CD38

CD38 was first identified in 1980 as a surface marker (cluster of differentiation) of thymus cell lymphocytes.{{cite book |editor1-last=Lee | editor1-first= H.C. | title = A Natural History of the Human CD38 Gene. In:Cyclic ADP-Ribose and NAADP | publisher = Springer Publishing | doi=10.1007/978-1-4615-0269-2_4 | date = 2002 | isbn = 978-1-4613-4996-9}}{{cite journal | vauthors=Reinherz EL, Kung PC, Schlossman SF | title=Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage| journal=Proceedings of the National Academy of Sciences of the United States of America | volume=77 | issue=3 | pages=1588–1592 | year=1980 | doi =10.1073/pnas.77.3.1588 | pmc=348542 | pmid=6966400| bibcode=1980PNAS...77.1588R| doi-access=free}} 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 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.{{cite journal | vauthors=van de Donk N, Richardson PG, Malavasi F | title=CD38 antibodies in multiple myeloma: back to the future | journal=Blood | volume=131 | issue=1 | pages=13–29 | year=2018 | doi =10.1182/blood-2017-06-740944 | pmid=29118010| doi-access=free}}

CD38 can function either as a receptor or as an enzyme.{{cite journal | vauthors=Nooka AK, Kaufman JL, Hofmeister CC, Joseph NS | title=Daratumumab in multiple myeloma| journal= Cancer | volume=125 | issue=14 | pages=2364–2382 | year=2019 | doi = 10.1002/cncr.32065 | pmid=30951198| s2cid=96435958| doi-access=free}} 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 activation cooperates with TRPM2 channels to initiate physiological responses such as cell volume regulation.{{cite journal | vauthors=Numata T, Sato K, Christmann J, Marx R, Mori Y, Okada Y, Wehner F | title=The ΔC splice-variant of TRPM2 is the hypertonicity-induced cation channel in HeLa cells, and the ecto-enzyme CD38 mediates its activation | journal = J. Physiol. | volume=590 | issue=5 | pages=1121–1138 | year=2012 | doi = 10.1113/jphysiol.2011.220947 | pmid=22219339 | pmc = 3381820 | doi-access=free}}

CD38 is also a component of the B-cell co-receptor complex, where it associates with CD19. It plays an essential role in regulating B-cell receptor (BCR) signaling, thereby influencing B-cell activation upon antigenic recognition.{{cite journal | vauthors=Camponeschi A, Kläsener K, et al. | title=Human CD38 regulates B cell antigen receptor dynamic organization in normal and malignant B cells | journal=Journal of Experimental Medicine | volume=219 | issue=9 | pages=e20220201 | year=2022 | doi=10.1084/jem.20220201 | pmid=35819358 | pmc=9280193 | doi-access=free}}

CD38 is a multifunctional enzyme that catalyzes the synthesis of ADP ribose (ADPR) (97%) and cyclic ADP-ribose (cADPR) (3%) from NAD+.{{cite journal | vauthors = Kar A, Mehrotra S, Chatterjee S | title = CD38: T Cell Immuno-Metabolic Modulator | journal = Cells | volume = 9 | issue = 7 | pages = 1716 | date=2020 | doi = 10.3390/cells9071716 | pmc =7408359 | pmid = 32709019| doi-access = free}}{{cite journal | vauthors = Guedes A, Dileepan M, Jude JA, Kannan MS | title = Role of CD38/cADPR signaling in obstructive pulmonary diseases | journal = Current Opinion in Pharmacology | volume = 51 | pages = 29–33 | date=2020 | doi = 10.1016/j.coph.2020.04.007 | pmc =7529733 | pmid = 32480246}} 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.{{cite journal | vauthors = Braidy N, Berg J, Clement J, Sachdev P | title = Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes | journal = Antioxidants & Redox Signaling | volume = 10 | issue = 2 | pages = 251–294 | date=2019 | doi = 10.1089/ars.2017.7269 | pmc =6277084 | pmid = 29634344}} When nicotinic acid is present under acidic conditions, CD38 can hydrolyze nicotinamide adenine dinucleotide phosphate (NADP+) to NAADP.{{cite journal | vauthors = Chini EN, Chini CC, Kato I, Takasawa S, Okamoto H | title = CD38 is the major enzyme responsible for synthesis of nicotinic acid-adenine dinucleotide phosphate in mammalian tissues | journal = The Biochemical Journal | volume = 362 | issue = Pt 1 | pages = 125–30 | date = February 2002 | pmid = 11829748 | pmc = 1222368 | doi=10.1042/0264-6021:3620125}}

