Central tolerance
Encyclopedia
Central tolerance is the mechanism by which newly developing T cell
s and B cell
s 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 Burnet. Lederberg hypothesized that it is the age of the lymphocyte that defines whether an antigen that is encountered will induce tolerance, with immature lymphocytes being tolerance sensitive. Lederberg's theory that self-tolerance is 'learned' during lymphocyte development was a major conceptual contribution to immunology, and it was experimentally substantiated in the late 1980s when tools to analyze lymphocyte development became available. Central tolerance is distinct from periphery tolerance in that it occurs while cells are still present in the primary lymphoid organs (thymus and bone-marrow), prior to export into the periphery, while peripheral tolerance is generated after the cells reach the periphery. Regulatory T cells can be considered both central tolerance and peripheral tolerance mechanisms, as they can be generated from self(or foreign)-reactive T cells in the thymus during T cell differentiation, but they exert their immune suppression in the periphery on other self(or foreign)-reactive T cells.
and B cell receptor genes contain multiple gene segments (the V, D, J - segments) which need to be physically rearranged together by somatic gene rearrangement - called V(D)J-Recombination
- to make a functional gene. At the site of segment recombination additional bases will be inserted which results in additional Diversity - called the junctional Diversity - and gives rise to the complementary determining regions (CDR)
. This random Generation of Diversity combinations and base insertions allows the creation of T cell receptor
s and antibodies against antigens which the host has never encountered during its evolutionary history, and is thus a powerful defense against rapidly evolving pathogens. Conversely, the random nature of the Generation of Diversity creates, by chance, a population of T cells and B cells that are self-reactive (ie, recognize an antigen which is a constituent component of the host).
In mammals the process occurs in the thymus
(T cells) and bone marrow
(B cells). These are the two primary lymphoid organs where T cells and B cells mature. During the maturation phases of both T cells and B cells the cells are sensitive to antigen-recognition. Unlike mature peripheral lymphocytes, which become activated upon encountering their specific antigen, the immature lymphocytes respond to stimulation with antigen by undergoing a rewiring of the cellular processes. The response to antigen at this stage depends on the properties of the antigen, the cell type and the developmental stage, and can lead to the cell becoming non-responsive (anergic), undergoing directed suicide (negative selection
), altering its antigen receptor (receptor editing) or entering a regulatory lineage.
As this tolerance is dependent on encountering the self-antigens during maturation, lymphocytes can only develop central tolerance towards those antigens present in primary lymphoid organs. In the case of B cells in the bone marrow
, this is limited to ubiquitous and bone-marrow specific antigens present in the bone-marrow and additional antigens imported by circulation (either as raw antigens or presented by circulating dendritic cells). The thymus has an additional source of antigen through the action of the transcription factor AIRE
, which allows the expression of organ-specific antigens such as insulin
in the thymus.
s in the bone marrow
is critical to the development of immunological tolerance
to self. This process produces a population of B cells that do not recognize self-antigens but may recognize antigen
s derived from pathogen
s (non-self).
Immature B cells expressing only surface IgM
molecules undergo negative selection by recognizing self-molecules present in the bone marrow. This antigen induced loss of cells from the B cell repertoire is known as clonal deletion
. B cells may encounter two types of antigen, multivalent cell surface antigens or low valence soluble antigens:
Even if mature self-reacting B cells were to survive intact, they would very rarely be activated. This is because B cells need co-stimulatory signals from T cells as well as the presence of its recognized antigen to proliferate and produce antibodies
(Peripheral tolerance
). If mature peripheral B cells encounter multivalent antigen (eg cell surfaces) they are eliminated via apoptosis
. If mature B cells recognize soluble antigen in the periphery in the absence of T cell help, they lose surface IgM
receptors and become anergic
.
s are selected for survival much more rigorously than B cells. They undergo both positive and negative selection to produce T cells that recognize self- major histocompatibility complex
(MHC) molecules but do not recognize self-peptides. T cell tolerance is induced in the thymus
Positive selection occurs in the thymic cortex. This process is primarily mediated by thymic epithelial cells, which are rich in surface MHC
molecules. If a maturing T cell is able to bind to a surface MHC
molecule in the thymus it is saved from programmed cell death; those cells failing to recognize MHC on thymic epithelial cells die. Thus, positive selection ensures that T cells only recognize antigen in association with MHC
. This is important because one of the primary functions of T cells is to identify and respond to infected host cells as opposed to extracellular pathogen
s. The process of positive selection also determines whether a T cell ultimately becomes a CD4+ cell or a CD8+ cell
: prior to positive selection, all thymocyte
s are double positive (CD4+CD8+) i.e. bear both co-receptor
s. During positive selection they are transformed into either CD4+CD8- or CD8+CD4- T cells depending on whether they recognize MHC II or MHC I, respectively.
