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 immunophenotyping of cells. In terms of physiology, CD molecules can act in numerous ways, often acting as receptors or ligands important to the cell. A signal cascade is usually initiated, altering the behavior of the cell (see cell signaling ). Some CD proteins do not play a role in cell signaling, but have other functions, such as cell adhesion . CD for humans is numbered up to 371 (as of 21 April 2016 ).
34-563: 4TMF , 1YH3 , 1ZVM , 2EF1 , 2HCT , 2I65 , 2I66 , 2I67 , 2O3Q , 2O3R , 2O3S , 2O3T , 2O3U , 2PGJ , 2PGL , 3DZF , 3DZG , 3DZH , 3DZI , 3DZJ , 3DZK , 3F6Y , 3I9M , 3I9N , 3OFS , 3RAJ , 3ROK , 3ROM , 3ROP , 3ROQ , 3U4H , 3U4I , 4CMH , 4F45 , 4F46 , 4OGW , 4XJS , 4XJT , 5F1K , 5F1O , 5F21 952 12494 ENSG00000004468 ENSMUSG00000029084 P28907 P56528 NM_001775 NM_007646 NP_001766 NP_031672 CD38 ( cluster of differentiation 38), also known as cyclic ADP ribose hydrolase ,
68-410: A chemokine receptor on the surface of a T helper cell to gain entry. The number of CD4 and CD8 T cells in blood is often used to monitor the progression of HIV infection . While CD molecules are very useful in defining leukocytes, they are not merely markers on the cell surface . Though only a fraction of known CD molecules have been thoroughly characterised, most of them have important functions. In
102-578: A stem cell , as opposed to a fully differentiated endothelial cell . Some cell populations can also be defined as , , or (alternatively, , , or ), indicating an overall variability in CD expression , particularly when compared to other cells being studied. A review of the development of T cells in the thymus uses this nomenclature to identify cells transitioning from CD4 /CD8 double-positive cells to CD4 /CD8 . Since 1982 there have been nine Human Leukocyte Differentiation Antigen Workshops culminating in
136-569: A "secondary effector" whose effects depend on the particular secondary messenger system. Calcium ions are one type of second messengers and are responsible for many important physiological functions including muscle contraction , fertilization , and neurotransmitter release. The ions are normally bound or stored in intracellular components (such as the endoplasmic reticulum(ER) ) and can be released during signal transduction. The enzyme phospholipase C produces diacylglycerol and inositol trisphosphate , which increases calcium ion permeability into
170-567: A binding site for a G-protein . The G-protein (named for the GDP and GTP molecules that bind to it) is bound to the inner membrane of the cell and consists of three subunits: alpha, beta and gamma. The G-protein is known as the " transducer ." When the G-protein binds with the receptor, it becomes able to exchange a GDP (guanosine diphosphate) molecule on its alpha subunit for a GTP (guanosine triphosphate) molecule. Once this exchange takes place,
204-426: A conference. The CD system is commonly used as cell markers in immunophenotyping , allowing cells to be defined based on what molecules are present on their surface. These markers are often used to associate cells with certain immune functions . While using one CD molecule to define populations is uncommon (though a few examples exist), combining markers has allowed for cell types with very specific definitions within
238-537: 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
272-460: 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 inhibitors may be used as therapeutics for
306-456: 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
340-455: 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 is present under acidic conditions, CD38 can hydrolyze nicotinamide adenine dinucleotide phosphate (NADP+) to NAADP . These reaction products are essential for the regulation of intracellular Ca. CD38 occurs not only as an ectoenzyme on cell outer surfaces, but also occurs on
374-666: The endothelium . CD38 on leukocytes attaching to CD31 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 Ca, thereby increasing dysfunctional contractility resulting in asthma . The CD38 protein
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#1732780461517408-488: 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
442-486: The phospholipid bilayer to initiate changes within the cell directly—unlike steroid hormones , which usually do. This functional limitation requires the cell to have signal transduction mechanisms to transduce first messenger into second messengers, so that the extracellular signal may be propagated intracellularly. An important feature of the second messenger signaling system is that second messengers may be coupled downstream to multi-cyclic kinase cascades to greatly amplify
476-469: The alpha subunit of the G-protein transducer breaks free from the beta and gamma subunits, all parts remaining membrane-bound. The alpha subunit, now free to move along the inner membrane, eventually contacts another cell surface receptor - the "primary effector." The primary effector then has an action, which creates a signal that can diffuse within the cell. This signal is called the "second (or secondary) messenger." The secondary messenger may then activate
510-425: The capacity to synthesize the calcium-releasing second messengers cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). 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. CD38 can function either as a receptor or as an enzyme. As a receptor, CD38 can attach to CD31 on
544-509: The cell in response to exposure to extracellular signaling molecules—the first messengers . (Intercellular signals, a non-local form of cell signaling , encompassing both first messengers and second messengers, are classified as autocrine , juxtacrine , paracrine , and endocrine depending on the range of the signal.) Second messengers trigger physiological changes at cellular level such as proliferation , differentiation , migration, survival, apoptosis and depolarization . They are one of
578-595: The cyclases that synthesize cyclic nucleotides , or by opening of ion channels to allow influx of metal ions, for example Ca signaling . These small molecules bind and activate protein kinases, ion channels, and other proteins, thus continuing the signaling cascade. There are three basic types of secondary messenger molecules: These intracellular messengers have some properties in common: There are several different secondary messenger systems ( cAMP system, phosphoinositol system, and arachidonic acid system), but they all are quite similar in overall mechanism, although
