CD20
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| Aliases | MS4A1,B1, Bp35, CD20, CVID5, LEU-16, MS4A2, S7, membrane spanning 4-domains A1, FMC7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:112210;MGI:88321;HomoloGene:7259;GeneCards:MS4A1;OMA:MS4A1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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B-lymphocyte antigen CD20orCD20is B lymphocyte cell-surface molecule.
It is a 33-37 kDanon-glycosylatedprotein. CD20 is expressed on the surface ofB-cellsfrom the pre-B phase, the expression is lost in terminally differentiatedplasma cells.[5][6]
CD20 is used as a therapeutical target of B-cell malignancies and autoimmune diseases.[6]
Gene[edit]
In humans CD20 is encoded by theMS4A1genelocalized to 11q12.[7][8]
The gene is 16 kbp long and consists of 8 exons. There are at least 3 mRNA transcripts (resulting fromalternative splicing), that are all translated into an identical full-length CD20 protein product.[6][8]Variants 1 and 2 are poorlytranslateddue to inhibitoryupstream open reading framesandstem-loopstructures within their 5'untranslated regions.The relative abundance of translation-competent variant 3, as opposed to the poorly translated variants 1 and 2, may be a key determinant of CD20 levels in normal and malignant human B cells and their responses to CD20-directedimmunotherapies.[9]
MS4A1gene is a member of themembrane-spanning 4Agene family. Members of this nascent protein family are characterized by common structural features and similarintron/exonsplice boundaries and display unique expression patterns amonghematopoieticcells and non-lymphoid tissues.[8]
Structure[edit]
CD20 is a transmembrane protein consisting of fourhydrophobictransmembrane domains, one intracellular domain and two extracellular loops. There are three different forms of CD20 according to variable phosphorylation.
CD20 is located on the cell surface as homo-dimeric and homo-tetrameric oligomers. It is associated with other cell-surface and cytoplasmic proteins connected to thesignal transduction(CD53,CD81,CD82).
CD20 is also known to be physically coupled tomajor histocompatibility complex class II(MHCII),CD40andB-cell receptor(BCR).[6]
Function[edit]
The biological function of CD20 as well as its naturalligandis not fully elucidated.[6][10]
CD20 deletion in mice does not impair B-cell differentiation, isotype switch, maturation, proliferation or tissue localization. However, CD20−/− mice show decreasedhumoral immunityresponses in both T-cell dependent and T-cell independent manner.[6]
Functional studies suggest that CD20 molecule is required for efficient BCR signaling. It possibly acts as a calcium channel (CD20 has structural similarities with some knownion channels) or is directly connected to calcium flux.
It is not fully understood, if other molecular pathways or B and T-cell interactions might be affected by CD20 levels on the B-cell surface.[6][11]
Expression[edit]
CD20 is expressed on all stages of B cell development from pre-B cells in the bone-marrow through immature,naive,mature andmemory cellsinlymphoid tissuesand blood. The expression is lost on plasma blasts andplasma cells.[12][13]
CD20 is a marker of B cell malignancies. It is found on B-celllymphomas,hairy cell leukemia,B-cellchronic lymphocytic leukemia,and melanomacancer stem cells.[14]
Immunohistochemistrycan be used to determine the presence of CD20 on cells inhistologicaltissue sections. Because CD20 remains present on the cells of most B-cellneoplasms,and is absent on otherwise similar appearingT-cellneoplasms, it can be very useful in diagnosing conditions such as B-cell lymphomas and leukaemias.
However, the presence or absence of CD20 in such tumours is not relevant to prognosis, with the progression of the disease being much the same in either case. CD20 positive cells are also sometimes found in cases ofHodgkins disease,myeloma,andthymoma.[15]
Even though B cells represent the majority of CD20+ cells, a subset of CD3+ T cells also expresses CD20. CD20+ T cells are mostly CD8+ effector memory T cells with proinflammatory features. Further work is needed to understand the contribution of these cells to immune responses.[16]
Anti-CD20 monoclonal antibodies[edit]
The targeting of CD20 molecule is highly effective way to deplete B-cell populations.[11]Thus, anti-CD20monoclonal antibodies(mAbs) play a crucial role in the management ofB cell malignanciesas well as some inflammatory andautoimmune diseases.The first anti-CD20 mAb approved by FDA in 1997 wasRituximab,defining a new epoch inhematooncology.
