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{{Infobox_gene}}
{{Infobox_gene}}
'''B-lymphocyte antigen CD19''', also known as '''CD19''' ('''C'''luster of '''D'''ifferentiation '''19'''), is a [[protein]] that in humans is encoded by the ''CD19'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: CD19 CD19 molecule| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=930| accessdate = }}</ref><ref name="pmid2472450">{{cite journal | vauthors = Tedder TF, Isaacs CM | title = Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily | journal = Journal of Immunology | volume = 143 | issue = 2 | pages = 712–7 | date = Jul 1989 | pmid = 2472450 | doi =  }}</ref> It is found on the surface of [[B-cells]], a type of [[white blood cell]].
'''B-lymphocyte antigen CD19''', also known as '''CD19 molecule''' ([[Cluster of differentiation|'''C'''luster of '''D'''ifferentiation]] '''19'''), '''B-Lymphocyte Surface Antigen B4''', '''T-Cell Surface Antigen Leu-12''' and '''CVID3''' is a transmembrane protein that in humans is encoded by the gene ''CD19''.<ref name="entrez">{{cite web | title = Entrez Gene: CD19 CD19 molecule| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=930| access-date = }}</ref><ref name="pmid2472450">{{cite journal | vauthors = Tedder TF, Isaacs CM | title = Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily | journal = Journal of Immunology | volume = 143 | issue = 2 | pages = 712–7 | date = July 1989 | pmid = 2472450 | doi =  }}</ref> In humans, CD19 is expressed in all B lineage cells, except for [[plasma cell]]s, and in [[follicular dendritic cells]].<ref name="Schroeder_2013">{{cite book | title = Clinical immunology: Principles and Practice | last1 = Schroeder | first1 = Harry W | last2 = Rich | first2 = Robert R. | name-list-format = vanc | year = 2013 | isbn = 978-0-7234-3691-1 | edition = 4th | location = London | pages = 47–51 | chapter = Chapter 4: Antigen receptor genes, gene products, and co-receptors | oclc = 823736017 }}</ref><ref name="Scheuermann_1995">{{cite journal | vauthors = Scheuermann RH, Racila E | title = CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy | journal = Leukemia & Lymphoma | volume = 18 | issue = 5–6 | pages = 385–97 | date = August 1995 | pmid = 8528044 | doi = 10.3109/10428199509059636 }}</ref> CD19 plays two major roles in human [[B cell]]s. It acts as an [[Signal transducing adaptor protein|adaptor protein]] to recruit cytoplasmic [[signaling proteins]] to the membrane and it works within the CD19/CD21 complex to decrease the threshold for [[B-cell receptor|B cell receptor]] signaling pathways. Due to its presence on all B cells, it is a [[Biomarker (cell)|biomarker]] for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia [[Immunotherapy|immunotherapies]].<ref name="Scheuermann_1995" />
 
== Structure ==
In humans, CD19 is encoded by the 7.41 kilobase ''CD19'' gene located on the short arm of chromosome 16.<ref name="Wang_2012">{{cite journal | vauthors = Wang K, Wei G, Liu D | title = CD19: a biomarker for B cell development, lymphoma diagnosis and therapy | journal = Experimental Hematology & Oncology | volume = 1 | issue = 1 | pages = 36 | date = November 2012 | pmid = 23210908 | pmc = 3520838 | doi = 10.1186/2162-3619-1-36 }}</ref><ref name="Zhou_1992">{{cite journal | vauthors = Zhou LJ, Ord DC, Omori SA, Tedder TF | title = Structure of the genes encoding the CD19 antigen of human and mouse B lymphocytes | journal = Immunogenetics | volume = 35 | issue = 2 | pages = 102–11 | date = 1992 | pmid = 1370948 }}</ref> It contains at least fifteen [[exon]]s, four that encode extracellular domain and nine that encode cytoplasmic domains, with a total of 556 amino acids.<ref name="Zhou_1992" /> Experiments show that there are multiple [[Messenger RNA|mRNA]] transcripts; however, only two have been isolated [[in vivo|''in vivo''.]]<ref name="Wang_2012" />
 
