IL2RA

The human protein interleukin-2 receptor subunit alpha is encoded by a gene called IL2RA with a length around 51,6 kb. Alternative names for this protein coding gene are IL2R, IDDM10 and TCGFR. Location of IL2RA in human genome is on the short arm of 10th chromosome (10p15.1). Several frequent point mutations, single nucleotide polymorphism (SNP), have been identified in or in close proximity to IL2RA gene in the population. These SNPs have been linked mainly to susceptibility to immune dysregulation disorders, with majority found in research on multiple sclerosis (MS) and type 1 diabetes mellitus. IL2RA gene orthologues with identical protein functionality are relatively abundant and constant among animal species, especially in mammals subgroups. Moreover, conserved homologs of this gene are in mouse, rat, dog, cow, chimpanzee and Rhesus monkey. == Expression ==

CD25 is expressed broadly among leukocytes. The highest surface expression of this protein is on regulatory T cells (Tregs), where CD25 is expressed constitutively, especially on a subset classified as naturally occurring Tregs. It can also be found on activated B cells, NK (natural killer) cells, thymocytes, and some myeloid lineage cells (e.g. macrophages, dendritic cells). IL2RA has been used as a marker to identify CD4+FoxP3+ regulatory T cells in mice. However, there are species differences as CD25 is constitutively expressed by a large proportion of resting memory T cells non-regulatory CD4 T cells in humans that are absent in mice. High expression of CD25 is also found on TCR activated conventional T cells (both CD8+ and CD4+ T lymphocytes), where it is considered to be a marker of T cell activation. Additionally, expression of the IL-2 receptor alpha subunit can be found in non-lymphoid tissues such as lungs (alveolar macrophages), liver (Kupffer cells) and skin (Langerhans cells). == Structure ==

Interleukin-2 receptor alpha chain is an integral-membrane protein, more precisely type I transmembrane protein. This bitopic polypeptide is constructed by a sequence of 272 amino acids and has a molecular mass of around 30.8 kDa. == Signalling cascade of interleukin-2 receptor ==

Interleukin-2 can interact with intermediate-affinity dimeric IL-2 receptor, which consists of beta (CD122) and gamma (CD132) chains, or with high-affinity trimeric complex, where the addition of an alpha subunit (CD25) constructs the IL-2 receptor and provides enhanced specific binding force. After activation of the receptor by its ligand, heterodimerisation of beta and gamma intracellular domains takes place. ==Clinical significance==

Roifman's group was the first to identify immunological consequences of CD25 loss and the patient has suffered from chronic infections and severe autoimmunity resembling Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome, caused by mutations in FOXP3 gene. In cancer, increased levels of this soluble protein are diagnostic marker for leukemia and lymphoma. Furthermore, sIL-2Rα levels have some significance also in infectious diseases and transplantation. Higher serum levels were correlated with severity and need for hospitalisation of COVID-19 patients. sIL-2Rα amount in plasma of HIV ( human immunodeficiency virus) positive patients has a correlation to HIV viral load and so to disease progression. Similarly in Chagas disease, caused by the protozoan Trypanosoma cruzi, patients have increased levels of sIL-2Rα and autoantibodies. In regard to transplantation, higher levels of sCD25 may be used as a predictor of organ rejection and graft-versus-host disease (GVHD) for hematopoietic transplantations. Concerning CVD (cardiovascular diseases) soluble IL-2Rα has positive correlation with hypertension, type 2 diabetes mellitus, cardiac sarcoidosis, stroke and heart failure. For neurological disorders, high levels of sIL-2Rα are a sign for increased risk of developing schizophrenia. Antibodies directly against CD25 have been altered to contain ‘activating’ Fc regions for the purpose of antibody-dependent cell-mediated cytotoxicity, in this case Treg depletion. Antibody marks a cell with IL-2Rα subunit on the surface, which is subsequently recognized and cleared by myeloid cell with Fc receptor. From the other side, treatment strategies for autoimmune and inflammatory diseases need selectivity for Tregs and suppression of immune system. IL-2Rα subunit expression on Tregs secures better sensitivity to IL-2. Therefore, administration of low doses of the cytokine preferentially stimulates T regulatory cells over others. Low-dose IL-2 therapy is used for graft-versus-host disease, type 1 diabetes mellitus, hepatitis C virus-induced vasculitis and systemic lupus. == References ==