Multiple sclerosis: causes and pathogenesis

Causes of Multiple Sclerosis

The cause of multiple sclerosis remains unknown. There is no conclusive evidence that a virus or any other infectious agent is the only cause of this disease. Nevertheless, the viruses were considered the most likely etiologic factor of the disease, which was confirmed by epidemiological data and some of their well-known properties. Certain viruses can affect the state of the immune system, persist in latent form in the central nervous system and cause demyelination in the central nervous system. Moreover, according to some data, in patients with multiple sclerosis there is an altered immune reactivity to some frequently occurring viruses, including an intensified reaction to measles viruses. The model of persistence of viruses in the central nervous system can serve as a subacute sclerosing panencephalitis - a rare complication of measles infection, manifested many years after the outwardly successful resolution of the disease. Some viruses and some bacteria can be associated with the development of acute disseminated encephalomyelitis (OMEM). This is usually a monophasic demyelinating disease, pathomorphologically similar to multiple sclerosis, but not identical to it. It was assumed that the canine plague virus, which is close to the measles virus, was the "primary affect of multiple sclerosis" by Kurtzke, which the indigenous inhabitants of the Faroe Islands had contracted from dogs brought to the islands by British troops. The virus of Tayler's mouse encephalomyelitis related to picornaviruses is an experimental model of the central nervous system demyelination in rodents, their natural hosts.

[1], [2], [3], [4]

Possible mechanisms of virus-induced demyelination

• Direct viral exposure
• The penetration of viruses into oligodentrocytes or Schwann cells causes demyelination due to cell lysis or changes in cellular metabolism
• Destruction of myelin membrane by virus or its products
• Virus-induced immune response
• Antibody production and / or cell-mediated response in response to viral antigens on the cell membrane
• Sensitization of the host organism to myelin antigens
• The decomposition of myelin under the influence of infection with the entry of its fragments into the total blood flow
• Incorporation of myelin antigens into the viral envelope
• Modification of myelin membrane antigens
• Cross-reacting antigens of the myelin virus and proteins
• Demyelination as a side process
• Dysfunction of regulatory mechanisms of the immune system under the influence of viruses

The disease, similar to the spinal form of multiple sclerosis, is caused by a retrovirus, a human T-cell lymphotropic virus of type I. The disease is known in various geographical areas as tropical spastic paraparesis or HIV-associated myelopathy. Both tropical spastic paraparesis and HIV-associated myelopathy are slow progressive myelopathies characterized by vasculopathy and demyelination. The evidence that multiple sclerosis is caused by a retrovirus remains unconvincing, despite the fact that DNA sequences of the human T-cell lymphotropic virus type I have been detected in some patients with multiple sclerosis. Massive demyelination associated with subacute infection with the herpes simplex virus type 6 is also described. According to some data, the development of multiple sclerosis can be associated with some bacteria, in particular - chlamydia, but they also need confirmation.

The role of genetic factors in the development of multiple sclerosis

The role of racial and ethnic factors in the formation of a predisposition to multiple sclerosis is difficult to separate from the influence of external factors. Thus, the descendants of immigrants from Scandinavia and Western Europe, characterized by a high risk of multiple sclerosis, settled Canada, the northern and western regions of the United States, where there is also a relatively high prevalence of multiple sclerosis. Although Japan is located at the same distance from the equator, the prevalence of multiple sclerosis in this country is low. Moreover, several studies have shown that the risk of developing the disease is not the same for different ethnic groups living in the same zone. Thus, the disease is rare in black Africans and is not known in some ethnically pure Aboriginal populations, including Eskimos, Inuit, Indians, Aboriginal Australians, Maori tribe in New Zealand or the Saami tribe.