These reaction products are essential for the regulation of intracellular Ca²⁺.{{cite journal | vauthors = Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, Vaisitti T, Aydin S | title = Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology | journal = Physiological Reviews | volume = 88 | issue = 3 | pages = 841–86 | date = July 2008 | pmid = 18626062 | doi = 10.1152/physrev.00035.2007}} 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 is believed to control or influence neurotransmitter release in the brain by producing cADPR.{{cite journal | vauthors = Guerreiro S, Privat A, Bressac L, Toulorge D | title = CD38 in Neurodegeneration and Neuroinflammation | journal = Cells | volume = 9 | issue = 2 | pages = 471 | date=2020 | doi = 10.3390/cells9020471 | pmc =7072759 | pmid = 32085567| doi-access = free}} CD38 within the brain enables release of the affiliative neuropeptide oxytocin.{{cite journal | vauthors = Tolomeo S, Chiao B, Lei Z, Chew SH, Ebstein RP | title = A Novel Role of CD38 and Oxytocin as Tandem Molecular Moderators of Human Social Behavior | journal = Neuroscience & Biobehavioral Reviews | volume = 115 | pages = 251–272 | date=2020 | doi = 10.1016/j.neubiorev.2020.04.013 | pmid = 32360414| s2cid = 216638884 | url = https://discovery.dundee.ac.uk/en/publications/7b019211-b792-409d-aed3-c54512271345}}

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.{{cite journal | vauthors=Higashida H, Hashii M, Tanaka Y, Matsukawa S | title=CD38, CD157, and RAGE as Molecular Determinants for Social Behavior | journal= Cells | volume=9 | issue=1 | pages=62 | year=2019 | doi = 10.3390/cells9010062| pmc=7016687 | pmid=31881755| doi-access=free}} The SARM1 enzyme also catalyzes the formation of cADPR from NAD+,{{cite journal | vauthors=Lee HC, Zhao YJ | title=Resolving the topological enigma in Ca 2+ signaling by cyclic ADP-ribose and NAADP | journal= Journal of Biological Chemistry | volume=294 | issue=52 | pages=19831–19843 | year=2019 | doi = 10.1074/jbc.REV119.009635 | pmc=6937575 | pmid=31672920| doi-access=free}} but SARM1 elevates cADPR much more efficiently than CD38.{{cite journal | vauthors = Zhao ZY, Xie XJ, Li WH, Zhao YJ | title = A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death | journal = iScience | volume = 15 | pages = 452–466 | date=2016 | doi = 10.1016/j.isci.2019.05.001 | pmc =6531917 | pmid = 31128467}}

The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism.{{cite journal | vauthors = Higashida H, Yokoyama S, Huang JJ, Liu L, Ma WJ, Akther S, Higashida C, Kikuchi M, Minabe Y, Munesue T | s2cid = 33172185 | title = Social memory, amnesia, and autism: brain oxytocin secretion is regulated by NAD+ metabolites and single nucleotide polymorphisms of CD38 | journal = Neurochemistry International | volume = 61 | issue = 6 | pages = 828–38 | date = November 2012 | pmid = 22366648 | doi = 10.1016/j.neuint.2012.01.030 | url = https://kanazawa-u.repo.nii.ac.jp/?action=repository_uri&item_id=30999 | hdl = 2297/32816 | hdl-access = free}}

