How immunological tolerance was discovered
The possibility of artificial "tolerance" to foreign antigens was successfully proven in a classic experiment on mice. The essence of the procedure was administering donor cells to a recipient at a stage when their immune system had not yet matured.
- Induction: bone marrow and spleen cells from C57BL/6 mice (black) were injected in utero (in utero) or immediately after birth into A/J mice (white).
- Testing: when the white mice grew up (6–8 weeks), a skin graft from black mice was transplanted onto them.
- Result: the graft successfully engrafted. Meanwhile, intact (control) mice rejected such skin within 10–12 days. If skin from a third-party (unrelated) line was transplanted to tolerant mice, it was rejected within the normal timeframe, proving the specificity of the state.
An alternative model was demonstrated by M. Hašek: he artificially connected the circulatory systems of chicken embryos (embryonic parabiosis), and the hatched chicks subsequently did not reject each other's skin grafts.
Conditions and methods of induction
The state of the immune system is critically important for the development of tolerance. A "window of opportunity" exists until the completion of its maturation (the process of "peripheralization" — colonization of secondary lymphoid organs by T cells and reduction of their dependence on the thymus). In adult animals, induction is possible only after preliminary destruction of their own lymphoid tissue (by irradiation or cytostatics).
Tolerance can be induced via two main pathways:
- Cellular material. Optimally — dividing blood and immune system cells. They are capable of surviving long-term in the body and actively express MHC molecules. The main requirement is the establishment of prolonged chimerism (presence of donor cells in the body) and the preservation of donor dendritic cells.
- Soluble antigens. Serum proteins cleared of aggregates are used. They do not activate macrophages, preventing them from releasing cytokines required for the maturation of immunogenic dendritic cells (DC1). Consequently, the antigen is captured by tolerogenic DC2 cells, which induce anergy (unresponsiveness) in T lymphocytes. This type of tolerance is temporary.
Autotolerance and Burnet's theory
P. Ehrlich was the first to propose the concept of horror autotoxicus ("fear of self-poisoning") — the impossibility of immune aggression against one's own tissues. In the 1950s, F.M. Burnet proposed the clonal selection theory explaining this phenomenon:
- Lymphocytes carry receptors of only a single specificity on their surface (clonal distribution).
- The reaction depends on the cell's maturity. Contact of an immature lymphocyte with an antigen leads to its death (this is how clones reacting to "self" are eliminated). Contact of a mature lymphocyte with an antigen causes activation (this is how the response to "non-self" develops).
It was from this theory that the idea arose: if a foreign antigen is administered before the onset of immunological maturity, tolerance to it will be formed (which was proven by experiments on mice).
Mechanisms of autotolerance
The absence of a response to own tissues is the result of events occurring during ontogenesis (most often before or immediately after birth). Modern science distinguishes active and passive mechanisms of autotolerance.
Active mechanisms:
- Elimination of autospecific clones (death via apoptosis) — the central mechanism.
- Editing of receptor genes that recognize own tissues.
- Induction of anergy (a state of profound unresponsiveness) in the periphery.
- Suppression of the response by specialized regulatory cells (dominant mechanism).
Passive mechanism:
- Ignorance. The immune system "does not notice" its own antigens due to their minuscule concentration or reliable isolation by anatomical barriers.v
Briefly: answers to topical questions
Which immunoprivileged organs are protected from the immune system by the passive mechanism of ignorance?
Passive ignorance of autoantigens is caused by their excessively low concentration or isolation from the immune system by anatomical barriers. Immunologically privileged organs include the internal chambers of the eye, the brain (CNS), testes, ovaries, hair follicles, and the pregnant uterus. Sources do not indicate that each of these organs is protected by a specific barrier listed in the original answer.
Which surface markers are expressed by regulatory T cells that provide dominant autotolerance?
Regulatory T cells providing dominant autotolerance express a specific set of membrane markers on their surface. These include:
- CD4 — the main membrane marker.
- CD25 (CD25hi) — a marker expressed at high density.
- CTLA-4 — a costimulatory molecule with suppressive effect.
- PD-1 — a receptor transmitting suppressive signals.
- GITR is an additional surface marker.
- TCR (αβTCR) — the antigen-recognizing T-cell receptor.
The intracellular differentiation factor of these cells is the FOXP3 protein.
What molecular mechanisms underlie the induction of T-lymphocyte anergy in the periphery?
The induction of T-lymphocyte anergy in the periphery is based on the absence of one of the components of the costimulatory system — B7 molecules on antigen-presenting cells or CD28 on T cells — at the moment of antigen recognition. This leads to the weakening of intracellular signal transmission and the following changes:
- disruption of the formation of the AP-1 transcription factor (c-Fos/c-Jun dimer) is most severely affected;
- expression of the IL-2 gene is reduced to the greatest extent;
- the Cbl-b factor, which acts as an activation inhibitor, participates in the induction of anergy.
The usual outcome of anergy is accelerated cell death via apoptosis.
Class and exam questions
What is the difference between immunological tolerance and immunosuppression?
Immunosuppression is a general decrease in the immune response to any stimuli. Tolerance is a strictly specific unresponsiveness to one particular antigen while maintaining a normal reaction to all others.
Can the state of tolerance be reversed?
Yes. Spontaneously, this occurs when the antigen is removed from the body (e.g., upon the disappearance of chimerism). Artificially, it can be broken by administering lymphocytes from non-tolerant animals or by immunizing with an antigen that cross-reacts with the original one.
Why are aggregate-free forms specifically important in protein-based tolerance induction?
Aggregate-free antigens do not activate macrophages, so proinflammatory cytokines are not produced. Without them, tolerogenic dendritic cells (DC2) are formed, which induce anergy of T lymphocytes rather than their activation.
What else to study on this topic
- The role of dendritic cells (DC1 and DC2) in choosing the pathway of the immune response
- Negative selection of T lymphocytes in the thymus
- Mechanisms of formation and maintenance of chimerism
- Differences between high-dose and low-dose tolerance
- Application of tolerance principles in bone marrow transplantation (GvHD prophylaxis)
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Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"
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