Autoimmune regulator
Encyclopedia
The autoimmune regulator (AIRE) 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.
Each T cell
attacks a foreign substances which it identifies with its receptor
. T cells have receptors which are generated by randomly shuffling gene segments. Each T cell attacks a different substance. T cells that attack the body's own proteins are eliminated in the thymus. Thymic epithelial cells express major proteins from elsewhere in the body, and T cells that respond to those proteins are eliminated through cell suicide (apoptosis
).
The AIRE controls the expression of those thymic epithelial cells in the medulla (inner part) of the thymus. When AIRE is defective, T cells can attack the body, resulting in autoimmune disease
.
of a wide selection of organ-specific genes that create proteins that are usually only expressed in peripheral tissues, creating an "immunological self-shadow" in the thymus. It is important that self-reactive T cells that bind strongly to self-antigen
are eliminated in the thymus (via the process of negative selection
), otherwise they can later bind to their corresponding self-proteins and create an autoimmune reaction. So the expression of non-local proteins by AIRE reduces the threat of the occurrence of autoimmunity
later on by allowing for the elimination of auto-reactive T cells that bind antigens not traditionally found in the thymus.
Research in knockout mice
has demonstrated that Aire functions through initiating the transcription
of a diverse set of self-antigens, such as insulin
, in the thymus
. This expression then allows maturing thymocytes to become tolerant
towards peripheral organs, thereby suppressing autoimmune disease.
The AIRE gene is expressed in many other tissues as well.
A gene knockout
of the murine homolog Aire has created a transgenic mouse model to study the mechanism of disease in human patients.
with CREB binding protein
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the AIRE gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. AIRE is a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
expressed in the medulla
Medulla
Medulla refers to the middle of something and derives from the Latin word for marrow. Its anatomical uses include:* Medulla oblongata, a part of the brain stem* Renal medulla, a part of the kidney* Adrenal medulla, a part of the adrenal gland...
of 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....
and controls the mechanism that prevents the immune system from attacking the body itself.
Each T cell
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...
attacks a foreign substances which it identifies with its 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...
. T cells have receptors which are generated by randomly shuffling gene segments. Each T cell attacks a different substance. T cells that attack the body's own proteins are eliminated in the thymus. Thymic epithelial cells express major proteins from elsewhere in the body, and T cells that respond to those proteins are eliminated through cell suicide (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...
).
The AIRE controls the expression of those thymic epithelial cells in the medulla (inner part) of the thymus. When AIRE is defective, T cells can attack the body, resulting in autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
.
Function
In the thymus, the autoimmune regulator causes transcriptionTranscription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of a wide selection of organ-specific genes that create proteins that are usually only expressed in peripheral tissues, creating an "immunological self-shadow" in the thymus. It is important that self-reactive T cells that bind strongly to self-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...
are eliminated in the thymus (via the process of 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...
), otherwise they can later bind to their corresponding self-proteins and create an autoimmune reaction. So the expression of non-local proteins by AIRE reduces the threat of the occurrence of 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...
later on by allowing for the elimination of auto-reactive T cells that bind antigens not traditionally found in the thymus.
Research in knockout mice
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
has demonstrated that Aire functions through initiating the transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of a diverse set of self-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
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....
. This expression then allows maturing thymocytes to become tolerant
Central 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...
towards peripheral organs, thereby suppressing autoimmune disease.
The AIRE gene is expressed in many other tissues as well.
Pathology
The autoimmune regulator is mutated in the rare autoimmune syndrome Autoimmune Polyendocrinopathy Syndrome type 1 (APS-1), also known as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED). Disruption of AIRE results in the development of a range of autoimmune diseases, the most common clinical conditions in the syndrome are hypoparathyroidism, primary adrenocortical failure and chronic mucocutaneous candidiasis.A gene knockout
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
of the murine homolog Aire has created a transgenic mouse model to study the mechanism of disease in human patients.
Interactions
Autoimmune regulator has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with CREB binding protein
CREB binding protein
CREB-binding protein, also known as CREBBP or CBP, is a protein that in humans is encoded by the CREBBP gene.The CREB protein carries out its function by activating transcription, where interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor...
.
See also
- List of human clusters of differentiation for a list of CD molecules
- Immune systemImmune systemAn 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...
- Immune toleranceImmune toleranceImmune 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...