612-426: The designation (e.g., CD2 molecule). Currently, "CD2" is generally used to designate the molecule, and "CD2 antibody " is used to designate the antibody. Cell populations are usually defined using a '+' or a '−' symbol to indicate whether a certain cell fraction expresses or lacks a CD molecule. For example, a " CD34 +, CD31 −" cell is one that expresses CD34 but not CD31. This CD combination typically corresponds to
646-486: The example of CD4 and CD8, these molecules are critical in antigen recognition. Others (e.g., CD135 ) act as cell surface receptors for growth factors . Recently, the marker CD47 was found to have anti- phagocytic signals to macrophages and inhibit natural killer (NK) cells. This enabled researchers to apply CD47 as a potential target to attenuate immune rejection . Second messenger system Second messengers are intracellular signaling molecules released by
680-509: The immune system. CD molecules are utilized in cell sorting using various methods, including flow cytometry . Two commonly used CD molecules are CD4 and CD8 , which are, in general, used as markers for helper and cytotoxic T cells, respectively. These molecules are defined in combination with CD3+, as some other leukocytes also express these CD molecules (some macrophages express low levels of CD4; dendritic cells express high levels of CD8). Human immunodeficiency virus binds CD4 and
714-488: The inner surface of cell membranes, facing the cytosol performing the same enzymatic functions. CD38 is believed to control or influence neurotransmitter release in the brain by producing cADPR. 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
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#1732780461517748-511: The liver to convert glycogen to glucose (sugar) in liver cells, but epinephrine alone would not convert glycogen to glucose. He found that epinephrine had to trigger a second messenger, cyclic AMP , for the liver to convert glycogen to glucose. The mechanisms were worked out in detail by Martin Rodbell and Alfred G. Gilman , who won the 1994 Nobel Prize. Secondary messenger systems can be synthesized and activated by enzymes, for example,
782-486: The major cause of NAD+ depletion with age. Decline of NAD+ in the brain with age may be due to increased CD38 on astrocytes and microglia , leading to neuroinflammation and neurodegeneration . Cluster of differentiation The CD nomenclature was proposed and established in the 1st International Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA), held in Paris in 1982. This system
816-541: The membrane. Active G-protein open up calcium channels to let calcium ions enter the plasma membrane. The other product of phospholipase C, diacylglycerol, activates protein kinase C , which assists in the activation of cAMP (another second messenger). IP 3 , DAG, and Ca are second messengers in the phosphoinositol pathway. The pathway begins with the binding of extracellular primary messengers such as epinephrine, acetylcholine, and hormones AGT, GnRH, GHRH, oxytocin, and TRH, to their respective receptors. Epinephrine binds to
850-409: The molecule. If the molecule has not been well characterized or has only one mAb, it is usually given the provisional indicator "w" (as in " CDw186 "). For instance, CD2 mAbs are reagents that react with a 50‐kDa transmembrane glycoprotein expressed on T cells . The CD designations were used to describe the recognized molecules but had to be clarified by attaching the term antigen or molecule to
884-576: The other hand, mice overexpressing CD38 exhibit reduced NAD+ and mitochondrial dysfunction . Macrophages are believed to be primarily responsible for the age-related increase in CD38 expression and NAD+ decline. Cellular senescence of macrophages increases CD38 expression. Macrophages accumulate in visceral fat and other tissues with age, leading to chronic inflammation . The inflammatory transcription factor NF-κB and CD38 are mutually activating. Secretions from senescent cells induce high levels of expression of CD38 on macrophages, which becomes
918-488: The strength of the original first messenger signal. For example, RasGTP signals link with the mitogen activated protein kinase (MAPK) cascade to amplify the allosteric activation of proliferative transcription factors such as Myc and CREB . Earl Wilbur Sutherland Jr. , discovered second messengers, for which he won the 1971 Nobel Prize in Physiology or Medicine . Sutherland saw that epinephrine would stimulate
952-406: The substances involved and overall effects can vary. In most cases, a ligand binds to a cell surface receptor . The binding of a ligand to the receptor causes a conformation change in the receptor. This conformation change can affect the activity of the receptor and result in the production of active second messengers. In the case of G protein-coupled receptors , the conformation change exposes
986-431: The surface of T cells , thereby activating those cells to produce a variety of cytokines . CD38 activation cooperates with TRPM2 channels to initiate physiological responses such as cell volume regulation. 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
1020-509: The treatment of asthma. 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
1054-491: The triggers of intracellular signal transduction cascades. Examples of second messenger molecules include cyclic AMP , cyclic GMP , inositol triphosphate , diacylglycerol , and calcium . First messengers are extracellular factors, often hormones or neurotransmitters , such as epinephrine , growth hormone , and serotonin . Because peptide hormones and neurotransmitters typically are biochemically hydrophilic molecules, these first messengers may not physically cross
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1088-586: The α1 GTPase Protein Coupled Receptor (GPCR) and acetylcholine binds to M1 and M2 GPCR. Binding of a primary messenger to these receptors results in conformational change of the receptor. The α subunit, with the help of guanine nucleotide exchange factors (GEFS), releases GDP, and binds GTP, resulting in the dissociation of the subunit and subsequent activation. The activated α subunit activates phospholipase C, which hydrolyzes membrane bound phosphatidylinositol 4,5-bisphosphate (PIP 2 ), resulting in
1122-420: 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). 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
1156-461: Was intended for the classification of the many monoclonal antibodies (mAbs) generated by different laboratories around the world against epitopes on the surface molecules of leukocytes (white blood cells). Since then, its use has expanded to many other cell types, and more than 370 CD unique clusters and subclusters have been identified. The proposed surface molecule is assigned a CD number once two specific monoclonal antibodies are shown to bind to
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