Genetic markers of predisposition to multiple sclerosis are revealed in the study of twins and family cases of the disease. In Western countries, the nearest relatives of the patient (persons of the first degree of kinship) risk of getting sick is 20-50 times higher than the average for the population. The degree of concordance in identical twins, according to several studies, is approximately 30%, while in the case of fraternal twins and other siblings, less than 5%. Moreover, it was shown that the degree of concordance in identical twins may be higher when taking into account the cases in which magnetic resonance therapy (MRI) reveals asymptomatic lesions in the brain. In these studies, the clinical features or severity of the disease was not dependent on its family nature. Specific genes associated with multiple sclerosis are not identified, and the type of transmission of the disease corresponds to polygenic inheritance.

Screening of the genome

To identify possible genes of multiple sclerosis, multicentre studies are carried out that perform screening of the entire genome. In these studies, more than 90% of the human genome has already been tested, but genetic markers of the disease have not been detected. At the same time, a genetic link was established with the HLA region on the short arm of the 6th chromosome (6p21), which coincides with the data on the increased susceptibility to multiple sclerosis of individuals carrying certain HLA alleles. Although American and British researchers showed a moderately strong association with the HLA region, Canadian scientists did not find such a connection, but, like the Finnish scientists, they revealed a strong connection with the gene localized on the short arm of the 5th chromosome. It is known that some HLA alleles are associated with a higher risk of multiple sclerosis, especially the HLA-DR2 haplotype (subtype Drw15). The risk of developing multiple sclerosis in white Europeans and North Americans carrying the DR2 allele is four times higher than the average for the population. But the predictive value of this trait is limited, since 30-50% of patients with multiple sclerosis are DR2-negative, and on the other hand, DR2 is detected in 20% of individuals in the general population.

Other risk factors for the development of multiple sclerosis

The risk of developing multiple sclerosis at a young age in women is 2 times higher than that of men. But after 40 years, the sex ratio among patients with multiple sclerosis is equalized. The period of the highest risk of developing the disease falls on the 2nd-6th decades of life, although cases of multiple sclerosis among young children and the elderly have been reported. According to several studies, multiple sclerosis in childhood, either clinically or in the course of the course, does not differ significantly from that in adults. After 60 years, multiple sclerosis develops rarely, and in some clinical series, these cases account for less than 1% of the total number of cases.

Higher socioeconomic status is associated with a higher risk of the disease, and the transferred viral infection is associated with exacerbations of the disease. It has been suggested that physical trauma may be the cause of multiple sclerosis, but this opinion is controversial, since such a link has not been convincingly confirmed by either retrospective or prospective studies. Studies of the course of the disease during pregnancy show that during this period, the activity of the disease decreases, but in the first 6 months after delivery, the risk of exacerbations of the disease increases.

Myelin-oligodendocyt complex

Myelin is a complex metabolically active layered shell surrounding large diameter axons. It is formed by bilayer membrane outgrowths of oligodendrocytes (in the central nervous system) and Schwann cells (in the peripheral nervous system - PNS ). The inner layer of the membrane is filled with the cytoplasm of the corresponding myelin-forming cells. Although the myelin sheath is sensitive to direct damage, it can also suffer from damage to the cells that form it. Myelin sheath in the central nervous system and PNS has a different sensitivity to inflammatory damage. In this case myelin PNS is less likely to be damaged during demyelination of the central nervous system and vice versa. Differences between myelin CNS and PNS are traced both in the structure of structural proteins, antigenic structure, functional relationships with the corresponding cells. In myelin CNS, the main structural protein is a protelipid protein (50%), which contacts in the extracellular space. The next most prevalent protein is myelin basic protein (30%), which is localized on the inner surface of a two-layer membrane. Other proteins, although present in small amounts, can also play the role of an antigen in the immunopathogenesis of multiple sclerosis. These include myelin-associated glycoprotein (1%) and myelin-oligodendrocyte glycoprotein (less than 1%).

Since the myelin oligogendrocyte complex of the central nervous system covers more axons than the myelin-lemocyte complex of PNS, it is more sensitive to damage. Thus, in the central nervous system, one oligodendrocyte can be myelinated to 35 axons, whereas in the PNS one Schwann cell is required per axon.