The advantages of CD20 as a therapeutic target are:
- conserved expressionCD20 is expressed on the surface of virtually all mature B-cells. The expression on malignous B-cells is also relatively constant.
- limited off-target toxicityAnti-CD20 therapy does not affect hematopoietic stem cells and plasma cells, since they do not express CD20. It is important for B-cell repopulation following the therapy and retaining humoral protection against previously encountered pathogens via plasma cells, respectively.
- epitopestabilityThe extracellular loops of CD20 are conserved sequences and undergo only a littlepost-translational modifications.It provides stable and predictable binding epitopes for mAbs.
Mechanism[edit]
Mechanism of action of anti-CD20 effects include:[11][17]
- Complement dependent cytotoxicityAnti-CD20 mAbs interact withC1q complement protein,leading toclassical complement pathwayactivation and eventualcomplement dependent cytotoxicity.
- Fcγ receptor mediated effectsFcγ receptors expressed onneutrophils,NK cellsormacrophagesinteract withFc partof anti-CD20 mAb. The interaction leads to enhanced cytotoxic activity of NK cells (antibody-dependent cell-mediated cytotoxicity) andphagocytosisby macrophages and neutrophils (antibody-dependent cell-mediated phagocytosis).
- Hyper-crosslinkingThe accumulation of anti-CD20 mAbs on the cell surface may cause caspase-dependentapoptotic cell death.
In clinical practise[edit]
Examples of anti-CD20 mAbs and their approval status:[17]
| Generic name | Format | Indication | Approval status
(FDA/EMA) |
|---|---|---|---|
| Rituximab | chimericIgG1 | NHL | 1998/1997 |
| Ibritumomab | mouse IgG1 | NHL | 2002/2004 |
| Ofatumumab | human IgG1 | CLL | 2009/2009 |
| Obinutuzumab | humanized IgG1 | CLL | 2013/2014 |
| Ocrelizumab | humanized IgG1 | MS | 2017/under review |
| Veltuzumab | humanized IgG1 | NHL, CLL,ITP | clinical trials |
| Ublituximab | chimeric IgG1 | CLL, MS | clinical trials |
| Ocaratuzumab | humanized IgG1 | CLL | clinical trials |
CD20 is the target of the mAbsrituximab,ocrelizumab,obinutuzumab,ofatumumab,ibritumomab tiuxetan,tositumomab,andublituximab,which are all active agents in the treatment of all B celllymphomas,leukemias,and B cell-mediated autoimmune diseases.
The anti-CD20 mABofatumumab(Genmab) was approved by FDA in October 2009 forchronic lymphocytic leukemia.
The anti-CD20 mABobinutuzumab(Gazyva) was approved by FDA in November 2013 forchronic lymphocytic leukemia.
Ocrelizumabwas approved by the FDA in March 2017 formultiple sclerosisas the first treatment of the primary progressive form of MS. Clinical trials inrheumatoid arthritisandsystemic lupus erythematosuswere discontinued in 2010 due to an infection related safety risk.[18]
Although phase II trials for the use ofRituximabinmyalgic encephalomyelitisshowed promising results, these could not be replicated in a large randomized controlled trial[19]and preliminary results from a Phase III trial were negative.[20]
Additional anti-CD20 antibody therapeutics under development (phase II or III clinical trials in 2008) include:
- Obinutuzumabforsystemic lupus erythematosus,
- Ocaratuzumabforfollicular lymphomaandrheumatoid arthritis,
- TRU-015 (byTrubion), (discontinued in 2010[21])
- IMMU-106 (veltuzumab).[22]fornon-Hodgkin's lymphomaor (2015)immune thrombocytopenia.