CD31 on endothelial cells binds to the CD38 receptor on natural killer cells for those cells to attach to the endothelium.{{cite journal | vauthors = Zambello R, Barilà G, Sabrina Manni S | title = NK cells and CD38: Implication for (Immuno)Therapy in Plasma Cell Dyscrasias | journal = Cells | volume = 9 | issue=3 | pages = 768 | date=2020 | doi = 10.3390/cells9030768 | pmc=7140687 | pmid = 32245149| doi-access = free}}{{cite journal | vauthors = Glaría E, Valledor AF | title = Roles of CD38 in the Immune Response to Infection | journal = Cells | volume = 9 | issue=1 | pages = 228| date=2020 | doi = 10.3390/cells9010228 | pmc=7017097 | pmid = 31963337| doi-access = free}} 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 Ca²⁺, thereby increasing dysfunctional contractility resulting in asthma.{{cite journal | vauthors = Deshpande DA, Guedes A, Graeff R, Dogan S | title = CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms | journal = Mediators of Inflammation | volume = 2018 | pages = 8942042 | date=2018 | doi = 10.1155/2018/8942042 | pmc=5821947 | pmid = 29576747| doi-access = free}}

The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas,{{cite journal | vauthors =Marlein CR, Piddock RE, Mistry JJ, Zaitseva L, Hellmich C, Horton RH, Zhou Z, Auger MJ, Bowles KM, Rushworth SA | title = CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma | journal = Cancer Research | date = January 2019 | pmid = 30622116 | doi = 10.1158/0008-5472.CAN-18-0773 | volume=79 | issue = 9 | pages=2285–2297| doi-access = free}} 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 the treatment of asthma.{{cite journal | vauthors = Deshpande DA, Guedes AG, Lund FE, Kannan MS | title = CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets | journal = Pharmacology & Therapeutics | volume = 172 | pages = 116–126 | date=2017 | doi = 10.1016/j.pharmthera.2016.12.002 | pmc =5346344 | pmid = 27939939}}

CD38 has been used as a prognostic marker in leukemia.{{cite journal | vauthors = Deaglio S, Mehta K, Malavasi F | title = Human CD38: a (r)evolutionary story of enzymes and receptors | journal = Leukemia Research | volume = 25 | issue = 1 | pages = 1–12 | date = January 2001 | pmid = 11137554 | doi = 10.1016/S0145-2126(00)00093-X}}

Daratumumab (Darzalex) which targets CD38 has been used in treating multiple myeloma.{{cite journal | vauthors = McKeage K | s2cid = 11977989 | title = Daratumumab: First Global Approval | journal = Drugs | volume = 76 | issue = 2 | pages = 275–81 | date = February 2016 | pmid = 26729183 | doi = 10.1007/s40265-015-0536-1}}{{cite journal | vauthors = Xia C, Ribeiro M, Scott S, Lonial S | title = Daratumumab: monoclonal antibody therapy to treat multiple myeloma | journal = Drugs of Today | volume = 52 | issue = 10 | pages = 551–560 | date = October 2016 | pmid = 27910963 | doi = 10.1358/dot.2016.52.10.2543308}}

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.{{cite journal | vauthors = de Vooght KM, Lozano M, Bueno JL, Alarcon A, Romera I, Suzuki K, Zhiburt E, Holbro A, Infanti L, Buser A, Hustinx H, Deneys V, Frelik A, Thiry C, Murphy M, Staves J, Selleng K, Greinacher A, Kutner JM, Bonet Bub C, Castilho L, Kaufman R, Colling ME, Perseghin P, Incontri A, Dassi M, Brilhante D, Macedo A, Cserti-Gazdewich C, Pendergrast JM, Hawes J, Lundgren MN, Storry JR, Jain A, Marwaha N, Sharma RR | s2cid = 29156699 | title = Vox Sanguinis International Forum on typing and matching strategies in patients on anti-CD38 monoclonal therapy: summary | journal = Vox Sanguinis | volume = 113 | issue = 5 | pages = 492–498 | date = May 2018 | pmid = 29781081 | doi = 10.1111/vox.12653}} This can be sidelined by either pretreatment of the erythrocytes with dithiothreitol (DTT) or by using an anti-CD38 antibody neutralizing agent, e.g. D-REX or DaraEx.