Myelin is a substance with high resistance and low conductivity, which, along with the uneven distribution of sodium channels, provides the generation of action potentials in certain specialized axon sites - Ranvier intercepts. These interceptions are formed at the border of two sites covered with myelin. Depolarization of the axon membrane occurs only in the region of the Ranvier interception, as a result the nerve impulse moves along the nerve fiber by discrete jumps - from interception to interception - this fast and energetically effective method of carrying out is called salting.

Since the myelin oligodendrocyte complex is sensitive to a variety of damaging factors - metabolic, infectious, ischemic-hypoxic, inflammatory, - demyelination is possible in a variety of diseases. A common feature of demyelinating diseases is the destruction of the myelin sheath with relative preservation of axons and other supporting elements. A number of other effects, including carbon monoxide poisoning or other toxic substances, liver dysfunction, vitamin B12 deficiency, viral infections or post-virus reactions, should be excluded during the diagnosis of multiple sclerosis. Primary inflammatory demyelination in multiple sclerosis or OPEM is characterized by perivascular infiltration of inflammatory cells and a multifocal distribution of lesions in the subcortical white matter, the foci being symmetrical or fused.

Pathomorphology of multiple sclerosis

Important information about multiple sclerosis was obtained by comparative histological examination of the centers of demyelination (plaques) of different prescriptions in the same patient, and also when comparing patients with unequal clinical characteristics and course. Some of the patients died as a result of the lightning course of newly developed multiple sclerosis, others - from concomitant diseases or complications in the late stage of the disease.

Macroscopic changes in the brain and spinal cord with multiple sclerosis are usually not pronounced. Only mild atrophy of the cerebral cortex with expansion of the ventricles is noted, as well as atrophy of the trunk and spinal cord. On the ventral surface of the bridge, the medulla oblongata, the corpus callosum, the optic nerves and the spinal cord, dense pinkish-gray indentations can be seen indicating the presence of plaques under them. Plaques are found in white matter, sometimes in the gray matter of the brain. Plaques are most often located in certain areas of white matter - for example, near small veins or postcapillary venules. Often they are detected near the lateral ventricles - in those areas where sub-ependymal veins follow along the inner walls, as well as in the brainstem and the spinal cord - where the pialic veins adhere to the white matter. Individual plaques in the periventricular zone tend to merge as they increase, especially in the region of the posterior horns of the lateral ventricles. Discrete ovoid plaques in the white matter of the hemispheres, oriented perpendicular to the ventricles, are called Davson's fingers. Histologically, they are restricted areas of inflammation with or without demyelination, which surround the parenchymal veins and correspond to their radial movement into the interior of the white matter.

Clinical and pathomorphological data indicate a frequent lesion in demyelinating disease of the optic nerves and cervical spinal cord. It is believed that the frequent formation of plaques in these structures is explained by mechanical stretching, which they experience with eye movements or neck bending, however, the validity of this hypothesis is not proved. Often involved and some other areas of the brain - the bottom of the fourth ventricle, periakveduktalnaya zone, corpus callosum, brain stem, cerebellum tract. The site of the connection of gray and white matter of the cerebral hemispheres (corticomedullary transition zone) may also be involved, however subcortical U-shaped usually remain intact.

Multifocal demyelination with multiple sclerosis is the rule. In an autopsy series of 70 patients with multiple sclerosis, only 7% of patients had brain damage (excluding the pathology of the optic nerves) not accompanied by involvement of the spinal cord, and only 13% of patients had spinal cord involvement without involvement of the brain.