T cells may also undergo negative selection in a process analogous to the induction of self-tolerance in B cells, this occurs in the cortex, at the cortico-medullary junction, and the medulla (mediated in the medulla predominately by medulary thymic epithelial cells (mTECs) and dendritic cell
s). mTEC display "self" antigens to developing T-cells and signal those "self-reactive" T-cells to die via programed cell death (apoptosis) and thereby deleted from the T cell repertoire. This process is highly dependent on the ectopic expression of tissue specific antigens (TSAs) which is regulated by AIRE
(the Autoimmune Regulator).
This clonal deletion of T cells in the thymus cannot eliminate every potentially self-reactive T cell; T cells that recognize proteins only found at other sites in the body or only at certain times of development (eg after puberty) must be inactivated in the periphery
. In addition, many self reactive T cells may not have sufficient affinity (binding strength) for the self antigen to be deleted in the thymus.
Regulatory T cell
s are another group of T cells maturing in the thymus
, they are also involved with immune regulation but are not directly involved in central tolerance.
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s and B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s are rendered non-reactive to self. The concept of central tolerance was proposed in 1959 by Joshua Lederberg
Joshua Lederberg
Joshua Lederberg ForMemRS was an American molecular biologist known for his work in microbial genetics, artificial intelligence, and the United States space program. He was just 33 years old when he won the 1958 Nobel Prize in Physiology or Medicine for discovering that bacteria can mate and...
, as part of his general theory of immunity and tolerance, and is often mistakenly attributed to MacFarlane Burnet. Lederberg hypothesized that it is the age of the lymphocyte that defines whether an antigen that is encountered will induce tolerance, with immature lymphocytes being tolerance sensitive. Lederberg's theory that self-tolerance is 'learned' during lymphocyte development was a major conceptual contribution to immunology, and it was experimentally substantiated in the late 1980s when tools to analyze lymphocyte development became available. Central tolerance is distinct from periphery tolerance in that it occurs while cells are still present in the primary lymphoid organs (thymus and bone-marrow), prior to export into the periphery, while peripheral tolerance is generated after the cells reach the periphery. Regulatory T cells can be considered both central tolerance and peripheral tolerance mechanisms, as they can be generated from self(or foreign)-reactive T cells in the thymus during T cell differentiation, but they exert their immune suppression in the periphery on other self(or foreign)-reactive T cells.
Requirement for central tolerance
Central tolerance for T cells is induced in the thymus, where developing thymocytes (T cells in thymus) that recognize self-peptide–MHC complexes with too high affinity are deleted. For B cells the central tolerance is executed in the bone marrow (the B cell receptor the membrane bound version of antibodies). First all T and B cell precursors have an identical genome, but then the variety of receptors is generated by the combination of 3 mechanisms. The first mechanism is the combination of the alpha and beta-chain for the TCR or of the heavy and light chain for the BCR each encoded by 2 different gene copies - the not used copy gets inactivated.The T cell receptorT cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
and B cell receptor genes contain multiple gene segments (the V, D, J - segments) which need to be physically rearranged together by somatic gene rearrangement - called V(D)J-Recombination
V(D)J recombination
VJ recombination, also known as somatic recombination, is a mechanism of genetic recombination in the early stages of immunoglobulin and T cell receptors production of the immune system...
- to make a functional gene. At the site of segment recombination additional bases will be inserted which results in additional Diversity - called the junctional Diversity - and gives rise to the complementary determining regions (CDR)
Complementarity determining region
Complementarity determining regions are regions within antibodies or T cell receptors where these proteins complement an antigen's shape. Thus, CDRs determine the protein's affinity and specificity for specific antigens...
. This random Generation of Diversity combinations and base insertions allows the creation of T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
s and antibodies against antigens which the host has never encountered during its evolutionary history, and is thus a powerful defense against rapidly evolving pathogens. Conversely, the random nature of the Generation of Diversity creates, by chance, a population of T cells and B cells that are self-reactive (ie, recognize an antigen which is a constituent component of the host).
