Multiple Sclerosis - Causes and Pathogenesis

Causes of Multiple Sclerosis

The cause of multiple sclerosis remains unknown. There is no convincing evidence that a virus or any other infectious agent is the sole cause of this disease. However, viruses have been considered the most likely etiologic factor of the disease, which was supported by epidemiological data and some of their well-known properties. Certain viruses can affect the state of the immune system, persist in a latent form in the CNS, and cause demyelination in the CNS. Moreover, according to some data, patients with multiple sclerosis have an altered immune reactivity to some common viruses, including an increased reaction to measles viruses. Subacute sclerosing panencephalitis, a rare complication of measles infection that manifests itself many years after an apparently favorable resolution of the disease, may serve as a model for the persistence of viruses in the CNS. Some viruses and some bacteria may be associated with the development of acute disseminated encephalomyelitis (ADEM). It is usually a monophasic demyelinating disease, pathologically similar to, but not identical to, multiple sclerosis. Canine distemper virus, which is closely related to measles virus, has been suggested to be Kurtzke's "primary affect of multiple sclerosis", which the native Faroese were infected with from dogs brought to the islands by British troops. Theiler's murine encephalomyelitis virus, a picornavirus, is an experimental model of CNS demyelination in rodents, their natural hosts.

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

Environmental factors

Environmental factors, including exposure to viral and bacterial agents such as Epstein-Barr virus (EBV), human herpes virus type 6, and Mycoplasma pneumoniae [ 5 ], as well as smoking [ 6 ], vitamin deficiency [ 7 ], diet [ 8 ], [ 9 ], and exposure to UV radiation [ 10 ] have been associated with the development of multiple sclerosis.

Foreign agents may have a nuclear antigen that is structurally homologous to components of the myelin sheath, such as proteolipid protein, myelin basic protein, and myelin-associated glycoprotein. Thus, when immune cells are activated by these pathogens, damage to the myelin sheath occurs.

There is now evidence that smoking plays an important role in the development of multiple sclerosis due to the formation of nitric oxide (NO) and carbon monoxide (CO). NO is a toxic soluble gas that, in pathological concentrations, can damage neurons and oligodendrocytes [ 11 ], [ 12 ]. NO-induced lipid peroxidation and mitochondrial damage can lead to oligodendrocyte apoptosis, axonal degeneration, and demyelination [ 13 ].

A previous study showed that CO exposure results in blockage of tissue oxygenation [ 14 ], degradation of myelin basic protein (MBP) and axonal injury, as well as a subsequent inflammatory response including invasion of activated microglia and CD4+ lymphocytes into the CNS, leading to demyelination [ 15 ].

Vitamin deficiency (especially vitamins D and B12) is considered a risk factor for multiple sclerosis. Vitamin D is a group of fat-soluble secosteroids that includes vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). Cholecalciferol can be produced in the skin by ultraviolet B radiation on 7-dehydrocholesterol, which is a precursor of cholecalciferol.

In the liver, cholecalciferol is converted to the prohormone calcidiol [25(OH)D3] by hepatic hydroxylation. In the kidneys, a renal hydroxylation step replaces part of the calcidiol with calcitriol, which is the biologically active form of vitamin D. In the circulation, calcitriol binds to vitamin D binding protein and is transported to various target tissues, from where it binds to specific intracellular receptors and plays an important role in cell proliferation and differentiation [ 16 ]. In addition, this vitamin plays a role in gene expression and immune regulation [ 17 ], as well as in the induction of B-lymphocyte apoptosis [ 18 ], IL-10 synthesis [ 19 ], and the suppression of proinflammatory cytokines such as IFN-γ [ 20 ] and IL-2 [ 21 ].

Vitamin B12 is an important factor in the formation of myelin sheath components. Thus, deficiency of this vitamin may be a major cause of neurological diseases such as multiple sclerosis. Results of a previous study of patients with multiple sclerosis showed that vitamin B12 supplementation improved the clinical course of multiple sclerosis [ 22 ].

In addition to vitamin deficiency, short-term exposure to sunlight has been identified as a potential risk factor for the development of multiple sclerosis. The results of a previous study demonstrated an inverse association between ultraviolet radiation exposure and the incidence of multiple sclerosis. In support of this relationship, sunlight is a major source of vitamin D3 and through the induction of T-regulatory (Treg) cells and anti-inflammatory cytokines such as IL-10 and TNF-α, it may exert immunomodulatory effects on the human body. MS [ 23 ].