• Cassic acid (Rhein) {{cite journal | vauthors = Blacher E, Ben Baruch B, Levy A, Geva N, Green KD, Garneau-Tsodikova S, Fridman M, Stein R | title = Inhibition of glioma progression by a newly discovered CD38 inhibitor | journal = International Journal of Cancer | volume = 136 | issue = 6 | pages = 1422–33 | date = March 2015 | pmid = 25053177 | doi = 10.1002/ijc.29095 | s2cid = 41844152 | doi-access = free}}
• CD38-IN-78c{{cite journal | vauthors = Tarragó MG, Chini CC, Kanamori KS, Warner GM, Caride A, de Oliveira GC, Rud M, Samani A, Hein KZ, Huang R, Jurk D, Cho DS, Boslett JJ, Miller JD, Zweier JL, Passos JF, Doles JD, Becherer DJ, Chini EN | title = + Decline | journal = Cell Metabolism | volume = 27 | issue = 5 | pages = 1081–1095.e10 | date = May 2018 | pmid = 29719225 | doi = 10.1016/j.cmet.2018.03.016 | pmc = 5935140 | doi-access = free}}
• Chrysanthemin (Kuromanin) {{cite journal | vauthors = Kellenberger E, Kuhn I, Schuber F, Muller-Steffner H | title = Flavonoids as inhibitors of human CD38 | journal = Bioorganic & Medicinal Chemistry Letters | volume = 21 | issue = 13 | pages = 3939–42 | date = July 2011 | pmid = 21641214 | doi = 10.1016/j.bmcl.2011.05.022}}
• compound 1ai {{cite journal | vauthors = Becherer JD, Boros EE, Carpenter TY, Cowan DJ, Deaton DN, Haffner CD, Jeune MR, Kaldor IW, Poole JC, Preugschat F, Rheault TR, Schulte CA, Shearer BG, Shearer TW, Shewchuk LM, Smalley TL, Stewart EL, Stuart JD, Ulrich JC | title = Discovery of 4-Amino-8-quinoline Carboxamides as Novel, Submicromolar Inhibitors of NAD-Hydrolyzing Enzyme CD38 | journal = Journal of Medicinal Chemistry | volume = 58 | issue = 17 | pages = 7021–56 | date = September 2015 | pmid = 26267483 | doi = 10.1021/acs.jmedchem.5b00992}}
• compound 1am {{cite journal | vauthors = Deaton DN, Haffner CD, Henke BR, Jeune MR, Shearer BG, Stewart EL, Stuart JD, Ulrich JC | title = 2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships | journal = Bioorganic & Medicinal Chemistry | volume = 26 | issue = 8 | pages = 2107–2150 | date = May 2018 | pmid = 29576271 | doi = 10.1016/j.bmc.2018.03.021}}{{cite journal | vauthors = Sepehri B, Ghavami R | title = Design of new CD38 inhibitors based on CoMFA modelling and molecular docking analysis of 4‑amino-8-quinoline carboxamides and 2,4-diamino-8-quinazoline carboxamides | journal = SAR and QSAR in Environmental Research | volume = 30 | issue = 1 | pages = 21–38 | date = January 2019 | pmid = 30489181 | doi = 10.1080/1062936X.2018.1545695 | bibcode = 2019SQER...30...21S | s2cid = 54158219}}
• Daratumumab{{cite journal | vauthors = Sidiqi MH, Gertz MA | title = Daratumumab for the treatment of AL amyloidosis | journal = Leukemia & Lymphoma | volume = 60 | issue = 2 | pages = 295–301 | date = February 2019 | pmid = 30033840 | doi = 10.1080/10428194.2018.1485914 | pmc = 6342668}}