Clinical significance[edit]
Diabetes mellitus[edit]
A link between theimmune system'sB cellsanddiabetes mellitushas been determined.[23]
In cases ofobesity,the presence of fatty tissues surrounding the body's major organ systems results in cellnecrosisand insulin insensitivity along the boundary between them. Eventually, the contents of fat cells that would otherwise have been digested by insulin are shed into the bloodstream. Aninflammationresponse that mobilizes bothTandB cellsresults in the creation ofantibodiesagainst these cells, causing them to become less responsive toinsulinby an as-yet-unknown mechanism and promotinghypertension,hypertriglyceridemia,andarteriosclerosis,hallmarks of themetabolic syndrome.
Obese mice administered anti-B cell CD-20 antibodies, however, did not become less responsive to insulin and as a result, did not develop diabetes mellitus or the metabolic syndrome, the posited mechanism being that anti-CD20 antibodies rendered the T cell antibodies dysfunctional and therefore powerless to cause insulin insensitivity by a B cell antibody-modulated autoimmune response. The protection afforded by anti-CD-20 lasted approximately forty days—the time it takes the body to replenish its supply of B cells—after which repetition was necessary to restore it. Hence, it has been argued that diabetes mellitus be reclassified as anautoimmune diseaserather than a purely metabolic one and focus treatment for it on immune system modulation.[24]
References[edit]
- ^abcGRCh38: Ensembl release 89: ENSG00000156738–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000024673–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^Hardy R (2008). "Chapter 7: B Lymphocyte Development and Biology". In Paul W (ed.).Fundamental Immunology(Book) (6th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 237–269.ISBN978-0-7817-6519-0.
- ^abcdefgPavlasova G, Mraz M (June 2020)."The regulation and function of CD20: an" enigma "of B-cell biology and targeted therapy".Haematologica.105(6): 1494–1506.doi:10.3324/haematol.2019.243543.PMC7271567.PMID32482755.
- ^Tedder TF, Streuli M, Schlossman SF, Saito H (January 1988)."Isolation and structure of a cDNA encoding the B1 (CD20) cell-surface antigen of human B lymphocytes".Proceedings of the National Academy of Sciences of the United States of America.85(1): 208–212.Bibcode:1988PNAS...85..208T.doi:10.1073/pnas.85.1.208.PMC279513.PMID2448768.
- ^abc"Entrez Gene: MS4A1 membrane-spanning 4-domains, subfamily A, member 1".
- ^Ang Z, Paruzzo L, Hayer KE, Schmidt C, Torres Diz M, Xu F, et al. (November 2023)."Alternative splicing of its 5'-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies".Blood.142(20): 1724–1739.doi:10.1182/blood.2023020400.PMC10667349.PMID37683180.S2CID261620430.
- ^Cragg MS, Walshe CA, Ivanov AO, Glennie MJ (2005). "The biology of CD20 and its potential as a target for mAb therapy".B Cell Trophic Factors and B Cell Antagonism in Autoimmune Disease.Current Directions in Autoimmunity. Vol. 8. pp. 140–74.doi:10.1159/000082102.ISBN978-3-8055-7851-6.PMID15564720.
- ^abcCasan JM, Wong J, Northcott MJ, Opat S (2 December 2018)."Anti-CD20 monoclonal antibodies: reviewing a revolution".Human Vaccines & Immunotherapeutics.14(12): 2820–2841.doi:10.1080/21645515.2018.1508624.PMC6343614.PMID30096012.
- ^Walport M, Murphy K, Janeway C, Travers PJ (2008).Janeway's Immunobiology(7th ed.). New York: Garland Science.ISBN978-0-8153-4123-9.
- ^Bonilla FA, Bona CA (1996). "5".Textbook of Immunology.Boca Raton: CRC. p. 102.ISBN978-3-7186-0596-5.
- ^Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, et al. (October 2005)."A tumorigenic subpopulation with stem cell properties in melanomas".Cancer Research.65(20): 9328–9337.doi:10.1158/0008-5472.CAN-05-1343.PMID16230395.
- ^Cooper K, Anthony Leong AS-Y (2003).Manual of diagnostic antibodies for immunohistology(2nd ed.). London: Greenwich Medical Media.ISBN978-1-84110-100-2.