According to previous reports, diet may be an environmental factor involved in the development of multiple sclerosis [ 24 ]. Studies have shown a significant negative association between the risk of multiple sclerosis and high fish intake [ 25 ], a positive significant association between high animal fat-based calorie intake and the risk of multiple sclerosis [ 26 ], a nonsignificant decreased risk between the incidence of multiple sclerosis and higher fish intake of linoleic acid, and a positive significant association between obesity in adolescent girls and the risk of multiple sclerosis [ 27 ].

Possible mechanisms of virus-induced demyelination

• Direct viral exposure
• Viral penetration into oligodendrocytes or Schwann cells causes demyelination by cell lysis or alteration of cellular metabolism
• Destruction of the myelin membrane by a virus or its products
• Virus-induced immune response
• Antibody production and/or cell-mediated response to viral antigens on the cell membrane
• Sensitization of the host organism to myelin antigens
• The breakdown of myelin due to infection, with fragments entering the general bloodstream
• Incorporation of myelin antigens into the viral envelope
• Modification of myelin membrane antigens
• Cross-reacting antigens of the virus and myelin proteins
• Demyelination as a side process
• Dysfunction of regulatory mechanisms of the immune system under the influence of viruses

A disease similar to spinal multiple sclerosis is caused by a retrovirus, human T-cell lymphotropic virus type 1. The disease is known in various geographic areas as tropical spastic paraparesis or HIV-associated myelopathy. Both tropical spastic paraparesis and HIV-associated myelopathy are slowly progressive myelopathies characterized by vasculopathy and demyelination. Evidence that multiple sclerosis is caused by a retrovirus remains inconclusive, despite the fact that human T-cell lymphotropic virus type 1 DNA sequences have been identified in some patients with multiple sclerosis. Massive demyelination associated with subacute infection with herpes simplex virus type 6 has also been described. There is some evidence that certain bacteria, particularly chlamydia, may be involved in the development of multiple sclerosis, but this also requires confirmation.

The role of genetic factors in the development of multiple sclerosis

The role of racial and ethnic factors in the formation of predisposition to multiple sclerosis is difficult to separate from the influence of external factors. Thus, 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 a relatively high prevalence of multiple sclerosis is also noted. Although Japan is located at the same distance from the equator, the prevalence of multiple sclerosis in this country is low. Moreover, a number of studies have shown that the risk of developing the disease varies among different ethnic groups living in the same area. For example, the disease is rare in black Africans and is unknown in some ethnically pure populations of aborigines, including the Eskimos, Inuits, Indians, Australian aborigines, the Maori tribe in New Zealand, or the Sami tribe.

Genetic markers of predisposition to multiple sclerosis are identified in studies of twins and familial cases of the disease. In Western countries, the risk of developing the disease in first-degree relatives of a patient is 20-50 times higher than the average for the population. The concordance rate in identical twins, according to several studies, is approximately 30%, while in fraternal twins and other siblings it is less than 5%. Moreover, it has been shown that the concordance rate in identical twins may be higher when taking into account cases in which magnetic resonance imaging (MRI) reveals asymptomatic lesions in the brain. These studies did not note a dependence of clinical features or severity of the disease on its familial nature. Specific genes associated with multiple sclerosis have not been identified, and the type of transmission of the disease corresponds to polygenic inheritance.

Genome screening

Multicenter studies screening the entire genome are being conducted to identify possible multiple sclerosis genes. These studies have already tested more than 90% of the human genome, but have failed to detect genetic markers for the disease. At the same time, a genetic link has been identified with the HLA region on the short arm of chromosome 6 (6p21), which coincides with data on an increased predisposition to multiple sclerosis in individuals carrying certain HLA alleles. Although American and British researchers have shown a moderate link with the HLA region, Canadian scientists have not found such a link, but, like Finnish scientists, have found a strong link with a gene localized on the short arm of chromosome 5. Some HLA alleles are known to be associated with a higher risk of multiple sclerosis, especially the HLA-DR2 haplotype (Drw15 subtype). The risk of developing multiple sclerosis in white Europeans and North Americans carrying the DR2 allele is four times higher than the population average. However, the predictive value of this trait is limited because 30-50% of patients with multiple sclerosis are DR2-negative, while DR2 is found in 20% of the general population.

