration and inflammation in the brain. Monocyte migration and LFA 1 mediated attachment to brain microvascular endothelia is regulated by SDF 1alpha through Lyn kinase. Using iron nanoparticles, involvement of macrophages in BBB breakdown can be detected. A special role is played by Matrix metalloproteinases. These increase BBB T cell permeability, specially in the case of MMP 9

Whether BBB dysfunction is the cause or the consequence of MS is disputed, because activated T Cells can cross a healthy BBB when they express adhesion proteins. Apart from that, activated T Cells can cross a healthy BBB when they express adhesion proteins.) In particular, one of these adhesion proteins involved is ALCAM (Activated Leukocyte Cell Adhesion Molecule, also called CD166), and is under study as therapeutic target. Another protein involved is CXCL12, which is found also in brain biopsies of inflammatory elements, and which could be related to the behavior of CXCL13 under methylprednisolone therapy. Some molecular biochemical models for relapses have been proposed. Normally, gadolinium enhancement is used to show BBB disruption on MRIs. Abnormal tight junctions are present in both SPMS and PPMS. They appear in active white matter lesions and in gray matter in SPMS. They persist in inactive lesions, particularly in PPMS. A uric acid deficiency was implicated in this process. Uric acid added in physiological concentrations (i. e. achieving normal concentrations) is therapeutic in MS by preventing BBB breakdown through inactivation of peroxynitrite. The low level of uric acid found in people with MS is manifestedly causative rather than a tissue damage consequence in the white matter lesions, but not in the grey matter lesions. Uric acid levels are lower during relapses.

It is not known what causes MS. Several problems appear together with the white matter lesions, like cortical lesions and normal appearing tissues. Several theories have been proposed to explain it. Some areas that appear normal under normal MRI look abnormal under special MRI, like magnetisation transfer MTR MRI. These are called Normal Appearing White Matter (NAWM) and Normal Appearing Grey Matter (NAGM). The cause why the normal appearing areas appear in the brain is unknown, but seems clear that they appear mainly in the ventricles and that they predict the course of the disease. Given that MS lesions begin inside the NAWM areas, these areas are expected to be produced by the same underlying condition that produces the lesions, and therefore the ultimate MS underlying condition, whatever it is. This theory in part could also explain why some patients report amelioration under dietary treatment.

Human endogenous retroviruses (HERVs) have been reported in MS for several years. In fact, one of the families, Human Endogenous Retrovirus W was first discovered while studying MS patients. Recent research as of 2019 point to one of the HERV W viruses (pHEV W), and specifically one of the proteins of the viral capsid that has been found to activate microglia in vitro. Activated microglia in turn produces demyelination. Some interactions between the Epstein Barr virus and the HERVs could be the trigger of the MS microglia reactions. Supporting this study, a monoclonal antibody against the viral capside (Temelimab) has shown good results in trials in phase IIb.

If as expected MS is an heterogeneous disease and the lesion development process would not be unique. In particular, some PPMS patients have been found to have a special genetic variant named rapidly progressive multiple sclerosis In some reports the MRZR showed a lower sensitivity than OCB (70% vs. 100%), but a higher specificity (69% vs. 92%) for MS.