Immune tolerance
Encyclopedia
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', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which 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).
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.
is immunological tolerance developed after T and B cells mature and enter the periphery.
, 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 sublingual
ly, 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
).
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
does not attack an antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
. It can be either 'natural' or 'self tolerance', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which 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
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
, such as in Autoimmune polyendocrine syndrome type 1 (APS-1) and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX).
Central tolerance
Central toleranceCentral tolerance
Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self. The concept of central tolerance was proposed in 1959 by Joshua Lederberg, as part of his general theory of immunity and tolerance, and is often mistakenly attributed to MacFarlane...
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
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
(T cells) and bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
(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
Autoimmune regulator
The autoimmune regulator is a protein that in humans is encoded by the AIRE gene. AIRE is a transcription factor expressed in the medulla of the thymus and controls the mechanism that prevents the immune system from attacking the body itself....
.
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 tolerancePeripheral tolerance
Peripheral tolerance is immunological tolerance developed after T and B cells mature and enter the periphery. These include the suppression of autoreactive cells by 'regulatory' T cells and the generation of hyporesponsiveness in lymphocytes which encounter antigen in the absence of the...
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 pregnancyImmune tolerance in pregnancy
Immune tolerance in pregnancy or gestational/maternal immune tolerance is the absence of a maternal immune response against the fetus and placenta, which thus may be viewed as unusually successful allografts, since they genetically differ from the mother. In the same way, many cases of spontaneous...
, where the fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
and the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
must be tolerated by the maternal immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
.
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 sublingual
Sublingual
Sublingual, literally 'under the tongue', from Latin, refers to the pharmacological route of administration by which drugs diffuse into the blood through tissues under the tongue...
ly, but specially orally. Immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
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
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
. 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
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
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
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
(Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
and ulcerative colitis
Ulcerative colitis
Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
).