Other risk factors for developing multiple sclerosis

The risk of developing multiple sclerosis in young women is twice as high as in men. However, after 40 years of age, the sex ratio among patients with multiple sclerosis levels out. The period of highest risk of developing the disease is in the 2nd to 6th decades of life, although cases of multiple sclerosis have been reported among young children and the elderly. According to several studies, multiple sclerosis in childhood does not differ significantly from the disease in adults in either clinical manifestations or course. After 60 years of age, multiple sclerosis develops rarely, and in some clinical series, these cases account for less than 1% of the total number of cases of the disease.

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

Myelino-oligodendocytic complex

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

Because the myelin-oligodendrocyte complex of the CNS covers more axons than the myelin-lemmocyte complex of the PNS, it is more sensitive to damage. Thus, in the CNS, one oligodendrocyte can myelinate up to 35 axons, whereas in the PNS there is one Schwann cell per axon.

Myelin is a substance with high resistance and low conductivity, which, along with the uneven distribution of sodium channels, ensures the generation of action potentials in certain specialized areas of the axon - the nodes of Ranvier. These nodes are formed at the border of two areas covered with myelin. Depolarization of the axon membrane occurs only in the area of the node of Ranvier, as a result of which the nerve impulse moves along the nerve fiber in discrete jumps - from node to node - this fast and energy-efficient method of conduction is called saltatory conduction.

Since the myelin-oligodendrocyte complex is sensitive to a number 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 poisoning with carbon monoxide or other toxic substances, liver dysfunction, vitamin B12 deficiency, viral infections or postviral reactions, must be excluded in the process of diagnosing multiple sclerosis. Primary inflammatory demyelination in multiple sclerosis or ADEM is characterized by perivascular infiltration of inflammatory cells and multifocal distribution of lesions in the subcortical white matter, and the foci can be symmetrical or confluent.

Pathomorphology of multiple sclerosis

Important information about multiple sclerosis has been obtained from comparative histological examination of demyelination lesions (plaques) of varying age in the same patient, as well as from comparison of patients with different clinical characteristics and course. Some of the patients died as a result of the fulminant course of recent multiple sclerosis, others - from concomitant diseases or complications at a late stage of the disease.

Macroscopic changes in the brain and spinal cord in multiple sclerosis are usually not sharply expressed. Only mild atrophy of the cerebral cortex with dilation of the ventricles, as well as atrophy of the brainstem and spinal cord are noted. Dense pinkish-gray depressions indicating the presence of plaques underneath may be detected on the ventral surface of the pons, medulla oblongata, corpus callosum, optic nerves, and spinal cord. Plaques are found in the white matter, sometimes in the gray matter of the brain. Plaques are most often located in certain areas of the white matter - for example, near small veins or postcapillary venules. They are often detected near the lateral ventricles - in those areas where the subependymal veins run along the inner walls, as well as in the brainstem and spinal cord - where the pial veins are adjacent to the white matter. Individual plaques in the periventricular zone often tend to merge as they enlarge, 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 Dawson's fingers. Histologically, they are limited zones of inflammation with or without demyelination that surround the parenchymatous veins and correspond to their radial course deep into the white matter.

Clinical and pathological data indicate that the optic nerves and cervical spinal cord are frequently affected in demyelinating disease. It is assumed that the frequent formation of plaques in these structures is explained by the mechanical stretching they experience during eye movements or neck flexion, but the validity of this hypothesis has not been proven. Some other areas of the brain are often involved - the floor of the fourth ventricle, the periaqueductal zone, the corpus callosum, the brainstem, and the cerebellar tracts. The junction of the gray and white matter of the cerebral hemispheres (the corticomedullary junction zone) may also be involved, but the subcortical U-shaped junctions usually remain intact.

Multifocal demyelination is the rule in multiple sclerosis. In an autopsy series of 70 patients with multiple sclerosis, only 7% of patients had brain damage (excluding optic nerve pathology) without spinal cord involvement, and only 13% of patients had spinal cord damage without brain involvement.

