AIRE - Autoimmune Regulator | Elisa - Clia - Antibody - Protein

Background:

The Autoimmune Regulator (AIRE) is a protein encoded by the AIRE gene, and it plays a critical role in immune tolerance and the prevention of autoimmune diseases. AIRE is primarily expressed in a specialized type of cell called medullary thymic epithelial cells (mTECs) found in the thymus gland. AIRE functions as a transcriptional regulator, controlling the expression of a wide range of tissue-specific antigens (TSAs) within mTECs. These TSAs represent proteins that are normally expressed in various tissues. By inducing the expression of TSAs in the thymus, AIRE ensures that developing T cells encounter a diverse array of self-antigens during their maturation process.The exposure of developing T cells to self-antigens in the thymus is crucial for their selection and education. T cells that recognize self-antigens too strongly or too weakly are eliminated or rendered tolerant, respectively, through a process known as central tolerance. AIRE-mediated expression of TSAs in mTECs is a key mechanism by which central tolerance is maintained, helping to prevent the development of autoimmune responses against self-tissues. Mutations in the AIRE gene lead to a rare autoimmune disorder known as autoimmune polyendocrine syndrome type 1 (APS-1), also called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). APS-1 is characterized by the development of multiple autoimmune diseases affecting various endocrine organs, such as the adrenal glands, parathyroid glands, and pancreas, as well as other tissues. These autoimmune manifestations result from defects in central tolerance due to impaired AIRE function, leading to the escape of autoreactive T cells from thymic deletion.

Protein Structure:

• Structure: AIRE is a protein of approximately 545 amino acids with several key functional domains:
• HSR (homogeneously staining region): Involved in chromatin binding and regulation of transcription.
• SAND (Sp100, AIRE-1, NucP41/75, DEAF-1) domain: Essential for DNA binding and transcriptional activity.
• PHD (Plant Homeodomain) fingers: Mediate interactions with other proteins and chromatin remodeling complexes.
• NLS (nuclear localization signals): Ensure the localization of AIRE to the nucleus.

Classification and Subtypes:

• Protein Family: AIRE is a member of the SAND domain family of proteins, characterized by their roles in gene regulation and chromatin interaction.
• Subtypes: There are no known subtypes of AIRE, but mutations within the AIRE gene can lead to different functional consequences.

Function and Biological Significance:

• Central Tolerance: AIRE promotes the expression of a wide array of peripheral tissue antigens (PTAs) in medullary thymic epithelial cells (mTECs). This expression allows for the deletion of self-reactive T cells that would otherwise cause autoimmune responses.
• Transcriptional Regulation: AIRE functions as a transcriptional regulator, influencing the expression of genes involved in immune tolerance.
• Immune System Homeostasis: By ensuring the removal of autoreactive T cells, AIRE maintains the balance and proper function of the immune system, preventing autoimmune diseases.

Interactions:

• Chromatin Remodeling Complexes: AIRE interacts with chromatin remodeling complexes, facilitating the accessibility of chromatin for transcription.
• DNA and RNA: The SAND domain and PHD fingers of AIRE are involved in binding to specific DNA and RNA sequences, promoting the transcription of target genes.
• Other Transcription Factors: AIRE collaborates with other transcription factors to regulate the expression of tissue-specific antigens in the thymus.

Clinical Issues:

• APECED/APS-1: Mutations in the AIRE gene lead to APECED, a rare autosomal recessive disorder characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. Patients with APECED suffer from a variety of autoimmune manifestations due to the loss of central tolerance.
• Autoimmune Diseases: Dysfunctional AIRE can result in the escape of autoreactive T cells, contributing to the development of multiple autoimmune conditions, including type 1 diabetes, thyroiditis, and more.
• Immunodeficiency: Besides autoimmunity, defects in AIRE function can lead to an overall dysregulated immune response, impacting the body's ability to respond to infections properly.

Summary:

Autoimmune regulator (AIRE) is a pivotal transcription factor responsible for maintaining central immune tolerance by promoting the expression of peripheral tissue antigens in the thymus. This process ensures the deletion of self-reactive T cells, preventing autoimmunity. AIRE's interactions with chromatin remodeling complexes, DNA, RNA, and other transcription factors underscore its critical role in gene regulation. Clinically, mutations in AIRE cause APECED/APS-1, a syndrome characterized by multiple autoimmune disorders. Understanding the function and significance of AIRE is vital for comprehending mechanisms underlying autoimmune diseases and developing potential therapeutic interventions.