CD19 is a 95 kd Type I transmembrane [[glycoprotein]] in the immunoglobulin superfamily ([[Immunoglobulin superfamily|IgSF]]) with two extracellular C2-set Ig-like domains and a relatively large, 240 [[amino acid]], cytoplasmic tail that is highly conserved among mammalian species.<ref name="Wang_2012" /><ref name="Mei_2012">{{cite journal | vauthors = Mei HE, Schmidt S, Dörner T | title = Rationale of anti-CD19 immunotherapy: an option to target autoreactive plasma cells in autoimmunity | journal = Arthritis Research & Therapy | volume = 14 Suppl 5 | issue = 5 | pages = S1 | date = November 2012 | pmid = 23281743 | pmc = 3535716 | doi = 10.1186/ar3909 }}</ref><ref name="Haas_2005">{{cite book | title = Mechanisms of Lymphocyte Activation and Immune Regulation X | volume = 560 | last1 = Haas | first1 = Karen M.| last2 = Tedder | first2 = Thomas F. | name-list-format = vanc | date = 2005 | publisher = Springer, Boston, MA | isbn = 978-0-387-24188-3 | series = Advances in Experimental Medicine and Biology | pages = 125–139 | doi = 10.1007/0-387-24180-9_16 |pmid = 15934172}}</ref><ref>{{cite journal | vauthors = Tedder TF, Isaacs CM | title = Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily | journal = Journal of Immunology | volume = 143 | issue = 2 | pages = 712–7 | date = July 1989 | pmid = 2472450 }}</ref>  The extracellular C2-type Ig-like domains are divided by a potential disulfide linked non-Ig-like domain and N-linked carbohydrate addition sites.<ref name="Haas_2005" /><ref name="Tedder_2009">{{cite journal | vauthors = Tedder TF | title = CD19: a promising B cell target for rheumatoid arthritis | journal = Nature Reviews. Rheumatology | volume = 5 | issue = 10 | pages = 572–7 | date = October 2009 | pmid = 19798033 | doi = 10.1038/nrrheum.2009.184 }}</ref> The cytoplasmic tail contains at least nine [[tyrosine]] residues near the [[C-terminus]].<ref name="Wang_2012" /><ref name="Haas_2005" /> Within these residues, Y391, Y482, and Y513 have been shown to be essential to the biological functions of CD19.<ref name="Del_Nagro_2005">{{cite journal | vauthors = Del Nagro CJ, Otero DC, Anzelon AN, Omori SA, Kolla RV, Rickert RC | title = CD19 function in central and peripheral B-cell development | journal = Immunologic Research | volume = 31 | issue = 2 | pages = 119–31 | date = 2005 | pmid = 15778510 | doi = 10.1385/IR:31:2:119  }}</ref> [[Phenylalanine]] substitution for tyrosine at Y482 and Y513 leads to the inhibition of [[phosphorylation]] at the other tyrosines.<ref name="Wang_2012" /><ref name="Carter_2002">{{cite journal | vauthors = Carter RH, Wang Y, Brooks S | title = Role of CD19 signal transduction in B cell biology | journal = Immunologic Research | volume = 26 | issue = 1–3 | pages = 45–54 | date = 2002 | pmid = 12403344 | doi = 10.1385/IR:26:1-3:045 }}</ref>
 
== Expression ==
CD19 is widely expressed during all phases of B cell development until terminal differentiation into plasma cells. During B cell [[lymphopoiesis]], CD19 surface expression starts during immunoglobulin (Ig) [[gene rearrangement]], which coincides during B lineage commitment from [[hematopoietic stem cell]].<ref name="Scheuermann_1995" /> Throughout development, the surface density of CD19 is highly regulated.<ref name="Wang_2012" /> CD19 expression in mature B cells is three fold higher than that in immature B cells.<ref name="Wang_2012" /> CD19 is expressed on all normal, mitogen-stimulated, and [[Malignancy|malignant]] B cells, excluding plasma cells. CD19 expression is even maintained in B lineage cells that undergo [[neoplastic transformation]].<ref name="Schroeder_2013" /><ref name="Carter_2002" /> Because of its ubiquity on all B cells, it can function as a B cell [[Cell marker|marker]] and a target for immunotherapies targeting neoplastic [[lymphocyte]]s.<ref name="Scheuermann_1995" /><ref name="Wang_2012" />


