CD38 гені: адам иммундық жүйесіндегі рөлі мен функциялары

Protein coding gene in the species Homo sapiens

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling. In humans, the CD38 protein is encoded by the CD38 gene which is located on chromosome 4. CD38 is a paralog of CD157, which is also located on chromosome 4 (4p15) in humans.

CD38 was first identified in 1980 as a surface marker (cluster of differentiation) of thymus cell lymphocytes. In 1992 it was additionally described as a surface marker on B cells, monocytes, and natural killer cells (NK cells).

CD38 can function either as a receptor or as an enzyme. As a receptor, CD38 can attach to CD31 on the surface of T cells, thereby activating those cells to produce a variety of cytokines. CD38 is a multifunctional enzyme that catalyzes the synthesis of ADP ribose (ADPR) (97%) and cyclic ADP ribose (cADPR) (3%) from NAD+. CD38 is thought to be a major regulator of NAD+ levels, its NADase activity is much higher than its function as an ADP rybosyl cyclase: for every 100 molecules of NAD+ converted to ADP ribose it generates one molecule of cADPR. These reaction products are essential for the regulation of intracellular Ca2+. CD38 occurs not only as an ectoenzyme on cell outer surfaces, but also occurs on the inner surface of cell membranes, facing the cytosol performing the same enzymatic functions. CD38 within the brain enables release of the affiliative neuropeptide oxytocin. Like CD38, CD157 is a member of the ADP ribosyl cyclase family of enzymes that catalyze the formation of cADPR from NAD+, although CD157 is a much weaker catalyst than CD38. The SARM1 enzyme also catalyzes the formation of cADPR from NAD+, but SARM1 elevates cADPR much more efficiently than CD38.

The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism. CD31 on endothelial cells binds to the CD38 receptor on natural killer cells for those cells to attach to the endothelium. CD38 on leukocytes attaching to CD16 on endothelial cells allows for leukocyte binding to blood vessel walls, and the passage of leukocytes through blood vessel walls. The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas, solid tumors, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions. CD38 increases airway contractility hyperresponsiveness, is increased in the lungs of asthmatic patients, and amplifies the inflammatory response of airway smooth muscle of those patients. CD38 has been used as a prognostic marker in leukemia. Daratumumab (Darzalex) which targets CD38 has been used in treating multiple myeloma. The use of Daratumumab can interfere with pre blood transfusion tests, as CD38 is weakly expressed on the surface of erythrocytes. Thus, a screening assay for irregular antibodies against red blood cell antigens or a direct immunoglobulin test can produce false positive results. This can be sidelined by either pretreatment of the erythrocytes with dithiothreitol (DTT) or by using an anti CD38 antibody neutralizing agent, e. g. DaraEx.

A gradual increase in CD38 has been implicated in the decline of NAD+ with age. Treatment of old mice with a specific CD38 inhibitor, 78c, prevents age related NAD+ decline. CD38 knockout mice have twice the levels of NAD+ and are resistant to age associated NAD+ decline, with dramatically increased NAD+ levels in major organs (liver, muscle, brain, and heart). On the other hand, mice overexpressing CD38 exhibit reduced NAD+ and mitochondrial dysfunction. Cellular senescence of macrophages increases CD38 expression. The inflammatory transcription factor NF κB and CD38 are mutually activating. Decline of NAD+ in the brain with age may be due to increased CD38 on astrocytes and microglia, leading to neuroinflammation and neurodegeneration.