Natural Tolerance (Autotolerance)
Natural immunological tolerance develops during ontogeny. It represents an absolute unresponsiveness of the immune system to self-antigens (autoantigens) of tissues and cells, reliably protecting the body from self-destruction. This crucial type of tolerance is implemented at two basic levels:
- Central tolerance (negative selection). At this stage, autoreactive lymphocyte clones capable of recognizing self-antigens undergo rigorous elimination. The destruction of these dangerous cells occurs in the primary lymphoid organs: T lymphocytes are selected in the thymus, and B lymphocytes in the bone marrow.
- Peripheral tolerance. Maintained by continuous tolerogenic signals from surrounding tissues. Specialized regulatory T cells ($T_{reg}$) play a key role in actively suppressing unwanted autoimmune reactions in the periphery.
Phenomenon of Immune-Privileged Organs
There are specific organs in the body whose antigens are normally sequestered behind tight barriers and do not contact circulating cells of the immune system. Due to this strict isolation, the autoimmune response against such tissues is entirely absent.
However, in the event of pathology—such as mechanical trauma or a prolonged inflammatory process—the natural tissue barrier can break down. Consequently, hidden antigens enter the systemic circulation, immediately provoking an aggressive autoimmune reaction against the self-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 bearing the corresponding Fas receptor (CD95) approaches them, the contact of these molecules triggers apoptosis (programmed cell death) of the lymphocyte itself, preventing an attack.
Artificial Tolerance and Historical Discovery
A state of tolerance can be induced artificially by administering a foreign antigen during the period of so-called 'immunological immaturity'—at the fetal stage or immediately after birth. As a result, the organism acquires a persistent unresponsiveness to the reintroduction of the same antigen in adult life.
Acquired immunological tolerance was first experimentally confirmed in animal experiments in 1953. For this outstanding discovery, scientists F. Macfarlane Burnet (Australia) and Peter Medawar (United Kingdom) were awarded the Nobel Prize in Physiology or Medicine in 1960.
Cellular Mechanisms of Tolerance Development
The formation of immunological tolerance at the cellular level occurs via two main pathways:
- Clonal deletion. This is the physical destruction of cells via apoptosis. Instead of activating upon antigen binding to cellular receptors, the lymphocyte dies. This mechanism forms the basis of central tolerance (in the thymus and bone marrow) and aims to completely eliminate autoreactive clones.
- Anergy (functional unresponsiveness). In this case, the lymphocyte clone survives physically, but enters a state of profound functional paralysis. Activation does not occur even upon successful antigen binding to the T-cell or B-cell receptor.
State of anergy can be triggered by several factors:
- Potent inhibitory signaling by $T_{reg}$ cells.
- Impaired or abnormal antigen presentation.
- Absence of required cytokines or costimulatory signals.
Molecular example of anergy: A T lymphocyte successfully recognizes an antigen, but the antigen-presenting cell (APC) lacks expression of the crucial costimulatory molecule B7 (CD80/CD86). Without this second signal, the cell becomes anergic.