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). These are the two primary lymphoid organs where T cells and B cells mature. During the maturation phases of both T cells and B cells the cells are sensitive to antigen-recognition. Unlike mature peripheral lymphocytes, which become activated upon encountering their specific antigen, the immature lymphocytes respond to stimulation with antigen by undergoing a rewiring of the cellular processes. The response to antigen at this stage depends on the properties of the antigen, the cell type and the developmental stage, and can lead to the cell becoming non-responsive (anergic), undergoing directed suicide (negative selection
Negative selection
Negative selection may refer to:*Negative selection , in natural selection it refers to the selective removal of rare alleles that are deleterious...
), altering its antigen receptor (receptor editing) or entering a regulatory lineage.
As this tolerance is dependent on encountering the self-antigens during maturation, lymphocytes can only develop central tolerance towards those antigens present in primary lymphoid organs. In the case of B cells in the 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...
, this is limited to ubiquitous and bone-marrow specific antigens present in the bone-marrow and additional antigens imported by circulation (either as raw antigens or presented by circulating dendritic cells). The thymus has an additional source of antigen through 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....
, which allows the expression of organ-specific antigens such as insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
in the thymus.
B cell tolerance
The recognition of antigens by the immature B cellB cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s in the 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...
is critical to the development of immunological tolerance
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', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which tolerance to external antigens can...
to self. This process produces a population of B cells that do not recognize self-antigens but may recognize 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...
s derived from pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s (non-self).
Immature B cells expressing only surface IgM
Immunoglobulin M
Immunoglobulin M, or IgM for short, is a basic antibody that is produced by B cells. It is the primary antibody against A and B antigens on red blood cells. IgM is by far the physically largest antibody in the human circulatory system...
molecules undergo negative selection by recognizing self-molecules present in the bone marrow. This antigen induced loss of cells from the B cell repertoire is known as clonal deletion
Clonal deletion
Clonal deletion is a process by which B cells and T cells are deactivated after they have expressed receptors for self-antigens and before they develop into fully immunocompetent lymphocytes.It is one method of immune tolerance....
. B cells may encounter two types of antigen, multivalent cell surface antigens or low valence soluble antigens:
- When immature B cells express surface IgMImmunoglobulin MImmunoglobulin M, or IgM for short, is a basic antibody that is produced by B cells. It is the primary antibody against A and B antigens on red blood cells. IgM is by far the physically largest antibody in the human circulatory system...
that recognizes ubiquitous self-cell-surface (i.e. multivalentPolyvalentIn chemistry, polyvalence or multivalence refers to species that are not restricted to a distinct number of valence bonds....
) antigens (such as those of the MHCMajor histocompatibility complexMajor histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
) they are eliminated by a process known as clonal deletion. These B cells are believed to undergo programmed cell death or apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. However, there is an interval before apoptosis during which the self-reactive B cell may be rescued by further gene rearrangements (receptor editingReceptor editingReceptor editing is a process that occurs during the maturation of B cells, which are part of the adaptive immune system. This process has the aim to change the specificity of the antigen receptor of immature B-cells, in order to rescue them from programmed cell death, called apoptosis.During...
) that may replace the self-reactive receptor with a new receptor, which is not auto-reactive .
- Immature B cells that bind soluble self-antigens (i.e. low valence) do not die but their ability to express IgMImmunoglobulin MImmunoglobulin M, or IgM for short, is a basic antibody that is produced by B cells. It is the primary antibody against A and B antigens on red blood cells. IgM is by far the physically largest antibody in the human circulatory system...
on their surfaces is lost. Thus, they migrate to the periphery only expressing IgDImmunoglobulin DImmunoglobulin D is an antibody isotype that makes up about 1% of proteins in the plasma membranes of immature B-lymphocytes where it is usually coexpressed with another cell surface antibody called IgM. IgD is also produced in a secreted form that is found in very small amounts in blood serum...
and are unable to respond to antigen. These B cells are said to be anergicAnergyAnergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal...
. Only B cells that do not encounter antigen whilst they are maturing in the bone marrow can be activated after they enter the periphery. These cells bear both IgMImmunoglobulin MImmunoglobulin M, or IgM for short, is a basic antibody that is produced by B cells. It is the primary antibody against A and B antigens on red blood cells. IgM is by far the physically largest antibody in the human circulatory system...
and IgDImmunoglobulin DImmunoglobulin D is an antibody isotype that makes up about 1% of proteins in the plasma membranes of immature B-lymphocytes where it is usually coexpressed with another cell surface antibody called IgM. IgD is also produced in a secreted form that is found in very small amounts in blood serum...
receptors and constitute the repertoire of B cells that recognize foreign antigen.
