Mutagenic factors and "forbidden clones"
One of the main mechanisms triggering autoaggression is the direct insertion of foreign or damaged genetic material into the genome of actively dividing immunocytes. The provokers are DNA fragments of viruses and bacteria, nucleic acid residues of destroyed normal or tumor cells, and specific enzymes—DNA restriction enzymes.
Under their influence, mutations occur, resulting in the formation of "forbidden clones". These are defective populations of T- and B-lymphocytes, as well as antigen-presenting cells. Due to distorted perception, they begin to identify the body's normal antigens as hostile.
- Abnormal T-killers carry out direct aggression, physically damaging healthy tissues.
- Plasma cells (matured B-lymphocytes) trigger massive autoantibody production.
Clinical manifestations: various cytopenias (hemolytic anemias, leukopenias, thrombocytopenias, pancytopenias), as well as cytotoxic reactions that often manifest after infection of B-lymphocytes with the lymphotropic Epstein–Barr virus.
Imbalance of regulatory cells and loss of anergy
In a healthy body, immune tolerance to the individual antigenic composition is maintained by a strict dynamic balance between T-helper cells and T-suppressor cells. When pathology develops, this ratio breaks down in two possible scenarios:
- A sharp decrease in the number or functional activity of T-suppressors.
- A pathological increase in the number or activity of T-helpers.
The outcome is always the same—intensive and uncontrolled proliferation of autoaggressive T-killers and B-lymphocytes. Systemic lupus erythematosus (SLE), multiple sclerosis, and rheumatoid arthritis develop through precisely this pathway.
An additional factor of autoaggression is the abrogation of anergy (physiological inactivity) of T-lymphocytes towards self-antigens. This process is triggered when antigen-presenting cells (monocytes and macrophages) begin to secrete an excess of costimulatory factors, such as interleukin-12. This mechanism is particularly characteristic of rheumatic diseases.
Failure in the global immune network
A healthy immune system is able to control itself through a complex "idiotype-anti-idiotype" system. In this network, anti-idiotypes act as "supervisors"—essentially autoantibodies generated against one's own autoantibodies, controlling their numbers.
If, under the influence of exogenous or endogenous factors, the level of anti-idiotypic antibodies changes inadequately (drops or rises), a powerful immunostimulatory or immunosuppressive effect occurs. Ideal conditions are created for the synthesis of "forbidden" classes of Ig against the structures of one's own body.
Main causes of network breakdown:
- Deficiency of T-suppressors against the background of hereditary or acquired immunodeficiencies.
- Excessive proliferation of T-helpers.
- Nonspecific stimulation of B-lymphocytes (provokers: mycoplasmas, Epstein–Barr virus, gram-negative bacterial lipopolysaccharides).
Examples of diseases: scleroderma, myopathy, immunogenic hemolytic anemias.
Polyclonal lymphocyte activation
Some microbial metabolic products and membrane lipopolysaccharides do not possess strict antigenic specificity. Entering the internal environment, they act as a nonspecific trigger, simultaneously stimulating multiple clones of T- and B-lymphocytes at once.
The result of such massive activation is a large-scale lytic effect—lymphocytes begin to randomly destroy cells of their own organism. A vivid example of the realization of this mechanism is macrophage activation syndrome. It inevitably leads to a severe immunodeficient state, against which secondary infections rapidly develop, up to generalized sepsis.
Briefly: answers to topical questions
Which specific autoantibodies are markers of systemic lupus erythematosus?
Markers of systemic lupus erythematosus are autoantibodies to nuclear antigens/components of cell nuclei. Based on sources, laboratory markers include:
- antinuclear factor / antinuclear antibodies;
- antibodies to native DNA, including double-stranded DNA (anti-dsDNA).
Through which type of hypersensitivity (according to Gell and Coombs) do autoimmune hemolytic anemias develop?
Autoimmune hemolytic anemias develop through type II hypersensitivity (according to Gell and Coombs). This type is cytotoxic, IgG-mediated. Immunoreagents are antibodies of IgG subtypes (IgG1, IgG3) and IgM. The mechanism involves antibody binding to the target cell surface followed by complement-dependent cytolysis.
What mechanisms ensure central immune tolerance in the thymus?
In the thymus, central immune tolerance is ensured by T-lymphocyte selection, primarily negative selection:
- clones of T-lymphocytes reacting too strongly to self-antigens are deleted;
- elimination of autoaggressive/autoreactive lymphocyte clones occurs;
- to prevent autoaggressive clones from exiting to the periphery, ectopic expression of organ-specific antigens controlled by the AIRE gene takes place in the thymus.
To understand the "idiotype-anti-idiotype" system, imagine internal affairs. Idiotypes are patrol officers (antibodies), and anti-idiotypes are the internal investigations department (antibodies to antibodies). If the investigations department disappears or malfunctions, patrol officers go out of control and attack peaceful citizens (self-cells).
Class and exam questions
What are "forbidden clones" in pathophysiology?
These are populations of mutated T- and B-lymphocytes, as well as antigen-presenting cells, that have lost the ability to distinguish "self" from "non-self". They mistakenly recognize normal body tissues as hostile antigens and begin attacking them.
What role do viruses and bacteria play in the development of autoaggression?
Fragments of their DNA and specific enzymes (DNA restriction enzymes) are capable of integrating into the genome of dividing immune cells, provoking dangerous mutations. In addition, bacterial lipopolysaccharides cause nonspecific polyclonal activation of multiple lymphocyte clones at once.
Why does the abrogation of T-lymphocyte anergy occur?
This process occurs due to the excessive secretion of costimulatory factors (e.g., interleukin-12) by macrophages and monocytes. Excessive stimulation forces T-cells to break their resting state and initiate an attack against self-antigens, which is typical of rheumatic pathologies.
What else to study on this topic
- The role of the lymphotropic Epstein–Barr virus in triggering cytotoxic reactions
- Pathogenesis and stages of development of macrophage activation syndrome
- Mechanisms of formation of immunogenic hemolytic anemias and pancytopenias
- The effect of gram-negative bacterial lipopolysaccharides (LPS) on B-lymphocytes
- Hereditary and acquired T- and B-cell immunodeficiencies as triggers of autoaggression
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