Causes of auto-tolerance breakdown
Normally, the immune system "ignores" its own tissues. This mechanism is called auto-tolerance. Pathology develops if one of the protective barriers fails:
- Impaired elimination. Auto-specific lymphocyte clones are not destroyed during maturation.
- Peripheral anergy failure. Surviving autoreactive lymphocytes are not suppressed in the periphery.
- Treg deficiency. The suppressive activity of regulatory T cells decreases.
- Increased antigen concentration. Antigens that were previously scarce for recognition begin to be actively released into the blood.
Sometimes T lymphocytes accidentally "slip past" negative selection. This happens if the cell does not physically encounter the autoantigen in the central lymphoid organ or fails to receive a lethal apoptotic signal.
Mechanisms triggering autoimmune reactions
For dormant autoreactive cells to begin attacking tissues, a triggering mechanism is required:
- Barrier disruption. Some organs (eyes, brain, testes) are isolated from the immune system by blood-tissue barriers. Upon trauma, antigens are exposed and recognized by the immune system as foreign.
- Extraordinary costimulator expression. In the context of inflammation (driven by IFNγ), ordinary cells begin to behave like antigen-presenting cells. They express MHC-II molecules and costimulators, directly activating T killers.
- Autoantigen modification. Self-proteins can change their structure under the influence of drugs (e.g., $\alpha$-methyldopa binds to erythrocytes). The immunity attacks the altered protein, but also "collaterally damages" normal ones.
- Antigenic mimicry. Pathogens possess epitopes similar to human tissues. For example, antibodies to Trypanosoma cruzi in Chagas disease destroy the patient's own myocardium.
Classification by immune response type
Diseases are divided into organ-specific (a specific organ is attacked) and systemic (the entire body is attacked).
| Response type | Organ-specific diseases | Systemic diseases |
|---|---|---|
| Cytotoxic (CD8+) | Type 1 diabetes mellitus, ulcerative colitis | No |
| Cellular (Th17/Th1) | Hashimoto's thyroiditis, multiple sclerosis | Rheumatoid arthritis |
| Humoral (Th2, antibodies) | Myasthenia gravis, Graves' disease | Systemic lupus erythematosus, scleroderma |
| Mixed / unclear | Myxedema, sympathetic ophthalmia | Sjögren's syndrome, dermatomyositis |
Genetics and apoptosis impairment
Severe autoimmune syndromes are often caused by defects in specific genes:
- AIRE gene. Normally responsible for presenting tissue-specific antigens in the thymus for lymphocyte "education". Mutation leads to APECED syndrome, characterized by multiple endocrine gland failures.
- Apoptosis genes (Fas and FasL). If the FAS receptor or its ligand is defective, autoreactive clones do not die. In humans, this causes autoimmune lymphoproliferative syndrome (Canale-Smith syndrome).
- FOXP3 gene. Responsible for the development of regulatory T cells (Tregs). Its defect deprives the immune system of its main "brakes", causing fatal X-linked IPEX syndrome.
The role of inflammation and Th17 cells
Modern immunology assigns a key role in the development of autoimmune pathologies to the Th17 cell subpopulation (replacing the outdated Th1/Th2 concept). The differentiation of these cells is triggered by TGFβ and IL-6 cytokines.
The IL-17 and IL-22 produced by them act as crucial factors in organ damage. Interestingly, during lymphopenia, compensatory division of T lymphocytes can occur in the body, leading to the formation of "surrogate" memory cells. They are activated much more easily than normal cells and, if autoreactive clones are present among them, are capable of rapidly provoking tissue destruction.
Briefly: answers to topical questions
Which organs are considered immunologically barrier-privileged?
Immunologically "barrier-privileged" organs and structures include:
- brain;
- eye, including the lens and retina, as well as the internal chambers of the eye;
- thyroid gland;
- testes and seminiferous tubules of the testes.
Immunologically privileged organs also include the ovaries, hair follicles, pregnant uterus, and developing fetus. In a broader sense, immunologically privileged zones include the intestinal mucosa and tumors.
Which infectious agents trigger autoimmune reactions via the mechanism of antigenic mimicry?
Antigenic (molecular) mimicry as a mechanism of auto-tolerance breakdown can be caused by infectious agents, including:
- viruses, in particular Coxsackie viruses, ECHO viruses, picornaviruses, influenza and rubella viruses, as well as parvovirus B19;
- bacteria, in particular Yersinia, group A β-hemolytic streptococcus, and the plague pathogen;
- parasites.
In this process, microbial antigens share structural similarities with the body's own tissue antigens, causing the immune response to cross-damage the body's cells.
Which non-lymphoid cells are capable of expressing MHC-II during extraordinary costimulator expression?
Activated endothelial and epithelial cells, as well as endocrine organ cells, possess the ability to express MHC-II molecules and costimulatory molecules.
- Endocrine organ cells (e.g., pancreatic β-cells) acquire the properties of antigen-presenting cells upon extraordinary expression of MHC-II together with costimulators (CD80).
- Endothelial and epithelial cells begin to express MHC-II and costimulatory molecules (CD40, CD80, CD86) under inflammatory conditions driven by pro-inflammatory cytokines (primarily IFNγ).
As a result, these non-lymphoid cells can activate autoreactive T lymphocytes.
Which specific autoantibodies are markers of systemic lupus erythematosus?
Specific serological markers of systemic lupus erythematosus (SLE) include the following autoantibodies:
- Antinuclear factor (ANF) — detected on HEp-2 cells (a positive titer of $\ge$ 1:80 is a mandatory diagnostic criterion).
- Antinuclear antibodies — determined using a dedicated panel.
- Antibodies to double-stranded DNA (anti-dsDNA).
- Antibodies to phospholipids and lipid factors — anticardiolipin antibodies, anti-β2-glycoprotein-1 antibodies (anti-β2-GP1), and lupus anticoagulant.
Which medications are capable of modifying erythrocyte autoantigens?
Drugs that cause drug sensitization accompanied by hemolytic anemia are capable of modifying erythrocyte antigens. These include:
- Phenacetin
- Chlorpromazine
The mechanism involves the drug binding to the surface of blood cells (erythrocytes) to form a complex. The immune system produces antibodies specific to this drug, which then attack the modified cell and cause its damage.
The mechanisms triggering autoimmune processes can be remembered using the "Four P's" rule: Barrier damage, Cross-reactivity (mimicry), Antigen restructuring (modification), and Over-stimulation of costimulation.
Class and exam questions
Why do autoimmune diseases have a chronic course?
Unlike infections, in which the pathogen is ultimately destroyed, an autoantigen is the body's own tissue. It cannot be completely eliminated, so autoimmune aggression sustains itself.
What is the essence of antigenic mimicry?
This is the structural similarity between microbes and human cells. The immune system produces antibodies against an infection, but due to cross-reactivity, they mistakenly bind to the body's own tissues.
How is the AIRE gene related to negative selection?
This gene ensures the expression of peripheral tissue antigens directly in the thymus. If the gene mutates, T lymphocytes are not exposed to these antigens, fail to undergo rigorous selection (negative selection), and enter the bloodstream ready to attack their own organs.
What else to study on this topic
- Pathogenesis of IPEX syndrome and APECED syndrome.
- Features of receptor apoptosis gene mutations (Fas and FasL).
- The mechanism of "surrogate" memory cell formation during lymphopenia.
- Experimental modeling of processes using Freund's adjuvant.
- Mechanisms of polyclonal lymphocyte stimulation by superantigens.
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