Immunological tolerance

Natural tolerance (autotolerance)

Natural immunological tolerance is formed during the individual development of the organism (ontogenesis). It represents an absolute unresponsiveness of the immune system to its own antigens (autoantigens) of tissues and cells, reliably protecting the organism from self-destruction. This crucial type of tolerance is implemented at two basic levels:

• Central tolerance (negative selection). At this stage, a strict weeding out of autoreactive lymphocyte clones capable of recognizing self-antigens takes place. The destruction of such dangerous cells occurs in the central organs of the immune system: T lymphocytes undergo selection in the thymus, and B lymphocytes in the bone marrow.
• Peripheral tolerance. It is ensured through constant tolerogenic signals from surrounding tissues. Specialized regulatory T lymphocytes ($T_{reg}$) play a key role in the active suppression of unwanted autoimmune reactions in the periphery.

The phenomenon of immune-privileged organs

There are specific organs in the body whose antigens are normally reliably isolated by tight barriers and do not contact circulating cells of the immune system at all. Due to this strict isolation, the autoimmune response to such tissues is completely absent.

However, when pathology develops—for example, as a result of mechanical trauma or a prolonged infectious process—the natural tissue barrier can be destroyed. As a result, hidden antigens enter the systemic bloodstream, which immediately triggers an aggressive autoimmune reaction against the own tissues of the damaged organ.

To protect against such a scenario, a special mechanism based on the Fas system is provided. Cells of immune-privileged organs express a special Fas ligand (FasL) on their surface. If a T lymphocyte with the corresponding Fas receptor (CD95) approaches them, the contact of these molecules triggers the process of apoptosis (programmed death) of the lymphocyte itself, preventing the attack.

Artificial tolerance and historical discovery

A state of tolerance can be induced artificially if a foreign antigen is administered during the period of so-called "immunological immaturity"—at the stage of intrauterine fetal development or immediately after birth. As a result, the organism acquires a persistent unresponsiveness to the repeated administration of this same antigen in adulthood.

Acquired immunological tolerance was first experimentally confirmed in animal experiments in 1953. For this outstanding discovery, scientists F. Burnet (Australia) and P. Medawar (UK) were awarded the Nobel Prize in Physiology and Medicine in 1960.

Cellular mechanisms of tolerance development

The formation of immunological tolerance at the cellular level is implemented through two main directions:

1. Deletion (removal) of a lymphocyte clone. This is the physical destruction of cells via apoptosis. Instead of being activated when the antigen binds to cellular receptors, the lymphocyte dies. This mechanism forms the basis of central tolerance (in the thymus and bone marrow) and aims at the complete elimination of autoreactive clones.
2. Anergy (functional unresponsiveness). In this case, the lymphocyte clone is physically preserved, but falls into a state of profound functional paralysis. Activation does not occur even upon successful binding of the antigen to the T- or B-cell receptor.

The development of a state of anergy can be triggered by several factors:

• Powerful inhibitory effects from $T_{reg}$ lymphocytes.
• Disruption of the normal antigen presentation process.
• Absence of necessary cytokines or co-stimulatory signals.

Molecular example of anergy: A T lymphocyte successfully recognizes an antigen, however, the expression of the crucial co-stimulatory molecule B7 (CD80/CD86) is absent on the antigen-presenting cell (APC). Without this second signal, the cell becomes anergic.

Class and exam questions

What else to study on this topic

• Maturation processes and mechanisms of negative selection of T lymphocytes in the thymus.
• Origin, phenotype, and mechanisms of action of regulatory T lymphocytes ($T_{reg}$).
• Molecular bases of co-stimulation: the role of the B7 family of molecules (CD80/CD86) and their receptors.
• Anatomical and histological features of the structure of blood-tissue barriers in immune-privileged organs.
• Pathogenesis of autoimmune diseases arising from the breakdown of natural tolerance mechanisms.

Other topics in "Immunology"

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