• Isatuximab{{cite web | title=Sarclisa EPAR | website=European Medicines Agency (EMA) | date=29 July 2021 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/sarclisa | access-date=29 July 2021}}
• Felzartamab (MOR202){{cite journal | vauthors = Raab MS, Engelhardt M, Blank A, Goldschmidt H, Agis H, Blau IW, Einsele H, Ferstl B, Schub N, Röllig C, Weisel K, Winderlich M, Griese J, Härtle S, Weirather J, Jarutat T, Peschel C, Chatterjee M | title = MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1-2a trial | journal = The Lancet. Haematology | volume = 7 | issue = 5 | pages = e381–e394 | date = May 2020 | pmid = 32171061 | doi = 10.1016/S2352-3026(19)30249-2 | s2cid = 212718499}}
• apigenin{{cite journal | vauthors = Escande C, Nin V, Price NL, Capellini V, Gomes AP, Barbosa MT, O'Neil L, White TA, Sinclair DA, Chini EN | title = Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome | journal = Diabetes | volume = 62 | issue = 4 | pages = 1084–1093 | date = April 2013 | pmid = 23172919 | pmc = 3609577 | doi = 10.2337/db12-1139}}
• Luteolinidin{{cite journal | vauthors = Boslett J, Hemann C, Zhao YJ, Lee HC, Zweier JL | title = Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H) | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 361 | issue = 1 | pages = 99–108 | date = April 2017 | pmid = 28108596 | pmc = 5363772 | doi = 10.1124/jpet.116.239459}}
• MK-0159{{cite journal | vauthors = Lagu B, Wu X, Kulkarni S, Paul R, Becherer JD, Olson L, Ravani S, Chatzianastasiou A, Papapetropoulos A, Andrzejewski S | title = Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart | journal = Journal of Medicinal Chemistry | volume = 65 | issue = 13 | pages = 9418–9446 | date = July 2022 | pmid = 35762533 | doi = 10.1021/acs.jmedchem.2c00688 | s2cid = 250090300}}{{cite journal | vauthors = Chen PM, Katsuyama E, Satyam A, Li H, Rubio J, Jung S, Andrzejewski S, Becherer JD, Tsokos MG, Abdi R, Tsokos GC | title = CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy | journal = Science Advances | volume = 8 | issue = 24 | pages = eabo4271 | date = June 2022 | pmid = 35704572 | pmc = 9200274 | doi = 10.1126/sciadv.abo4271 | bibcode = 2022SciA....8O4271C}}
• TNB-738{{cite journal | vauthors = Ugamraj HS, Dang K, Ouisse LH, Buelow B, Chini EN, Castello G, Allison J, Clarke SC, Davison LM, Buelow R, Deng R, Iyer S, Schellenberger U, Manika SN, Bijpuria S, Musnier A, Poupon A, Cuturi MC, van Schooten W, Dalvi P | title = TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity | journal = mAbs | volume = 14 | issue = 1 | pages = 2095949 | date = 2022 | pmid = 35867844 | pmc = 9311320 | doi = 10.1080/19420862.2022.2095949}}