Histological changes in multiple sclerosis

The earliest changes preceding demyelination remain controversial. In the brain of patients with multiple sclerosis, perivascular infiltrates consisting of lymphocytes, plasma cells, and macrophages are found in both demyelinated and normally myelinated white matter. These cells can accumulate in the perivenular Virchow-Robin spaces between blood vessels and the brain parenchyma, which are connected to the cerebrospinal fluid circulation system. These data can be considered evidence of the decisive 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 of similar perivascular accumulations of lymphocytes in the retina, devoid of myelinated fibers, in patients with multiple sclerosis. In multiple sclerosis, perivascular infiltrates and focal disturbances of the blood-retinal barrier are observed.

Various interpretations of the mechanism of myelin destruction in multiple sclerosis foci have been proposed. Some believe that monocytes only absorb fragments of the myelin sheath that have already been destroyed by other factors. Others believe that monocytes are directly involved in the destruction of myelin. Macrophage membranes contain clathrin-coated depressions that are adjacent to the myelin sheath. It is assumed that this is where the Fc-dependent interaction between the antibody and the receptor occurs, leading to opsonization of myelin by monocytes. Macrophages have also been shown to directly penetrate the myelin sheath, causing the formation of vesicles within the myelin.

Myelin degradation products in the cytoplasm of macrophages are markers of acute demyelination. The composition and ultrastructure of these fragments located inside macrophages correspond to normal myelin. As the decomposition proceeds, the ultrastructure is destroyed, droplets of neutral fat are formed, 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 large numbers of cells, predominantly B cells, plasma cells, CD4 ⁺ and CD8 ⁺ T lymphocytes, and early reactive macrophages, which are found within the plaque and at its margins. Morphologically, acute axonal changes in the form of globules may be detected. Complete or abortive remyelination is often observed at the periphery of the lesions. Sometimes, signs of repeated demyelination are found in these or adjacent areas. Sometimes the entire plaque is remyelinated. Such plaques are called "shadowed" because they merge with the surrounding normal white matter both on macroscopic examination and on neuroimaging.

The origin of the remyelinating cell populations remains unknown. The source of remyelinating oligodendrocytes may be mature cells that have escaped destruction at the site of injury, cells that have migrated from an adjacent area, or juvenile oligodendrocytes that have formed from precursor cells. It is believed that the degree of destruction of mature oligodendrocytes determines the remyelination potential at a given site, which can be highly variable. Schwann cells have been reported to migrate into the spinal cord and remyelinate axons.

Compared with normal axons, remyelinated axons have a thinner myelin sheath with shortened myelin segments and widened nodes of Ranvier. Experimental data show that demyelinated axons can restore electrophysiological functions, but whether this is associated with symptom regression in multiple sclerosis remains unknown. After remyelination of experimentally demyelinated axons using transplanted glial cells, almost complete restoration of normal conductivity was observed, indicating that cell transplantation may be effective in multiple sclerosis.

Old lesions with inactive central zones usually contain few macrophages and other inflammatory cells, although active demyelination and inflammatory infiltration may occur at the margins. Chronically demyelinated axons are embedded in a matrix of fibrous astroglial processes, hence the term sclerosis. Blood vessel walls may be thickened by hyalinization. Remyelination potential appears to be lower in old lesions than in fresh lesions because they contain fewer viable oligodendrocytes.

Magnetic resonance imaging (MRI) is a very sensitive technique for imaging plaques. Although plain MRI does not reliably distinguish edema from demyelination, gliosis, or axonal loss, these lesions are often referred to as demyelination lesions. Sagittal, coronal, and axial MRI images of the brain and spinal cord allow the topography of the lesions to be examined in a given patient. Sagittal images of the brain best show lesions in the corpus callosum and their extension superiorly through the optic radiation to the cortex. Coronal images allow the location of lesions in relation to the ventricular walls to be studied. Axial images are most useful for localizing and quantifying lesions. Multiple sclerosis lesions appear on T2-weighted images as hyperintense (white) areas that contrast well against the darker background of normal white matter but are poorly differentiated from the cerebrospinal fluid (CSF) of the ventricles. On proton density images, the lesions have a higher intensity than the CSF and apparently intact white matter, which are darker in color. On FLAIR images, the contrast between the lesion and the surrounding white matter is enhanced.