Histological changes in multiple sclerosis

The question of the earliest changes preceding demyelination remains controversial. In the brain, in patients with multiple sclerosis both in demyelinated and in normal myelinated white matter, perivascular infiltrates are detected, consisting of lymphocytes, plasma cells and macrophages. These cells can accumulate in the periveneular Virchov-Robin spaces between the blood vessels and the brain parenchyma, which are connected to the circulatory system of the cerebrospinal fluid. These data can be considered evidence of the crucial pathogenetic role of the immune system in multiple sclerosis. According to indirect signs, the inflammatory reaction occurs not only as a consequence of changes in myelin. This is evidenced by the presence in patients with multiple sclerosis of similar perivascular clusters of lymphocytes in the retina devoid of myelinated fibers. With multiple sclerosis, infiltrates around the vessels and focal disturbances of the hematoretinal barrier are observed.

Various interpretations of the mechanism of myelin decomposition in the foci of multiple sclerosis are suggested. Some believe that monocytes only absorb fragments of the myelin sheath, already destroyed by other factors. Others believe that monocytes are directly involved in the destruction of myelin. The macrophage membranes contain clathrin-coated cavities that are adjacent to the myelin sheath. It is assumed that it is in this region that an Fc-dependent interaction occurs between the antibody and receptor, which leads to opsonization of myelin by monocytes. It is also shown that macrophages directly penetrate the myelin sheath, causing the formation of vesicles inside myelin.

Myelin degradation products in the cytoplasm of macrophages are markers of acute demyelination. The composition and ultrastructure of these macrophage-located fragments correspond to normal myelin. As the decay breaks, the ultrastructure is destroyed, neutral fat drops form, and the macrophages acquire a foamy appearance. Such macrophages disappear from the foci much more slowly and are detected there 6-12 months after acute demyelination.

"Fresh" foci of demyelination are characterized by the presence of a large number of cells, predominantly B cells, plasma cells, CD4 ⁺ and CD8 ⁺ T lymphocytes and early reactive macrophages that are found inside the plaque and at its edges. Morphologically, acute axonal changes in the form of balls can be detected. A complete or abortive remyelination is often observed around the periphery of the foci. Sometimes in these or adjacent areas there are signs of repeated demyelination. Sometimes the whole plaque is remyelinated. Such plaques are called "shaded", because both with macroscopic examination and with neuroimaging they merge with the surrounding normal white matter.

The origin of cell populations that provide remyelination remains unknown. The source of remyelinating oligodendrocytes can be mature cells that have failed to die in the lesion, cells that migrated from the adjacent zone, or young oligodendrocytes formed from progenitor cells. It is suggested that the degree of destruction of mature oligodendrocytes determines the potential for remyelination in a given outbreak, which is highly variable. It was reported on the ability of Schwann cells to migrate into the spinal cord and provide for the remyelination of axons.

In comparison with normal axons, the remyelinated axons have a thinner myelin sheath with shortened myelin segments and enhanced Ranvier intercepts. Experimental data show that demyelinated axons can restore electrophysiological functions, but whether this is due to the regression of symptoms in multiple sclerosis remains unknown. After remyelination of the experimentally demyelinated axons with the help of transplanted glial cells, almost complete restoration of normal conductivity was noted, which indicates that multiple transplantation can be effective in cell transplantation.

Old foci with inactive central zones usually contain a small number of macrophages and other inflammatory cells, although active demyelination can occur at the edges and inflammatory infiltration can be noted. Chronically demyelinated axons are built into the matrix of fibrous astroglial processes - hence the term "sclerosis". The walls of the blood vessels can be thickened by hyalinization. The potential for remyelination appears to be lower in old foci than in fresh foci, since they contain less preserved oligodendrocyte vitality.