- ^de Sèze J, Maillart E, Gueguen A, Laplaud DA, Michel L, Thouvenot E, et al. (23 March 2023)."Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic".Frontiers in Immunology.14:1004795.doi:10.3389/fimmu.2023.1004795.PMC10076836.PMID37033984.
- ^abMarshall MJ, Stopforth RJ, Cragg MS (4 October 2017)."Therapeutic Antibodies: What Have We Learnt from Targeting CD20 and Where Are We Going?".Frontiers in Immunology.8:1245.doi:10.3389/fimmu.2017.01245.PMC5632755.PMID29046676.
- ^"Roche and Biogen Idec Announce Their Decision to Discontinue the ocrelizumab Clinical Development Programme in Patients with Rheumatoid Arthritis".investors.biogen.com.Retrieved6 January2022.
- ^Fluge Ø, Rekeland IG, Lien K, Thürmer H, Borchgrevink PC, Schäfer C, et al. (May 2019). "B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial".Annals of Internal Medicine.170(9): 585–593.doi:10.7326/M18-1451.PMID30934066.S2CID91186383.
- ^"ME-studie med negative resultater".Dagens Medicin(in Norwegian).Retrieved6 January2022.
- ^"Trubion announces Pfizer's decision to discontinue development of TRU-015 for RA".Trubion Pharmaceuticals, Inc. press release.15 June 2010.
- ^Note: information included in this article only found in table present in print version of article.Morrow Jr KJ (15 June 2008)."Methods for Maximizing Antibody Yields".Genetic Engineering & Biotechnology News.Mary Ann Liebert, Inc.p. 36. Archived fromthe originalon 13 February 2009.Retrieved6 July2008.
- ^Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, et al. (May 2011)."B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies".Nature Medicine.17(5): 610–617.doi:10.1038/nm.2353.PMC3270885.PMID21499269.
- Krista Conger (17 April 2011)."Type-2 diabetes linked to autoimmune reaction in study".Stanford School of Medicine.Archived fromthe originalon 6 May 2011.
- ^"Diabetes Mellitus".The Lecturio Medical Concept Library.Retrieved9 July2021.
Further reading[edit]
- Macardle PJ, Nicholson IC (2003). "CD20".Journal of Biological Regulators and Homeostatic Agents.16(2): 136–138.PMID12144126.
- Tamayose K, Sato N, Ando J, Sugimoto K, Oshimi K (December 2002). "CD3-negative, CD20-positive T-cell prolymphocytic leukemia: case report and review of the literature".American Journal of Hematology.71(4): 331–335.doi:10.1002/ajh.10224.PMID12447967.S2CID23999423.
- Küster H, Zhang L, Brini AT, MacGlashan DW, Kinet JP (June 1992)."The gene and cDNA for the human high affinity immunoglobulin E receptor beta chain and expression of the complete human receptor".The Journal of Biological Chemistry.267(18): 12782–12787.doi:10.1016/S0021-9258(18)42344-7.PMID1535625.
- Einfeld DA, Brown JP, Valentine MA, Clark EA, Ledbetter JA (March 1988)."Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains".The EMBO Journal.7(3): 711–717.doi:10.1002/j.1460-2075.1988.tb02867.x.PMC454379.PMID2456210.
- Tedder TF, Disteche CM, Louie E, Adler DA, Croce CM, Schlossman SF, et al. (April 1989)."The gene that encodes the human CD20 (B1) differentiation antigen is located on chromosome 11 near the t(11;14)(q13;q32) translocation site".Journal of Immunology.142(7): 2555–2559.doi:10.4049/jimmunol.142.7.2555.PMID2466898.S2CID20030567.
- Tedder TF, Klejman G, Schlossman SF, Saito H (April 1989)."Structure of the gene encoding the human B lymphocyte differentiation antigen CD20 (B1)".Journal of Immunology.142(7): 2560–2568.doi:10.4049/jimmunol.142.7.2560.PMID2466899.S2CID30587436.
