Mechanisms of autoimmune damage

Cellular mechanisms of damage

Cell-mediated autoimmune response more frequently causes localized damage to specific organs. It is based on two main scenarios:

1. Cytotoxic mechanism. Cytotoxic T lymphocytes (CD8+) play the main role here. They recognize the body's own cells as foreign and trigger apoptosis in them. The feature of this pathway is that macrophages manage to phagocytose the dying cell even before its complete destruction. This protects the intercellular space from the release of intracellular contents. However, the same macrophages process the captured material and begin presenting autoantigens to new T cells, thereby maintaining and enhancing the autoimmune process.

1. Inflammatory type of immune response. It proceeds with the active participation of Th1 and Th17 cells. Interferon-gamma (IFNγ) secreted by them potently activates macrophages. Activated phagocytes synthesize nitric oxide (NO) and reactive oxygen species, acquiring the ability to kill not only bacteria but also the body's own tissue cells. In addition, they secrete pro-inflammatory cytokines that provoke vascular reactions and destroy cartilage and bone tissue (for example, during the formation of rheumatoid pannus). According to the Coombs and Gell classification, this is delayed-type hypersensitivity (type IV).

Humoral autoimmune response

Humoral reactions predominate in systemic diseases and are controlled by Th2 cells. Autoantibodies cause the primary damage. Immunoglobulins of classes IgG1 and IgG3 possess the greatest destructive potential, as their Fc fragment effectively binds the complement system, natural killer cells (NK cells), and phagocytes.

Three pathways of antibody-mediated tissue damage are distinguished:

• Cytotoxic effect. Direct antibody attack on target cells. Corresponds to hypersensitivity type II.
• Immune complex pathology. Antibodies bind to soluble antigens, forming free immune complexes. When there are too many of them, macrophages cannot cope with clearance. These complexes deposit in tissues containing Fc receptors (vessel walls, basement membranes). Macrophages attracted thither trigger local inflammation. This is hypersensitivity type III.
• Interaction with cell receptors. Antibodies can bind to surface receptors and alter their function. The effect can be blocking (leading to organ hypofunction) or stimulating (leading to hyperfunction).

Comparison of systemic and local pathologies

Autoimmune diseases are generally divided into two large groups depending on prevalence and the predominant mechanism.

Clinical consequences and examples

The exact clinical manifestation of an autoimmune disease depends on the function of the affected organ and the nature of the antibodies:

1. Loss of cell function. For example, in insulin-dependent diabetes mellitus (type I), β-cells of the islets of Langerhans are destroyed. Absolute insulin deficiency occurs, leading to severe metabolic disorders (hyperglycemia, ketoacidosis).
2. Enhancement of organ function. In diffuse toxic goiter (Graves' disease), stimulating antibodies bind to TSH receptors. The thyroid gland begins to produce hormones uncontrollably. Normal negative feedback does not work here because the process is triggered by antibodies, not the pituitary gland.
3. Generalized damage. In systemic lupus erythematosus (SLE), all connective tissue in the body is affected, causing severe systemic disorders.

Since hyperreactivity of the immune system underlies all these processes, basic therapy is based on suppressing immunological reactions. Patients are prescribed glucocorticoids, cytostatics, and modern anti-cytokine anti-inflammatory drugs.

Pathogenesis using type I diabetes mellitus as an example

Type I diabetes mellitus clearly demonstrates the coordinated work of cellular immunity during autoimmune aggression. It is suggested that the protein p40 and glutamic acid decarboxylase serve as targets.

Stages of pancreatic β-cell destruction:

1. Dendritic cells capture autoantigens from destroyed β-cells and present them to CD4+ T lymphocytes.
2. CD4+ T lymphocytes differentiate into Th1 cells and begin actively secreting interferon-gamma (IFNγ), which activates macrophages.
3. In parallel, dendritic cells present the same antigens to CD8+ T cells.
4. Th1 cells secrete interleukin-2 (IL-2), which causes CD8+ cells to proliferate and differentiate into mature cytotoxic T lymphocytes.
5. Cytotoxic lymphocytes directly destroy β-cells, closing the vicious circle of the disease.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of autotolerance formation
• Coombs and Gell classification of hypersensitivity (types I–IV)
• Pathogenesis of systemic lupus erythematosus (SLE)
• The role of Th17 in autoimmune inflammation
• Modern approaches to anticytokine therapy

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

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