A gradual increase in CD38 has been implicated in the decline of NAD+ with age.{{cite journal | vauthors = Camacho-Pereira J, Tarragó MG, Chini CC, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN | title = CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism | journal = Cell Metabolism | volume = 23 | issue = 6 | pages = 1127–1139 | date = June 2016 | pmid = 27304511 | pmc = 4911708 | doi = 10.1016/j.cmet.2016.05.006}}{{cite journal | vauthors = Schultz MB, Sinclair DA | title = Why NAD(+) Declines during Aging: It's Destroyed | journal = Cell Metabolism | volume = 23 | issue = 6 | pages = 965–966 | date = June 2016 | pmid = 27304496 | pmc = 5088772 | doi = 10.1016/j.cmet.2016.05.022}} Treatment of old mice with a specific CD38 inhibitor, 78c, prevents age-related NAD+ decline.{{cite journal | vauthors = Tarragó MG, Chini CC, Kanamori KS, Warner GM, Caride A, de Oliveira GC, Rud M, Samani A, Hein KZ, Huang R, Jurk D, Cho DS, Boslett JJ, Miller JD, Zweier JL, Passos JF, Doles JD, Becherer DJ, Chini EN | title = A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline | journal = Cell Metabolism | volume = 27 | issue = 5 | pages = 1081–1095.e10 | date = May 2018 | pmid = 29719225 | pmc = 5935140 | doi = 10.1016/j.cmet.2018.03.016}} CD38 knockout mice have twice the levels of NAD+ and are resistant to age-associated NAD+ decline,{{cite journal | vauthors=Cambronne XA, Kraus WL | title=Location, Location, Location: Compartmentalization of NAD + Synthesis and Functions in Mammalian Cells | journal= Trends in Biochemical Sciences | volume=45 | issue=10 | pages=858–873 | year=2020 | url=https://www.jbc.org/content/294/52/19831.long |doi = 10.1016/j.tibs.2020.05.010 | pmc=7502477 | pmid=32595066}} with dramatically increased NAD+ levels in major organs (liver, muscle, brain, and heart).{{cite journal | vauthors=Kang BE, Choi J, Stein S, Ryu D | title=Implications of NAD + boosters in translational medicine | journal= European Journal of Clinical Investigation | volume=50 | issue=10 | pages=e13334 | year=2020 | doi = 10.1111/eci.13334 | pmid=32594513| s2cid=220254270 | doi-access=free}} On 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.{{cite journal | vauthors=Yarbro JR, Emmons RS, Pence BD | title=Macrophage Immunometabolism and Inflammaging: Roles of Mitochondrial Dysfunction, Cellular Senescence, CD38, and NAD | journal=Immunometabolism | volume=2 | issue=3 | pages=e200026 | year=2020 | doi = 10.20900/immunometab20200026 | pmc=7409778 | pmid=32774895}} Cellular senescence of macrophages increases CD38 expression. Macrophages accumulate in visceral fat and other tissues with age, leading to chronic inflammation.{{cite journal | vauthors = Oishi Y, Manabe I | title = Macrophages in age-related chronic inflammatory diseases | journal = npj Aging and Mechanisms of Disease | pages = 16018 | date=2016 | volume = 2 | doi = 10.1038/npjamd.2016.18 | pmc=5515003 | pmid = 28721272}} 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 the major cause of NAD+ depletion with age.{{cite journal |vauthors=Covarrubias AJ, Kale A, Verdin E |title=Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages |journal=Nature Metabolism |volume=2 |issue=11 |pages=1265–1283 |year=2020 |doi= 10.1038/s42255-020-00305-3 |pmc=7908681 |pmid=33199924}}