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

Magnetic resonance imaging in dynamics allows obtaining information on the development of pathological changes in the brain over time. The integrity of the blood-brain barrier can be assessed using a contrast agent - gadolinium-diethientriaminepenta acetate (Gd-DPTA) - a paramagnetic agent that increases the T1 relaxation time of surrounding mobile water protons, due to which foci on T1-weighted images appear brighter. The permeability of the blood-brain barrier is associated with the presence of vesicles inside endothelial cells that contain Gd. Studies on laboratory animals and humans have shown that the degree of contrasting with Gd-DPTA reflects the severity of perivascular inflammation. A series of MRIs with the introduction of Gd-DPTA shows contrasting at an early stage of lesion development, which lasts from 2 weeks to 3 months. As the lesions become de-enhanced, they disappear completely or appear as hyperintense areas on T2-weighted images.

The localization of lesions on MRI often does not correspond to clinical symptoms, although the activity of lesions has some relationship with the course of multiple sclerosis. For example, new lesions are more likely to increase signal in secondary progressive than in primary progressive multiple sclerosis. These changes are visible on both T2-weighted images and on T1-weighted images with contrast and indicate the presence of vasogenic edema and increased extracellular water content. Detection of active lesions can be improved by administering a higher dose of Gd-DPTA.

Magnetic resonance spectroscopy (MRS), which quantifies brain metabolism in vivo, can determine axonal integrity using proton resonance of N-acetylaspartate (NAA) contained in neurons. In larger lesions (as determined by conventional MRI) and in more severe disease, the level of NAA in the lesions is lower.

Immunopathogenesis of multiple sclerosis

The prevailing opinion among experts is that multiple sclerosis is based on a cellular immune reaction directed against one or more CNS myelin antigens. Histopathological changes at the early stage of demyelination lesion development convincingly indicate a key role of T lymphocytes. T helper cells (CD4 lymphocytes) are detected in the lesion at an early stage and are believed to initiate the inflammatory cascade. Suppressor/cytotoxic T cells (CD8 lymphocytes) are found at the lesion perimeter and in perivascular spaces and may have a counter-regulatory effect on proinflammatory processes. In addition, local enhancement of immune reactivity with the expression of major histocompatibility complex (MHC) class I and II molecules on both immune and non-immune cells, including astrocytes and vascular endothelial cells, is detected. Thus, these cells can potentially participate in the immune response by presenting myelin autoantigens to CD8 and CD4 cells. Importantly, oligodendrocytes do not appear to express MHC class I or II molecules, suggesting that they do not play a major role in immunopathogenesis. Macrophages present in the lesion are recruited to the CNS from the periphery and/or are derived from local microglial cells.

Although a specific autoantigen in multiple sclerosis has not been identified, a working hypothesis is that the disease is based on a T-cell proliferative response to one or more myelin antigens. The specificity of T-cell receptors for myelin antigens at an early stage may not correspond to the repertoire of T-cell receptors at an 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 from patients with multiple sclerosis are able to react with multiple CNS myelin antigens, including myelin basic protein (MBP), proteolytic protein (PLP), myelin-associated glycoprotein (MAG), and myelin-oligodendrocyte glycoprotein (MOG). However, T cells capable of reacting with MBP and PLB are also detected in healthy individuals.

If MS is caused by activated myelin-sensitized T cells, this suggests a breakdown in immune tolerance mechanisms. Central immune tolerance is established early in the thymus and involves both positive and negative selection of T cells recognizing MHC antigens, eliminating those with affinity for autoantigens. Peripheral immune tolerance is maintained by active suppression of potentially autoreactive cells. It remains unknown how tolerance to CNS antigens develops, since the CNS is normally a “privileged zone” for the immune system. Evidence that T cells contact MHC outside the CNS comes from the discovery of the Golli-MBP gene (expressed in oligodendrocyte lineages). This gene, which is expressed in the fetal thymus, spleen, and leukocytes, may be involved in mechanisms of positive or negative selection of MBP-reactive T cells in the thymus.

