Tolerance and Mechanisms of Tolerance

Tolerance

Tolerance is a state of specific immunological unresponsiveness to a certain antigen or epitope, although the immune system is otherwise functioning normally. The antigens that are present during embryonic life are usually considered self and do not stimulate an immunologic response, hence the host remains tol-erant to those antigens. The absence of an immune response in the fetus is due to the deletion of self-reactive T-cell precursors in the thymus. On the other hand, the antigens that are not pres-ent during the process of maturation are considered nonself and usually elicit an immunologic response against those antigens.

Mechanisms of Tolerance

Both T cells and B cells participate in tolerance, but it is T-cell tolerance that plays a major role.

◗ T-cell tolerance

T-cell tolerance is explained by theories of (a) clonal deletion, (b) clonal anergy, and (c) clonal ignorance.

       Clonal deletion: The theory of clonal deletion describedby Burnet, Fenner, and Medawar based on their studies on mice was the first theory of tolerance. The recent studies suggest that T lymphocytes acquire the ability to distin-guish self from nonself by the process of clonal deletion during the early phases of life. This process involves the killing of T cells (negative selection) that acts against anti-gens, mainly self-MHC (major histocompatibility com-plex) molecules present in the fetus during that time. The self-reactive cells die by apoptosis, a process of programed cell death.

       Clonal anergy: Clonal anergy is a process that leads to theincapacitation of the self-reactive T cells. These cells become incapable of mounting an immune response due to lack of proper costimulation and are called as anergic.

Clonal ignorance: This is the term used to describe self-reactive T cells that ignore self-antigens. These self-reactive T cells ignore self-antigens because the antigens are present in very small quantities. Also, these self-reactive cells are kept ignorant by physical separation from the target antigens, such as blood–brain barrier.

◗ B-cell tolerance

B cells become tolerant to self-antigens also by (a) clonal dele-tion of B-cell precursors while they are in the bone marrow and (b) clonal anergy of B cells in the periphery.