Immune or immunological tolerance is the process by which the immune system does not attack an antigen. An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor An antigen (from antibody-generating) or immunogen is a substance that prompts the generation of Antibodies and can cause an immune response It occurs in three forms: central tolerance, peripheral tolerance and acquired tolerance.
Genetic defects in these processes lead to autoimmunity, such as in the human syndromes APS-1 and IPEX. In Medicine, autoimmune polyendocrine syndromes are a heterogeneous group of Rare diseases characterised by Autoimmune activity against more than one
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Central tolerance
Central tolerance occurs during lymphocyte development and operates in the thymus and bone marrow. Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self 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)[1][2] and bone marrow (B cells), when maturing lymphocytes are exposed to self antigens. In Human anatomy, the thymus is an organ located in the upper Anterior portion of the chest cavity just behind the Sternum. Bone marrow is the flexible tissue found in the hollow interior of Bones In adults marrow in large bones produces new Blood cells It constitutes 4% of A lymphocyte is a type of White blood cell in the Vertebrate Immune system. 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. The Autoimmune Regulator abbreviated AIRE, is a human gene which is expressed in the Thymus.
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. Others that do no undergo death by neglect involving apoptosis. 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. The cells are controlled through peripheral tolerance mechanisms. These include the suppression of autoreactive cells by 'regulatory' T cells and the generation of hyporesponsiveness (anergy) in lymphocytes which encounter antigen in the absence of the co-stimulatory signals that accompany inflammation.
Ignorance
Potentially self-reactive T-cells are not activated at immunoprivileged sites, where antigens are expressed in non-surveillanced areas. This can occur in the testes, for instance.
Some antigens are at too low a concentration to cause an immune response - a subthreshold stimulation will lead to apoptosis in a T cell.
Split Tolerance
As many pathways of immunity are interdependent, they do not all need to be tolerised. For example, tolerised T cells will not activate autoreactive B cells. Without this CD4+ T-cell help the B cells will not be activated.
Induced anergy
T-cells can be made non-responsive to antigens presented if the T-cell engages an MHC molecule without co-stimulatory molecules. This will occur if there is no acute inflammation, leading to no co-stimulator upregulation due to the low concentration of cytokines.
Suppression
Auto-reactive T-cells are prevented from reacting due to the presence of T-reg cells. Experimentally, removal of T-reg cells leads to autoimmune attack.
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. An antigen (from antibody-generating) or immunogen is a substance that prompts the generation of Antibodies and can cause an immune response One of the most important natural kinds of acquired tolerance occurs during pregnancy, where the fetus and the placenta must be tolerated by the maternal immune system. An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor One model for the induction of tolerance during the very early stages of pregnancy is the eutherian fetoembryonic defense system (eu-FEDS) hypothesis. The Eutherian Fetoembryonic Defense System (eu-FEDS is a hypothetical model describing a method by which immune systems are capable of recognizing additional states of relatedness [3] However, another model suggests that the induction of tolerance primarily requires the participation of regulatory T cells[4].
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. 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. Transplant rejection occurs when a transplanted organ or tissue fails to be accepted by the body of the transplant recipient 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. [5] 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. [6] 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).
References
- ^ Sprent J, Kishimoto H (2001). "The thymus and central tolerance". Philos Trans R Soc Lond B Biol Sci 356 (1409): 609-16. PMID 11375064.
- ^ Hogquist K, Baldwin T, Jameson S (2005). "Central tolerance: learning self-control in the thymus". Nat Rev Immunol 5 (10): 772-82. PMID 16200080.
- ^ Clark, Clark G. F. , Dell A. , Morris H. R. , Patankar M. S. , and Easton R. L. (2001) The species recognition system: a new corollary to the human fetoembryonic defense system hypothesis. Cells Tissues Organs 168, 113-21 PMID 11114593
- ^ Trowsdale J, and Betz AG. 2006. Mother's little helpers: mechanisms of maternal-fetal tolerance. Nature Reviews Immunology 7:241-6 PMID 16482172
- ^ Lloyd Mayer, Kirk Sperber, Lisa Chan, Joseph Child, Lisa Toy (2001) Oral tolerance to protein antigens Allergy 56 (s67), 12–15. doi:10. 1111/j. 1398-9995. 2001. 00904. x
- ^ Howard L. Wiener. "Oral tolerance, an active immunologic process mediated by multiple mechanisms. " (October 2000) Journal of Clinical Investigation. Volume 106, Number 8, pages 935-937
See also
External links
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