Magnetic resonance imaging (MRI) is a very sensitive method that allows you to obtain an image of plaques. Although the usual MP signal does not reliably distinguish edema from demyelination, gliosis or loss of axons, these lesions are often called foci of demyelination. Sagittal, coronary and axial MRI images of the brain and spinal cord allow us to study the topography of the affected areas in this patient. On sagittal images of the brain, foci in the corpus callosum are best seen and their spreading upwards through the visual radiance to the cortex. Coronal images allow to study the location of the foci in relation to the walls of the ventricles. Axial images are most suitable for determining the location and quantification of foci. Foci of multiple sclerosis on T2-weighted images are visualized as hyperintensive (white) zones, well contrasting on a darker background of normal white matter, but poorly differentiated with cerebrospinal fluid (CSF) of the ventricles. In images in the proton density mode, the foci have a higher intensity than CSF and an externally intact white substance with a darker color. On images in FLAIR mode (f1uid-attenuated inversion recovery), the contrast between the focus and the surrounding white matter is enhanced.

MPT, MPC and the evolution of pathological changes in multiple sclerosis

Carrying out magnetic resonance tomography in dynamics allows obtaining information about the development of pathological changes in the brain in time. The integrity of the blood-brain barrier can be assessed using contrasting substance - gadolinium-diethylentriamine penta acetate (Gd-DPTA) - a paramagnet that increases the relaxation time T1 of the surrounding mobile water protons, so that the foci on the T1-weighted images appear brighter. The permeability of the blood-brain barrier is associated with the presence of vesicles within endothelial cells that contain Gd. In studies on laboratory animals and humans, it was shown that the degree of contrast of Gd-DPTA reflects the severity of perivascular inflammation. On a series of MRI with the introduction of Gd-DPTA, contrasting is shown at an early stage of foci development, which persists from 2 weeks to 3 months. As the foci cease to contrast, they completely disappear or appear as hyperintense zones on T2-weighted images.

Localization of foci on MRI often does not correspond to clinical symptoms, although the activity of foci has some connection with the course of multiple sclerosis. For example, new foci often produce signal amplification with a secondary progression than with primarily progressive multiple sclerosis. These changes are noticeable both on T2-weighted images and on T1-weighted images with contrasting and indicate the presence of vasogenic edema and an increase in the content of extracellular water. The detection of active foci can be improved by the administration of a higher dose of Gd-DPTA.

Magnetic resonance spectroscopy (MRS) quantifying brain metabolism in vivo allows one to determine the integrity of axons using the proton resonance of N-acetylaspartate (NAA) contained in neurons. In larger foci (according to conventional MRI) and in more severe disease, the level of NAA in the foci is lower.

Immunopathogenesis of multiple sclerosis

Among experts, the opinion prevails that the basis of multiple sclerosis is a cellular immune response directed against one or more CNS myelin antigens. Histopathological changes at an early stage of the development of the demyelination focus convincingly demonstrate the key role of T-lymphocytes. T-helpers (CD4-lymphocytes) are detected in the outbreak at an early stage and are believed to initiate an inflammatory cascade. Suppressor / cytotoxic T cells (CD8 lymphocytes) are found around the perimeter of the focus and in the perivascular spaces and can have a counter-regulatory effect on proinflammatory processes. In addition, local enhancement of immune reactivity with the expression of molecules of the main histocompatibility complex (MHC) of classes I and II in both immune and non-immune cells, including astrocytes and endothelial cells of blood vessels, is revealed. Thus, these cells can potentially participate in the immune response by presenting autoantigens of myelin to CD8- and CD4-cells. It is important to note that oligodendrocytes do not seem to express MHC class I or II molecules, which indicates that they do not play a major role in immunopathogenesis. Macrophages located in the outbreak are recruited to the central nervous system from the periphery and / or are formed from local microglial cells.

Although a specific autoantigen has not been identified in multiple sclerosis, a hypothesis can be adopted as a working one, according to which the T-cell proliferative reaction to one or more myelin antigens is based on the disease. The specificity of T-cell receptors for myelin antigens at an early stage may not correspond to the repertoire of T-cell receptors at the advanced stage of the disease, possibly due to the phenomenon of "epitope expansion", as a result of which T cells in situ acquire affinity for a wider range of autoantigens. Peripheral T cells obtained in patients with multiple sclerosis are able to react with multiple CNS myelin antigens, including the main myelin protein (OBM), proteolyiid protein (PLB), myelin-associated glyco-myotin (MAG), myelin oligodendrocyte glyco-myotene ( MOG). However, T cells that are able to react with OBM and PLL are also found in healthy individuals.

