CD38 (

cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...

38), also known as cyclic ADP ribose hydrolase is a

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as g ...

found on the surface of many immune cells (

white blood cell White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

s), including

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...

⁺, CD8⁺,

B lymphocyte B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted ...

s and

natural killer cell Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repres ...

s. CD38 also functions in

cell adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indir ...

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...

and

calcium signaling Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts all ...

. In humans, the CD38 protein is encoded by the CD38

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

which is located on

chromosome 4 Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 186 million base pairs (the building material of DNA) and represents between 6 and 6.5 percent of the to ...

. CD38 is a

paralog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...

of CD157, which is also located on chromosome 4 (4p15) in humans.

History

CD38 was first identified in 1980 as a surface marker (

) of thymus cell

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...

s. In 1992 it was additionally described as a surface marker on

B cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...

s, and

s (NK cells). About the same time, CD38 was discovered to be not simply a marker of cell types, but an activator of B cells and T cells. In 1992 the enzymatic activity of CD38 was discovered, having the capacity to synthesize the calcium-releasing second messengers cyclic ADP-ribose (cADPR) and

nicotinic acid adenine dinucleotide phosphate Nicotinic acid adenine dinucleotide phosphate, (NAADP), is a Ca2+-mobilizing second messenger synthesised in response to extracellular stimuli. Like its mechanistic cousins, IP3 and cyclic adenosine diphosphoribose ( Cyclic ADP-ribose), NAADP bin ...

(NAADP).

Tissue distribution

CD38 is most frequently found on plasma B cells, followed by natural killer cells, followed by B cells and T cells, and then followed by a variety of cell types.

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 cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell ...

s, thereby activating those cells to produce a variety of

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in a ...

s.CD38 activation cooperates with TRPM2 channels to initiate physiological responses such as cell volume regulation. CD38 is a multifunctional

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

that catalyzes the synthesis of ADP ribose (ADPR) (97%) and cyclic ADP-ribose (cADPR) (3%) from

NAD+ Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...

. 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. When

nicotinic acid Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. It can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a variet ...

is present under acidic conditions, CD38 can hydrolyze

nicotinamide adenine dinucleotide phosphate Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...

(NADP+) to NAADP. 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 The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

performing the same enzymatic functions. CD38 is believed to control or influence

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...

release in the brain by producing cADPR. CD38 within the brain enables release of the affiliative

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like th ...

oxytocin Oxytocin (Oxt or OT) is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. It plays a role in social bonding, reproduction, childbirth, and the period after childbirth. Oxytoci ...

. 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.

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 cell The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ves ...

s binds to the CD38 receptor on

s for those cells to attach to the

endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...

. CD38 on

leukocyte White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mul ...

s 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 Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

and the

Gram negative The gram (originally gramme; SI unit symbol g) is a unit of mass in the International System of Units (SI) equal to one one thousandth of a kilogram. Originally defined as of 1795 as "the absolute weight of a volume of pure water equal to t ...

bacterial cell wall component

lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer ...

induce CD38 expression on macrophages. Interferon gamma strongly induces CD38 expression on

s. The cytokine

tumor necrosis factor Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homologo ...

strongly induces CD38 on airway

smooth muscle Smooth muscle is an involuntary non- striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit ...

cells inducing cADPR-mediated Ca²⁺, thereby increasing dysfunctional contractility resulting in

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, c ...

. The CD38 protein is a marker of cell activation. It has been connected to

HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immu ...

infection,

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, a ...

s, 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

tic patients, and amplifies the inflammatory response of airway smooth muscle of those patients. Increased expression of CD38 is an unfavourable diagnostic marker in

chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, n ...

and is associated with increased disease progression. CD38 is upregulated on plasmacytoid dendritic cells (pDCs) ''in vivo'' during human influenza infection and blocking CD38 prevents the ability of pDCs to produce type I interferon ''in vitro''.

Clinical application

CD38 inhibitors may be used as therapeutics for the treatment of asthma. CD38 has been used as a prognostic marker in

. Daratumumab (Darzalex) which targets CD38 has been used in treating

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, ane ...

. The use of Daratumumab can interfere with pre-

blood transfusion Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but m ...

tests, as CD38 is weakly expressed on the surface of

erythrocytes Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

. 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

with

dithiothreitol Dithiothreitol (DTT) is the common name for a small-molecule redox reagent also known as Cleland's reagent, after W. Wallace Cleland. DTT's formula is C4H10O2S2 and the chemical structure of one of its enantiomers in its reduced form is shown on ...

(DTT) or by using an anti-CD38 antibody neutralizing agent, e.g. DaraEx.

Inhibitors

Cassic acid Rhein, also known as cassic acid, is a substance in the anthraquinone group obtained from rhubarb. Like all such substances, rhein is a cathartic. Rhein is commonly found as a glycoside such as rhein-8-glucoside or glucorhein. Rhein was first isol ...

(Rhein) *

CD38-IN-78c CD38-IN-78c is a drug which acts as a potent and selective inhibitor of the glycoprotein enzyme CD38. In animal studies it boosts levels of nicotinamide adenine dinucleotide (NAD+) in tissues via inhibition of CD38 mediated breakdown of nicotinam ...

* Chrysanthemin (Kuromanin) * compound 1ai * compound 1am * Daratumumab * Isatuximab * Felzartamab (MOR202) *

apigenin Apigenin (4′,5,7-trihydroxyflavone), found in many plants, is a natural product belonging to the flavone class that is the aglycone of several naturally occurring glycosides. It is a yellow crystalline solid that has been used to dye wool. ...

* Luteolinidin * MK-0159 * TNB-738

Aging studies

A gradual increase in CD38 has been implicated in the decline of

with age. Treatment of old mice with a specific CD38 inhibitor, 78c, prevents age-related NAD+ decline. CD38

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

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 Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of ...

. Macrophages are believed to be primarily responsible for the age-related increase in CD38 expression and NAD+ decline.

Cellular senescence Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approxi ...

of macrophages increases CD38 expression. Macrophages accumulate in visceral fat and other tissues with age, leading to chronic

inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

. The inflammatory

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

and CD38 are mutually activating.

Secretions 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classica ...

from senescent cells induce high levels of expression of CD38 on macrophages, which becomes the major cause of NAD+ depletion with age. Decline of NAD+ in the brain with age may be due to increased CD38 on

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...

s and

microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune ...

, leading to

neuroinflammation Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury,Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS ''et al.'' Molecular imaging of ...

and

neurodegeneration A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

References

External links

* * * GeneCard CD3

* {{Clusters of differentiation by lineage Clusters of differentiation