Immune tolerance

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens (see Immune response). Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar. Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens (see Immune response). Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar. Immune tolerance is important for normal physiology. Central tolerance is the main way the immune system learns to discriminate self from non-self. Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens, gut microbes, etc.). Deficits in central or peripheral tolerance also cause autoimmune disease, resulting in syndromes such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, autoimmune polyendocrine syndrome type 1 (APS-1), and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), and potentially contribute to asthma, allergy, and inflammatory bowel disease. And immune tolerance in pregnancy is what allows a mother animal to gestate a genetically distinct offspring with an alloimmune response muted enough to prevent miscarriage. Tolerance, however, also has its negative tradeoffs. It allows for some pathogenic microbes to successfully infect a host and avoid elimination. In addition, inducing peripheral tolerance in the local microenvironment is a common survival strategy for a number of tumors that prevents their elimination by the host immune system. The phenomenon of immune tolerance was first described by Ray D. Owens in 1945, who noted that dizygotic twin cattle sharing a common placenta also shared a stable mixture of each other's red blood cells (though not necessarily 50/50), and retained that mixture throughout life. Although Owens did not use the term immune tolerance, his study showed the body could be tolerant of these foreign tissues. This observation was experimentally validated by Rupert E. Billingham and Peter Medawar in 1953, who showed by injecting foreign cells into fetal or neonatal mice, they could become accepting of future grafts from the same foreign donor. However, they were not thinking of the immunological consequences of their work at the time: as Medawar explains: However, these discoveries, and the host of allograft experiments and observations of twin chimerism they inspired, were seminal for the theories of immune tolerance formulated by Sir Frank McFarlane Burnet and Frank Fenner, who were the first to propose the deletion of self-reactive lymphocytes to establish tolerance, now termed clonal deletion. Burnet and Medawar were ultimately credited for 'the discovery of acquired immune tolerance' and shared the Nobel Prize in Physiology or Medicine in 1960. In their Nobel Lecture, Medawar and Burnet define immune tolerance as 'a state of indifference or non-reactivity towards a substance that would normally be expected to excite an immunological response.' Other more recent definitions have remained more or less the same. The 8th edition of Janeway's Immunobiology defines tolerance as 'immunologically unresponsive…to another's tissues.'. Immune tolerance encompasses the range of physiological mechanisms by which the body reduces or eliminates an immune response to particular agents. It is used to describe the phenomenon underlying discrimination of self from non-self, suppressing allergic responses, allowing chronic infection instead of rejection and elimination, and preventing attack of fetuses by the maternal immune system. Typically, a change in the host, not the antigen, is implied. Though some pathogens can evolve to become less virulent in host-pathogen coevolution, tolerance does not refer to the change in the pathogen, but can be used to describe the changes in host physiology. Immune tolerance also does not usually refer to artificially induced immunosuppression by corticosteroids, lymphotoxic chemotherapy agents, sublethal irradiation, etc. Nor does it refer to other types of non-reactivity such as immunological paralysis. In the latter two cases, the host's physiology is handicapped but not fundamentally changed. Immune tolerance is formally differentiated into central or peripheral; however, alternative terms such as 'natural' or 'acquired' tolerance have at times been used to refer to establishment of tolerance by physiological means or by artificial, experimental, or pharmacological means. These two methods of categorization are sometimes confused, but are not equivalent—central or peripheral tolerance may be present naturally or induced experimentally. This difference is important to keep in mind. Central tolerance refers to the tolerance established by deleting autoreactive lymphocyte clones before they develop into fully immunocompetent cells. It occurs during lymphocyte development in the thymus and bone marrow for T and B lymphocytes, respectively. In these tissues, maturing lymphocytes are exposed to self-antigens presented by medullary thymic epithelial cells and thymic dendritic cells, or bone marrow cells. Self-antigens are present due to endogenous expression, importation of antigen from peripheral sites via circulating blood, and in the case of thymic stromal cells, expression of proteins of other non-thymic tissues by the action of the transcription factor AIRE.