If multiple sclerosis is caused by activated T-cell sensitized myelin, this suggests a violation of the mechanisms of immune tolerance. Central immune tolerance is formed in the thymus at an early stage of development and is associated with both positive and negative selection of T cells that recognize the antigens of GTG, which eliminates those who have affinity for autoantigens. Peripheral immune tolerance is supported by active suppression of potentially autoreactive cells. It remains unknown how the tolerance to antigens of the central nervous system develops, since the latter is normally a "privileged zone" in relation to the immune system. The evidence that T cells are in contact with MHC outside the central nervous system is due to the discovery of the Golly-OBM gene (expressed in oligodendrocyte lines). This gene, which is expressed in the thymus of the fetus, spleen and leukocytes, can participate in the mechanisms of positive or negative selection of MBM-reactive T cells in the thymus.

Special studies have been carried out to determine whether the number of pathogenic clones of T cells is limited in patients with multiple sclerosis. In most of these studies, the specificity of the alpha-beta chain of T-cell receptors was studied by gene rearrangement and antigen-induced proliferation data. The source of T cells in these studies was brain tissue, cerebrospinal fluid and peripheral blood. In some cases, multiple sclerosis, as well as EAE in rodents, revealed a limited repertoire of the variable region of the alpha-beta receptor chain of activated T cells, which may reflect specific reactivity to certain fragments of MBM. Comparison of MBM-reactive T-cells in various patients and types of laboratory animals reveals a wide variability in the expression of receptor genes and the specificity of MBM. The fact that people with HLA DR2 + have a higher risk of developing multiple sclerosis, indicates the importance of interaction with specific T-cell receptors. Steinman et a1. (1995) showed that streets with HLA DR2 + B-cell and T-cell responses are directed primarily against certain fragments of the peptide chain of MBM (from 84 to 103 amino acids).

Similar works have a practical application, they make it possible to develop peptides that can block or stimulate protective reactions, affecting the interaction of the T-cell receptor-antigen-MHC that triggers the pathological process. This approach, using a number of different peptides, has been tested in EAE and in clinical trials in patients with multiple sclerosis. Other T cell subtypes can also play a pathogenetic role in PC. So in the centers of multiple sclerosis, T cells bearing gamma-delta chain receptors (rather than alpha-beta chains characteristic of CD4 and CD8 cells) are found.

It can be assumed that the autoimmune reaction in multiple sclerosis includes a number of pathophysiological mechanisms, including the binding of viral or bacterial antigens to T-cell receptors that are potentially capable of interacting with myelin autoantigens (molecular mimicry) or polyclonal T cell activation, It is caused by binding to microbial toxins (superantigens) with common beta-chains of receptors.

An early stage in the development of demyelination may be diapedesis of activated lymphocytes through dense endothelial cell connections in the brain with penetration into the perivascular spaces. As already indicated, endothelial cells can play a role in the immune response, presenting an antigen in complex with the MHC receptors of class I and class II T cells. Endotheal cells of the brain can facilitate the penetration of T cells through the blood-brain barrier, expressing in an increased number of adhesive molecules, including ICAM-1 (intracellular adhesion molecule) and VCAM (vascular cell adhesion molecules - vascular cell adhesion molecules) that are attached to the corresponding ligands, namely, LFA-1 (lymphocyte function antigen) and VLA-4 (very late activation antigen). Activated lymphocytes also express a specific class of enzymes called matrix metalloproteinases that catalyze the breakdown of type IV collagen in the extracellular matrix and facilitate migration.