Specific studies have been conducted to determine whether the number of pathogenic T-cell clones is limited in patients with multiple sclerosis. Most of these studies have examined the alpha-beta chain specificity of the T-cell receptor using gene rearrangement and antigen-induced proliferation assays. The sources of T cells in these studies have been brain tissue, cerebrospinal fluid, and peripheral blood. In some cases of multiple sclerosis and EAE in rodents, a limited repertoire of the alpha-beta chain variable region of the receptor of activated T cells has been identified, which may reflect specific reactivity to certain fragments of MBP. Comparison of MBP-reactive T cells in different patients and laboratory animal species reveals wide variability in receptor gene expression and MBP specificity. The fact that individuals with HLA DR2+ have a higher risk of developing multiple sclerosis points to the importance of interaction with specific T-cell receptors. Steinman et al. (1995) showed that in HLA DR2+ individuals, B-cell and T-cell responses are directed mainly against certain fragments of the MBP peptide chain (from 84 to 103 amino acids).

Such studies have practical applications, making it possible to develop peptides that can block or stimulate protective reactions by influencing the T-cell receptor-antigen - MHC interaction 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 may also play a pathogenetic role in MS. Thus, T-cells carrying receptors with gamma-delta chains (rather than the alpha-beta chains characteristic of CD4 and CD8 cells) have been found in multiple sclerosis lesions.

It can be assumed that the autoimmune reaction in multiple sclerosis involves 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 activation of T-cells caused by binding to microbial toxins (superantigens) with common beta-chains of receptors.

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

A number of coreceptors and cytokines are involved in the initiation, maintenance and regulation of the local immune response. The trimolecular complex of the T-cell receptor, antigen and MHC provides specificity to the immune response. However, other receptor-mediated signals are required for T-cell activation. One such signal is the interaction of the B7.1 coreceptor on antigen-presenting cells with its ligand (CTIA-4) on lymphocytes. In the absence of this coreceptor interaction, the T cell does not respond to the antigen presented to it. Blocking this interaction with CTIA-4Ig may prevent EAE and graft rejection. Thus, this may be one of the promising approaches to the treatment of MS.

Other cytokine-mediated signals within the local microenvironment in the CNS may determine the involvement of certain effector cell subtypes in the reaction and the interactions between them. Thus, T-helpers (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 to implement delayed-type hypersensitivity, which leads to the activation of macrophages. Th1 cells are believed to play a key role in the pathological process in multiple sclerosis. T-helpers (CD4 ⁺ cells) with the Th2 phenotype are involved in the generation of antibodies by B cells, and this subtype of T-cells produces IL-4, -5, -6, and -10. A Th3 phenotype has also been identified, which produces transforming growth factor beta (TGFP).

It is known that INF stimulates macrophages to release tumor necrosis factor beta (TNFP, or lymphotoxin), which causes apoptosis in oligodendrocyte culture. 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 CNS, including endothelial cells, astrocytes, and microglia. In addition, activated macrophages express class II MHC molecules and Fc receptors and produce IL-1 and TNFa, which may also participate in the pathogenesis of multiple sclerosis.

Interferon gamma (type II interferon) for multiple sclerosis

The immunostimulatory effect of INFu is considered to be central in the pathogenesis of multiple sclerosis. During exacerbation of multiple sclerosis, an increase in the activity of INFu-secreting cells is detected both in unstimulated and in MBP-stimulated cultures of peripheral mononuclear cells. There are reports of an increase in INFu expression preceding the appearance of exacerbation symptoms, as well as an increased INFu level in active foci of multiple sclerosis. Moreover, INFu promotes the expression of adhesion molecules on endothelial cells and enhances the proliferative response of CD4+ cells to mitogenic stimulation through a transmembrane ion channel. This phenomenon may have some correlation with the course of the disease, assessed by the dynamics of symptoms and MRI data.

Experimental data indicate that in chronic progressive multiple sclerosis, there is an increase in IL-12 production, which in turn can promote an increase in INF production by stimulated CD4 ⁺ cells. In a clinical trial in patients with relapsing multiple sclerosis, the introduction of INF during the first month caused exacerbations, which forced the termination of further testing. The patients showed an INF-dependent increase in the number of activated monocytes (HLA-DR2+) in the peripheral blood.

