Immunological Tolerance: Mechanisms

AbstractImmunological tolerance refers to a reduction or complete inhibition of the ability of an individual to mount a specific immune response upon immunisation. Several mechanisms are involved in induction and maintenance of tolerance, including clonal deletion, clonal anergy, receptor editing, receptor down‐modulation and lymphocyte sequestration. The number of antigen presenting cells, the number and activity of regulatory T cells and regulatory B cells, the nature and amount of antigenic peptides generated and the presence of co‐stimulatory signals in a particular tissue are also important. Depending on the site and the level of antigen expression, different states of peripheral B‐cell and T‐cell tolerance can be reached. In certain situations, they could act in an additive manner. In humans, induction of immunological tolerance is an important issue in both transplantation biology and autoimmune diseases, and present research aims at designing novel strategies to induce specific tolerance.Key Concepts:Tolerance induction is easier in animals with an immature immune system or with a mature immune system that has been compromised by irradiation, drugs or thoracic drug drainage.In general, when a given antigen is used over a wide range of concentrations, intermediate doses induce immunity, and low and high doses induce tolerance.The introduction route is a key variable in tolerance induction, particularly in adult animals, presumably by determining the accessibility of the antigen to professional antigen presenting cells.The tolerant state is not absolute and tolerance is rarely complete. With time, it gradually wanes and eventually disappears, but it can be deliberately terminated by several means.Persistence of the tolerogen in the periphery and its accessibility to the immune system are generally required to maintain tolerance, which continuously inactivates newly emerging T and B cells that develop in lymphoid organs.T lymphocytes specific for self‐peptides bound to major histocompatibility complex peptides are eliminated by clonal deletion, a process known as negative selection. Similarly, self‐reactive B cells are purged from the functional repertoire during the transition from the pre‐B to mature B‐cell stage in the bone marrow.Anergy is a functionally silent state induced in B cells and T cells, allowing them to persist functionally inactivated in tolerant animals.Receptor editing is a form of receptor processing that markedly alters the variable region genes expressed by B cells and, consequently, changes the specificity of the surface immunoglobulin and maintains B‐cell tolerance to self.Two functional lymphocyte subsets, called regulatory T cells and regulatory B cells, have recently been found to contribute to the maintenance of the fine equilibrium required for immune tolerance.In humans, induction of immunological tolerance in the adult is an important issue in both transplantation biology and autoimmune diseases, and present research aims at designing novel strategies to induce specific tolerance.