A number of co-receptors and cytokines participate in initiation, maintenance and regulation of the local immune response. The tri-molecular complex of the T-cell receptor, antigen and MHC imparts specificity to the immune response. However, other receptor-mediated signals are required to activate T cells. One such signal arises from the interaction of the co-receptor B7.1 on antigen-presenting cells with the corresponding ligand (CTIA-4) on lymphocytes. In the absence of this co-receptor interaction, the T cell does not respond to the antigen presented to it. Blocking this interaction with CTIA-4Ig, it is possible to prevent the development of EAE and rejection of the graft. Thus, this may be one of the prospective approaches to PC treatment.

Other signals mediated by cytokines within the local microenvironment in the central nervous system can predetermine the involvement of certain subtypes of effector cells in the reaction and interaction between them. So the T helper cells (CD4 ⁺ cells) differentiate into the Th1 phenotype in the presence of gamma interferon (IFN) and interleukin 12 (IL-12) and in turn can produce IL-2 and gamma-interferon. The main function of Th1 cells is the realization of delayed type hypersensitivity, which leads to the activation of macrophages. It is believed that Th1-cells play a key role in the pathological process in multiple sclerosis. T helper cells (CD4 ⁺ cells) having the phenotype of Th2 participate in the generation of antibodies by B cells and this subtype of T cells produces IL-4, -5, -6 and -10. A Th3 phenotype that also produces a transforming growth factor beta (transformational growth factor - TGFP).

It is known that INFO stimulates macrophages to release the tumor necrosis factor-TNFP, or lymphotoxin, which causes apoptosis in the culture of oligodendrocytes. Moreover, gamma interferon activates and enhances the microbicidal functions of macrophages and induces the expression of class II MHC molecules on various cells within the central nervous system, including endothelial cells, astrocytes, microglia. In addition, activated macrophages express MHC class II molecules and Fc receptors and produce IL-1 and TNFa, which can also participate in the pathogenesis of multiple sclerosis.

Gamma-interferon (type II interferon) in multiple sclerosis

The immunostimulatory effect of INF is regarded as central in the pathogenesis of multiple sclerosis. With the aggravation of multiple sclerosis, an increase in the activity of the INFO-secreting cells is revealed both in the unstimulated and in the MBM-stimulated culture of peripheral mononuclear cells. There are reports of an increase in the expression of the INF, preceding the onset of symptoms of exacerbation, as well as an increased level of INF in active foci of multiple sclerosis. Moreover, the INFO promotes the expression of adhesive molecules on endothelial cells and enhances the proliferative response of CD4 + cells to mitogenic stimulation through the transmembrane ion channel. This phenomenon can have some correlation with the course of the disease, assessed by the dynamics of symptoms and MRI data.

Experimental data indicate that chronic progressive sclerosis progresses IL-12 production, which, in turn, can enhance the production of INFO by stimulated CD4 ⁺ cells. In a clinical study in patients with remitting multiple sclerosis, administration of INFO during the first month caused exacerbations, which forced to stop further testing. Patients had an INF-dependent increase in the number of activated monocytes (HLA-DR2 +) in the peripheral blood.

Immunocorrection with multiple sclerosis

One of the methods of immunocorrection for multiple sclerosis can be the use of T-suppressors (CD8 ⁺ cells). In addition, it is shown that a number of cytokines can reduce inflammatory demyelination. The most important of these are INFR and INF (type I interferons). In active foci of demyelination with the help of a special stain, INF and INF are detected in macrophages, lymphocytes, astrocytes, endothelial cells, and INFHR is the dominant cytokine in endothelial cells of an unaffected white matter. INFR blocks some of the proinflammatory effects of INFO, including the expression of class II MH II antigens in the culture of human astrocytes, and in other experimental models induces the expression of HLA-DR on cells. Additionally, INFD prevents the development of EAE in laboratory animals after systemic or intrathecal administration of the relevant antigens and increases the suppressor function of cells in vitro.