Even if mature self-reacting B cells were to survive intact, they would very rarely be activated. This is because B cells need co-stimulatory signals from T cells as well as the presence of its recognized antigen to proliferate and produce antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
(Peripheral tolerance
Peripheral 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...
). If mature peripheral B cells encounter multivalent antigen (eg cell surfaces) they are eliminated via apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. If mature B cells recognize soluble antigen in the periphery in the absence of T cell help, they lose surface IgM
Immunoglobulin M
Immunoglobulin M, or IgM for short, is a basic antibody that is produced by B cells. It is the primary antibody against A and B antigens on red blood cells. IgM is by far the physically largest antibody in the human circulatory system...
receptors and become anergic
Anergy
Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal...
.
T cell tolerance
T cellT cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s are selected for survival much more rigorously than B cells. They undergo both positive and negative selection to produce T cells that recognize self- major histocompatibility complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
(MHC) molecules but do not recognize self-peptides. T cell tolerance is induced 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....
Positive selection occurs in the thymic cortex. This process is primarily mediated by thymic epithelial cells, which are rich in surface MHC
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
molecules. If a maturing T cell is able to bind to a surface MHC
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
molecule in the thymus it is saved from programmed cell death; those cells failing to recognize MHC on thymic epithelial cells die. Thus, positive selection ensures that T cells only recognize antigen in association with MHC
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
. This is important because one of the primary functions of T cells is to identify and respond to infected host cells as opposed to extracellular pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s. The process of positive selection also determines whether a T cell ultimately becomes a CD4+ cell or a CD8+ cell
CD8+ cell
CD8+ cell commonly refers to a T cell that expresses CD8 on its cells surface. Usually the terms CD8+, CD8+ cell, CD8 T cell, and cytotoxic T cell are interchangeable....
: prior to positive selection, all thymocyte
Thymocyte
Thymocytes are hematopoietic progenitor cells present in the thymus. Thymopoiesis is the process in the thymus by which thymocytes differentiate into mature T lymphocytes. The primary function of thymocytes is the generation of T lymphocytes . The thymus provides an inductive environment, which...
s are double positive (CD4+CD8+) i.e. bear both co-receptor
Co-receptor
A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.-Co-receptor Properties:...
s. During positive selection they are transformed into either CD4+CD8- or CD8+CD4- T cells depending on whether they recognize MHC II or MHC I, respectively.
T cells may also undergo negative selection in a process analogous to the induction of self-tolerance in B cells, this occurs in the cortex, at the cortico-medullary junction, and the medulla (mediated in the medulla predominately by medulary thymic epithelial cells (mTECs) and dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s). mTEC display "self" antigens to developing T-cells and signal those "self-reactive" T-cells to die via programed cell death (apoptosis) and thereby deleted from the T cell repertoire. This process is highly dependent on the ectopic expression of tissue specific antigens (TSAs) which is regulated by AIRE
Aire
- Rivers :*River Aire, a river in Yorkshire, England*Aire , a river in the Ardennes département, northern France*Aire River , a river in the Canton of Geneva, in Switzerland*Aire River , a river in Australia- Towns :...
(the Autoimmune Regulator).
This clonal deletion of T cells in the thymus cannot eliminate every potentially self-reactive T cell; T cells that recognize proteins only found at other sites in the body or only at certain times of development (eg after puberty) must be inactivated in the periphery
Peripheral 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...
. In addition, many self reactive T cells may not have sufficient affinity (binding strength) for the self antigen to be deleted in the thymus.
Regulatory T cell
Regulatory T cell
Regulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...
s are another group of T cells maturing 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....
, they are also involved with immune regulation but are not directly involved in central tolerance.
Genetic diseases caused by defects in central tolerance
Genetic defects in central tolerance can lead to autoimmunity.- Autoimmune Polyendocrinopathy Syndrome Type I is caused by mutations in the human gene AIREAutoimmune regulatorThe 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....
. This leads to a lack of expression of peripheral antigens in the thymus, and hence a lack of negative selection towards key peripheral proteins such as insulin. Multiple autoimmune symptoms result. - Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome is caused by mutations in the human gene Foxp3FOXP3FOXP3 is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator in the development and function of regulatory T cells....
. In the absence of Foxp3, auto reactive T cells are unable to become regulatory T cells, and therefore instead of inhibiting disease in the periphery they aid disease progression. As Foxp3FOXP3FOXP3 is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator in the development and function of regulatory T cells....
is on the X-chromosome and the disease is fatal early on in life, only males can develop IPEX.