- Loken MR, Shah VO, Dattilio KL, Civin CI (November 1987)."Flow cytometric analysis of human bone marrow. II. Normal B lymphocyte development".Blood.70(5): 1316–1324.doi:10.1182/blood.V70.5.1316.1316.PMID3117132.
- Stamenkovic I, Seed B (June 1988)."Analysis of two cDNA clones encoding the B lymphocyte antigen CD20 (B1, Bp35), a type III integral membrane protein".The Journal of Experimental Medicine.167(6): 1975–1980.doi:10.1084/jem.167.6.1975.PMC2189672.PMID3260267.
- Bofill M, Janossy G, Janossa M, Burford GD, Seymour GJ, Wernet P, et al. (March 1985)."Human B cell development. II. Subpopulations in the human fetus".Journal of Immunology.134(3): 1531–1538.doi:10.4049/jimmunol.134.3.1531.PMID3871452.S2CID29484405.
- Deans JP, Kalt L, Ledbetter JA, Schieven GL, Bolen JB, Johnson P (September 1995)."Association of 75/80-kDa phosphoproteins and the tyrosine kinases Lyn, Fyn, and Lck with the B cell molecule CD20. Evidence against involvement of the cytoplasmic regions of CD20".The Journal of Biological Chemistry.270(38): 22632–22638.doi:10.1074/jbc.270.38.22632.PMID7545683.
- Valentine MA, Licciardi KA, Clark EA, Krebs EG, Meier KE (January 1993)."Insulin regulates serine/threonine phosphorylation in activated human B lymphocytes".Journal of Immunology.150(1): 96–105.doi:10.4049/jimmunol.150.1.96.PMID7678037.S2CID24522632.
- Bubien JK, Zhou LJ, Bell PD, Frizzell RA, Tedder TF (June 1993)."Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes".The Journal of Cell Biology.121(5): 1121–1132.doi:10.1083/jcb.121.5.1121.PMC2119683.PMID7684739.
- Shirakawa T, Li A, Dubowitz M, Dekker JW, Shaw AE, Faux JA, et al. (June 1994). "Association between atopy and variants of the beta subunit of the high-affinity immunoglobulin E receptor".Nature Genetics.7(2): 125–129.doi:10.1038/ng0694-125.PMID7920628.S2CID24026689.
- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides".Gene.138(1–2): 171–174.doi:10.1016/0378-1119(94)90802-8.PMID8125298.
- Szepetowski P, Perucca-Lostanlen D, Gaudray P (June 1993). "Mapping genes according to their amplification status in tumor cells: contribution to the map of 11q13".Genomics.16(3): 745–750.doi:10.1006/geno.1993.1257.PMID8325649.
- Algino KM, Thomason RW, King DE, Montiel MM, Craig FE (July 1996)."CD20 (pan-B cell antigen) expression on bone marrow-derived T cells".American Journal of Clinical Pathology.106(1): 78–81.doi:10.1093/ajcp/106.1.78.PMID8701937.
- Szöllósi J, Horejsí V, Bene L, Angelisová P, Damjanovich S (October 1996)."Supramolecular complexes of MHC class I, MHC class II, CD20, and tetraspan molecules (CD53, CD81, and CD82) at the surface of a B cell line JY".Journal of Immunology.157(7): 2939–2946.doi:10.4049/jimmunol.157.7.2939.PMID8816400.S2CID18389389.
- Kanzaki M, Lindorfer MA, Garrison JC, Kojima I (June 1997)."Activation of the calcium-permeable cation channel CD20 by alpha subunits of the Gi protein".The Journal of Biological Chemistry.272(23): 14733–14739.doi:10.1074/jbc.272.23.14733.PMID9169438.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library".Gene.200(1–2): 149–156.doi:10.1016/S0378-1119(97)00411-3.PMID9373149.
External links[edit]
- CD20+antigenat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- representations of the shape are foundhereand more detailhere
- HumanMS4A1genome location andMS4A1gene details page in theUCSC Genome Browser.
- HumanMS4A2genome location andMS4A2gene details page in theUCSC Genome Browser.