CD38


CD38, also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune 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 in humans.

Function

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 ectoenzyme that catalyzes the synthesis and hydrolysis of cyclic ADP-ribose from NAD+ to ADP-ribose in addition to synthesis of NAADP from NADP+. These reaction products are essential for the regulation of intracellular Ca2+. CD38 occurs not only as an ectoezyme on cell outer surfaces, but also occurs on the inner surface of cell membranes, facing the cytosol performing the same enzymatic functions.
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+.

Clinical significance

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 cytokine interferon gamma and the Gram negative bacterial cell wall component lipopolysaccharide induce CD38 expression on macrophages. Interferon gamma strongly induces CD38 expression on monocytes. The cytokine tumor necrosis factor strongly induces CD38 on airway smooth muscle cells inducing cADPR-mediated Ca2+, thereby increasing dysfunctional contractility resulting in asthma.
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 produces an enzyme which regulates the release of oxytocin within the central nervous system.
Increased expression of CD38 is an unfavourable diagnostic marker in chronic lymphocytic leukemia and is associated with increased disease progression.

Clinical application

CD38 has been used as a prognostic marker in leukemia.
Daratumumab 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 or by using an anti-CD38 antibody neutralizing agent, e.g. DaraEx.

Aging studies

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.
Macrophages accumulate in visceral fat and other tissues with age, leading to chronic inflammation. Secretions from senescent cells induce high levels of expression of CD38 on macrophages, which becomes the major cause of NAD+ depletion with age.