Immune tolerance

Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either 'natural' or 'self tolerance', where the body does not mount an immune response to self antigens, or 'induced tolerance', where tolerance to external antigens can be created by manipulating the immune system. It occurs in three forms: central tolerance, peripheral tolerance and acquired tolerance.

Genetic defects in these processes lead to autoimmunity, such as in Autoimmune polyendocrine syndrome type 1 (APS-1) and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX).

Central tolerance
Central tolerance occurs during lymphocyte development and operates in the thymus and bone marrow. Here, T and B lymphocytes that recognize self antigens are deleted before they develop into fully immunocompetent cells, preventing autoimmunity. This process is most active in fetal life, but continues throughout life as immature lymphocytes are generated.

In mammals the process occurs in the thymus (T cells) and bone marrow (B cells), when maturing lymphocytes are exposed to self antigens. Self antigens are present in both organs due to endogenous expression within the organ and importation of antigen due to circulation from peripheral sites. In the case of T cell central tolerance, additional sources of antigen are made available in the thymus by the action of the transcription factor AIRE.

Positive selection occurs first when naive T-cells are exposed to antigens in the thymus. T-cells which have receptors with sufficient affinity for self-MHC molecules are selected. Other cells that do not show sufficient affinity to self-antigens will undergo a deletion process known as death by neglect which involves apoptosis of the cells. The positive selection is a classical example of the importance of some degree of autorreactiveness. This does not occur in B-cells.

Negative selection of T-cells with a very high affinity of self-MHC molecules are induced to anergy, or lineage divergence to form T-regulatory cells.

Peripheral tolerance
Peripheral tolerance is immunological tolerance developed after T and B cells mature and enter the periphery.

Acquired tolerance
Acquired or induced tolerance refers to the immune system's adaptation to external antigens characterized by a specific non-reactivity of the lymphoid tissues to a given antigen that in other circumstances would likely induce cell-mediated or humoral immunity. One of the most important natural kinds of acquired tolerance is immune tolerance in pregnancy, where the fetus and the placenta must be tolerated by the maternal immune system.

In adults, tolerance may be induced by repeated administration of very large doses of antigen, or of small doses that are below the threshold required for stimulation of an immune response. Tolerance is most readily induced by soluble antigens administered either intravenously or sublingually, but specially orally. Immunosuppression also facilitates the induction of tolerance.

In clinical practice, acquired immunity is important in organ transplantation, when the body must be forced to accept an organ from another individual. The failure of the body to accept an organ is known as transplant rejection. To prevent rejection, a variety of medicines are used to produce induced tolerance.

One of the most important forms of acquired tolerance is oral tolerance. Oral tolerance, the specific suppression of cellular and/or humoral immune reactivity to an antigen by prior administration of the antigen by the oral route, probably evolved to prevent hypersensitivity reactions to food proteins and bacterial antigens present in the mucosal flora. It is of immense immunological importance, since it is a continuous natural immunologic event driven by exogenous antigen. Due to their privileged access to the internal milieu, antigens that continuously contact the mucosa represent a frontier between foreign and self components. Oral tolerance evolved to treat external agents that gain access to the body via a natural route as internal components without danger signals, which then become part of self. Failure of oral tolerance is attributed to the development and pathogenesis of several immunologically based diseases, including inflammatory bowel disease (Crohn's disease and ulcerative colitis).