Multiple sclerosis

Cellular and molecular mechanisms of pathogenesis

T lymphocytes play a central role in the development of autoimmune inflammation in multiple sclerosis, primarily CD4+ cells (Th1-type) and CD8+ T lymphocytes.

The pathological cascade begins when activated autoreactive T cells cross the blood-brain barrier. They migrate through the walls of postcapillary venules and enter the perivascular spaces of the central nervous system. Here, autoreactive Th1 lymphocytes actively secrete pro-inflammatory cytokines: tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ).

These mediators trigger the next wave of reactions:

• Activation of target cells: cytokine action activates vascular endothelial cells and resident macrophages located in the perivascular space.
• Chemotaxis: the complex of activated cells (monocytes, macrophages, T and B lymphocytes) begins producing chemokines. This leads to the massive recruitment of dendritic cells from the systemic circulation directly into the inflammation site.
• Direct damage: IFNγ secreted by Th1 lymphocytes stimulates macrophages and microglial cells. In response, they begin synthesizing specific myelinotoxic substances.

The natural consequence of these processes is the development of pronounced local inflammation, destruction of the myelin sheath (demyelination), and secondary damage to the nerve fibers (axons) themselves.

Neurodegenerative theory: an alternative perspective

In addition to the classical autoimmune concept, immunology also considers the neurodegenerative theory of multiple sclerosis development. It proposes a different sequence of events in which the autoimmune response is secondary.

According to this theory, immune aggression joins only at the later stages of the disease. The primary factor is degenerative damage to CNS structures, presumably caused by a persistent viral infection. Viruses exert prolonged effects on cells (primarily oligodendrocytes, which are responsible for myelin synthesis), leading to alterations in their antigenic structure. Only after this are the modified antigens recognized as foreign by the immune system, triggering an autoimmune response.

Morphological picture: from plaque to scar

The primary and most characteristic morphological sign of multiple sclerosis is the formation of specific lesions in the nervous tissue—plaques.

During the active inflammation stage, acute active plaques are formed. Structurally, they are perivascular cuffs—dense accumulations of cells around blood vessels. These cuffs are formed by:

• T lymphocytes migrated from postcapillary venules;
• Activated macrophages;
• Microglial cells.

The development of such a plaque is inevitably accompanied by myelin destruction. Regarding the outcome of the process, in rare cases, inflammatory lesions may resolve completely. However, full remyelination much more frequently fails to occur. Instead of restoring the normal structure of nervous tissue, a dense astroglial scar forms at the site of the destroyed myelin, permanently disrupting nerve impulse conduction.

For comparison: pathogenesis of rheumatoid arthritis

To better understand the mechanisms of autoimmune diseases, it is helpful to compare multiple sclerosis with rheumatoid arthritis (RA)—chronic inflammation of the synovial membrane of joints (found in 1% of the population, women are affected 2–3 times more often).

Unlike multiple sclerosis, where myelin is the target, in RA the process localizes in the joints. Inducers can include bacteria, viruses, or superantigens. The leading morphological sign of RA is the formation of a pannus (hyperplastic synovial membrane), whose intensive growth destroys cartilage and bone. At the same time, a mass of neutrophils, immune complexes, and pro-inflammatory cytokines accumulates in the synovial fluid.

A crucial marker of RA is the rheumatoid factor (RF)—autoantibodies against own class G immunoglobulins (anti-IgG). RF is detected in 70–80% of patients. It can be represented by natural antibodies (IgM isotype) or induced pathogenic ones (IgA and IgG isotypes). Small IgG-RF dimers penetrate the joint, form immune complexes, activate the complement system, and induce the synthesis of destructive cytokines by mononuclear cells.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of crossing the blood-brain barrier by autoreactive T cells
• The spectrum of chemokines involved in recruiting dendritic cells
• The nature of myelinotoxic substances produced by microglia
• The role of oligodendrocytes in normal conditions and during persistent viral infection
• Antibodies to type II collagen and citrullinated proteins in rheumatoid arthritis

Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"

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