Decline of NAD+ in the brain with age may be due to increased CD38 on astrocytes and microglia, leading to neuroinflammation and neurodegeneration.

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• {{cite journal | vauthors = Dianzani U, Bragardo M, Buonfiglio D, Redoglia V, Funaro A, Portoles P, Rojo J, Malavasi F, Pileri A | title = Modulation of CD4 lateral interaction with lymphocyte surface molecules induced by HIV-1 gp120 | journal = European Journal of Immunology | volume = 25 | issue = 5 | pages = 1306–11 | date = May 1995 | pmid = 7539755 | doi = 10.1002/eji.1830250526 | s2cid = 37717142}}
• {{cite journal | vauthors = Nakagawara K, Mori M, Takasawa S, Nata K, Takamura T, Berlova A, Tohgo A, Karasawa T, Yonekura H, Takeuchi T | title = Assignment of CD38, the gene encoding human leukocyte antigen CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase), to chromosome 4p15 | journal = Cytogenetics and Cell Genetics | volume = 69 | issue = 1–2 | pages = 38–9 | year = 1995 | pmid = 7835083 | doi = 10.1159/000133933}}
• {{cite journal | vauthors = Tohgo A, Takasawa S, Noguchi N, Koguma T, Nata K, Sugimoto T, Furuya Y, Yonekura H, Okamoto H | title = Essential cysteine residues for cyclic ADP-ribose synthesis and hydrolysis by CD38 | journal = The Journal of Biological Chemistry | volume = 269 | issue = 46 | pages = 28555–7 | date = November 1994 | doi = 10.1016/S0021-9258(19)61940-X | pmid = 7961800 | doi-access = free}}
• {{cite journal | vauthors = Takasawa S, Tohgo A, Noguchi N, Koguma T, Nata K, Sugimoto T, Yonekura H, Okamoto H | title = Synthesis and hydrolysis of cyclic ADP-ribose by human leukocyte antigen CD38 and inhibition of the hydrolysis by ATP | journal = The Journal of Biological Chemistry | volume = 268 | issue = 35 | pages = 26052–4 | date = December 1993 | doi = 10.1016/S0021-9258(19)74275-6 | pmid = 8253715 | doi-access = free}}
• {{cite journal | vauthors = Nata K, Takamura T, Karasawa T, Kumagai T, Hashioka W, Tohgo A, Yonekura H, Takasawa S, Nakamura S, Okamoto H | title = Human gene encoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase): organization, nucleotide sequence and alternative splicing | journal = Gene | volume = 186 | issue = 2 | pages = 285–92 | date = February 1997 | pmid = 9074508 | doi = 10.1016/S0378-1119(96)00723-8}}
• {{cite journal | vauthors = Feito MJ, Bragardo M, Buonfiglio D, Bonissoni S, Bottarel F, Malavasi F, Dianzani U | title = gp 120s derived from four syncytium-inducing HIV-1 strains induce different patterns of CD4 association with lymphocyte surface molecules | journal = International Immunology | volume = 9 | issue = 8 | pages = 1141–7 | date = August 1997 | pmid = 9263011 | doi = 10.1093/intimm/9.8.1141 | doi-access = free}}
• {{cite journal | vauthors = Ferrero E, Malavasi F | title = Human CD38, a leukocyte receptor and ectoenzyme, is a member of a novel eukaryotic gene family of nicotinamide adenine dinucleotide+-converting enzymes: extensive structural homology with the genes for murine bone marrow stromal cell antigen 1 and aplysian ADP-ribosyl cyclase | journal = Journal of Immunology | volume = 159 | issue = 8 | pages = 3858–65 | date = October 1997 | doi = 10.4049/jimmunol.159.8.3858 | pmid = 9378973 | s2cid = 25461949 | doi-access = free}}
• {{cite journal | vauthors = Deaglio S, Morra M, Mallone R, Ausiello CM, Prager E, Garbarino G, Dianzani U, Stockinger H, Malavasi F | title = Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member | journal = Journal of Immunology | volume = 160 | issue = 1 | pages = 395–402 | date = January 1998 | doi = 10.4049/jimmunol.160.1.395 | pmid = 9551996 | s2cid = 15132619 | doi-access = free}}
• {{cite journal | vauthors = Yagui K, Shimada F, Mimura M, Hashimoto N, Suzuki Y, Tokuyama Y, Nata K, Tohgo A, Ikehata F, Takasawa S, Okamoto H, Makino H, Saito Y, Kanatsuka A | title = A missense mutation in the CD38 gene, a novel factor for insulin secretion: association with Type II diabetes mellitus in Japanese subjects and evidence of abnormal function when expressed in vitro | journal = Diabetologia | volume = 41 | issue = 9 | pages = 1024–8 | date = September 1998 | pmid = 9754820 | doi = 10.1007/s001250051026 | doi-access = free}}

{{refend}}

• {{MeshName|CD38+Antigens}}
• {{UCSC gene info|CD38}}
• GeneCard CD38 [https://www.genecards.org/cgi-bin/carddisp.pl?gene=CD38]
• {{PDBe-KB2|P28907|ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1}}
• [https://en.longevitywiki.org/wiki/CD38 CD38]

{{PDB Gallery|geneid=952}}

{{Clusters of differentiation}}

{{Clusters of differentiation by lineage}}

Category:Clusters of differentiation

Category:Glycoproteins