Electrophysiology of demyelination in multiple sclerosis

A number of pathophysiological changes make it difficult to carry out action potentials on demyelinated but structurally intact axons. Deprived of myelin sheath with high resistance and low conductivity, the axon is not able to carry a sufficient electrical discharge to cause the depolarization of the membrane in the Ranvier intercept region. Violation of rapid saladatory conduction from one node to another leads to a decrease in speed and a block of conduction. Clinically, this is best revealed in the study of optic nerves and chiasma. The study of visual evoked potentials (VEP) involves the measurement of the occipital signal (P100) with the help of surface-located EEG electrodes in response to a change in visual stimulation. The increase in latency P100 is due to demyelination and inflammation of the visual pathways with acute optic neuritis. Latentia P100 often remains pathologically elongated even after normalization of vision. It can be elongated and in the absence of loss of vision in an anamnesis, reflecting subclinical demyelination of the optic nerve. Other evoked potentials similarly evaluate the performance of auditory and somatosensory myelinated afferent tracts. Demyelination also causes other clinically significant neurophysiological changes. The temporal dispersion of action potentials as a result of varying degrees of demyelination leads to differences in the speed of conduction between adjacent axons. It is suggested that because of this, with peripheral and central myelin lesions, vibration sensitivity is lost earlier than other modalities.

The destabilization of the demyelinated axon membrane can cause autonomous local generation of action potentials and, possibly, pathological efaptic transmission from one axon to another. This phenomenon can underlie the development of "positive" symptoms, including paresthesia, pain and paroxysmal dyskinesias. These changes often respond well to treatment with sodium channel blockers, such as carbamazepine or phenytoin. Reversible temperature-dependent changes in the function of demyelinated axons can explain the worsening of symptoms of multiple sclerosis with an increase in body temperature.

[5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]

Molecular organization of myelinated axons

The axon membrane in the interception region is well adapted to generate action potentials, whereas the membrane between the intercepts is relatively refractory to depolarization. The main feature of the membrane in the interception area is that the density of sodium channels is 100 times higher than in other sections of the axon. In the interception region, there are also slow potassium channels that modulate the elongated depolarization that occurs during high-frequency discharge. For the axonal membrane in the region adjacent to the interception, a relatively high density of fast potassium channels is characteristic, the activation of which leads to rapid hyperpolarization of the axon membrane. This mechanism prevents re-aberrant excitation of the interception area. Due to the low density of sodium channels in the axon covered areas of myelin, demyelination leads to the fact that at this point the impulse is lost without causing depolarization of pulses in axons newly demyelinated.

The changes observed in chronically demyelinated axons can contribute to a partial restoration of the exercise, which leads to a reduction in symptoms after exacerbation. Continuous (but not saladatory) conduction can be restored by increasing the density of sodium channels in the demyelinated areas of the axon. Although the source of these additional channels is unknown, they can be produced in the body of a neuron or astrocytes adjacent to a cemielinized segment.

It was shown that 4-aminopyridine (4-AP) , blocking the fast potassium channels, is able to improve the conductivity of demyelinated fibers. At the same time, 4-AP has minimal effect on intact axons, as myelin, covering the rapid potassium channels, makes them inaccessible to the drug. The clinical effect of 4-AP was confirmed in trials in patients with multiple sclerosis and myasthenic syndrome Lambert-Eaton. In patients with multiple sclerosis, the drug improved the objective indicators of visual function, including the latent period of VLD, contrast sensitivity, as well as other neurological functions. A favorable reaction to the drug was more often observed in patients with thermo-dependent symptoms, with a longer duration of the disease and a more severe neurologic defect. The ability of 4-AP to lower the threshold of exercise is also evident in the occurrence of some side effects, including paresthesia, dizziness, anxiety and confusion, and at high serum concentrations-generalized tonic-clonic seizures. At present, clinical trials of this drug with multiple sclerosis continue.