Immunocorrection in multiple sclerosis

One of the methods of immunocorrection in multiple sclerosis may be the use of T-suppressors (CD8 ⁺ cells). In addition, it has been shown that a number of cytokines are able to reduce inflammatory demyelination. The most important of them are INF and INFa (type I interferons). In active foci of demyelination, using special staining, INFa and INFa are detected in macrophages, lymphocytes, astrocytes, endothelial cells, and INFa is the dominant cytokine in endothelial cells of the unaffected white matter. INFa blocks some proinflammatory effects of INFa, including the expression of MHC class II antigens in human astrocyte culture, and in other experimental models induces HLA-DR expression on cells. Additionally, INFa prevents the development of EAE in laboratory animals after systemic or intrathecal administration of the corresponding antigens and increases the suppressor function of cells in vitro.

Electrophysiology of demyelination in multiple sclerosis

A number of pathophysiological changes impede the conduction of action potentials along demyelinated but structurally intact axons. Without the high-resistance, low-conductance myelin sheath, the axon is unable to deliver a sufficient electrical discharge to cause membrane depolarization at the node of Ranvier. Impaired rapid saltatory conduction from one node to the next results in decreased velocity and conduction block. Clinically, this is best demonstrated by examining the optic nerves and chiasm. Visual evoked potential (VEP) testing involves measuring the occipital signal (P100) with superficial EEG electrodes in response to changing visual stimulation. Increased P100 latency occurs due to demyelination and inflammation of the optic pathways in acute optic neuritis. P100 latency often remains pathologically prolonged even after vision has returned to normal. It may be prolonged even in the absence of a history of visual loss, reflecting subclinical demyelination of the optic nerve. Other evoked potentials similarly assess conduction along auditory and somatosensory myelinated afferent tracts. Demyelination also causes other clinically significant neurophysiological changes. The temporal dispersion of action potentials resulting from varying degrees of demyelination leads to differences in conduction velocity between adjacent axons. This is thought to be the reason why vibration sensitivity is lost earlier than other modalities in lesions of peripheral and central myelin.

Destabilization of the demyelinated axon membrane may cause autonomous local generation of action potentials and possibly abnormal ephaptic transmission from one axon to another. This phenomenon may 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 may explain the worsening of symptoms of multiple sclerosis with increasing body temperature.

[ 28 ], [ 29 ], [ 30 ], [ 31 ], [ 32 ], [ 33 ]

Molecular organization of myelinated axons

The axon membrane in the node region is well suited to generate action potentials, whereas the membrane between the nodes is relatively refractory to depolarization. The main feature of the membrane in the node region is that the density of sodium channels here is 100 times higher than in other parts of the axon. The node region also contains slow potassium channels, which modulate the prolonged depolarization that occurs during high-frequency discharge. The axonal membrane in the region adjacent to the node is characterized by a relatively high density of fast potassium channels, the activation of which leads to rapid hyperpolarization of the axon membrane. This mechanism prevents repeated aberrant excitation of the node region. Because of the low density of sodium channels in the myelinated regions of the axon, demyelination leads to the fact that the impulse is lost at this site, without causing depolarization of impulses in axons that have recently undergone demyelination.

Changes observed in chronically demyelinated axons may contribute to partial restoration of conduction, resulting in symptomatic relief after an exacerbation. Continuous (but not saltatory) conduction may be restored by increasing the density of sodium channels in demyelinated regions of the axon. Although the source of these additional channels is unknown, they may be produced in the cell body or astrocytes adjacent to the demyelinated segment.

It has been shown that 4-aminopyridine (4-AP), which blocks fast potassium channels, is able to improve conduction along demyelinated fibers. At the same time, 4-AP has a minimal effect on intact axons, since myelin, covering fast potassium channels, makes them inaccessible to the drug. The clinical effect of 4-AP has been confirmed in trials in patients with multiple sclerosis and Lambert-Eaton myasthenic syndrome. In patients with multiple sclerosis, the drug improved objective indices of visual function, including the latent period of VEP, contrast sensitivity, and other neurological functions. A favorable response to the drug was more often observed in patients with temperature-dependent symptoms, with a longer duration of the disease and a more severe neurological defect. The ability of 4-AP to lower the conduction threshold is also manifested in the occurrence of some side effects, including paresthesia, dizziness, anxiety and confusion, and at high serum concentrations - generalized tonic-clonic seizures. Currently, clinical trials of this drug in multiple sclerosis are ongoing.