== Function ==
== Function ==


[[Lymphocytes]] proliferate and differentiate in response to various concentrations of different [[antigens]]. The ability of the [[B cell]] to respond in a specific, yet sensitive manner to the various antigens is achieved with the use of low-affinity antigen receptors. The CD19 gene encodes a cell surface molecule that assembles with the antigen receptor of B lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation.<ref name="entrez"/>
=== Role in development & survival ===
Decisions to live, [[Cell proliferation|proliferate]], [[Cellular differentiation|differentiate]], or die are continuously being made during B cell development.<ref>{{cite journal | vauthors = Otero DC, Anzelon AN, Rickert RC | title = CD19 function in early and late B cell development: I. Maintenance of follicular and marginal zone B cells requires CD19-dependent survival signals | journal = Journal of Immunology | volume = 170 | issue = 1 | pages = 73–83 | date = January 2003 | pmid = 12496385 }}</ref> These decisions are tightly regulated through BCR interactions and signaling. The presence of a functional BCR is necessary during antigen-dependent differentiation and for continued survival in the peripheral immune system.<ref name="Haas_2005" /> Essential to the functionality of a BCR is the presence of CD19.<ref name="Sato_1999">{{cite journal | vauthors = Sato S | title = CD19 is a central response regulator of B lymphocyte signaling thresholds governing autoimmunity | journal = Journal of Dermatological Science | volume = 22 | issue = 1 | pages = 1–10 | date = December 1999 | pmid = 10651223 | doi = 10.1016/s0923-1811(99)00043-2 }}</ref> Experiments using CD19 knockout mice found that CD19 is essential for B cell differentiative events including the formation of [[B-1 cell|B-1]], [[germinal center]], and [[Marginal zone B-cell|marginal zone]] (MZ) B cells.<ref name="Haas_2005" /><ref name="Rickert_1995">{{cite journal | vauthors = Rickert RC, Rajewsky K, Roes J | title = Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice | journal = Nature | volume = 376 | issue = 6538 | pages = 352–5 | date = July 1995 | pmid = 7543183 | doi = 10.1038/376352a0 }}</ref><ref name="Engel_1995">{{cite journal | vauthors = Engel P, Zhou LJ, Ord DC, Sato S, Koller B, Tedder TF | title = Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule | journal = Immunity | volume = 3 | issue = 1 | pages = 39–50 | date = July 1995 | pmid = 7542548 | doi = 10.1016/1074-7613(95)90157-4 }}</ref> Analysis of mixed bone marrow [[Chimera (genetics)|chimeras]] suggest that prior to an initial antigen encounter, CD19 promotes the survival of [[Naive B cell|naive]] recirculating B cells and increases the in vivo life span of B cells in the peripheral B cell compartment.<ref name="Chung_2012">{{cite journal | vauthors = Chung EY, Psathas JN, Yu D, Li Y, Weiss MJ, Thomas-Tikhonenko A | title = CD19 is a major B cell receptor-independent activator of MYC-driven B-lymphomagenesis | journal = The Journal of Clinical Investigation | volume = 122 | issue = 6 | pages = 2257–66 | date = June 2012 | pmid = 22546857 | doi = 10.1172/jci45851 | pmc = 3366393 }}</ref> Ultimately, CD19 expression is integral to the propagation of BCR-induced survival signals and the maintenance of homeostasis through tonic signaling.


CD19 is expressed on [[follicular dendritic cells]] and B cells. In fact, it is present on B cells from earliest recognizable B-lineage cells during development to B-cell blasts but is lost on maturation to [[plasma cells]]. It primarily acts as a B cell co-receptor in conjunction with [[CD21]] and [[CD81]].  Upon activation, the cytoplasmic tail of CD19 becomes [[phosphorylated]], which leads to binding by [[Src (gene)|Src]]-family kinases and recruitment of [[PI-3 kinase]].
=== BCR-independent ===
Paired box transcription factor 5 ([[PAX5]]) plays a major role in B cell differentiation from pro B cell to mature B cell, the point at which the expression of non-B-lineage genes is permanently blocked.<ref name="Chung_2012" /><ref>{{cite journal | vauthors = Monroe JG | title = ITAM-mediated tonic signalling through pre-BCR and BCR complexes | journal = Nature Reviews. Immunology | volume = 6 | issue = 4 | pages = 283–94 | date = April 2006 | pmid = 16557260 | doi = 10.1038/nri1808 }}</ref><ref>{{cite journal | vauthors = Maier H, Ostraat R, Parenti S, Fitzsimmons D, Abraham LJ, Garvie CW, Hagman J | title = Requirements for selective recruitment of Ets proteins and activation of mb-1/Ig-alpha gene transcription by Pax-5 (BSAP) | journal = Nucleic Acids Research | volume = 31 | issue = 19 | pages = 5483–9 | date = October 2003 | pmid = 14500810 | pmc = 206479 | doi = 10.1093/nar/gkg785 }}</ref> Part of B cell differentiation is controlling [[Myc|c-MYC]] protein stability and steady-state levels through CD19, which acts as a PAX5 target and downstream effector of the [[PI3K/AKT/mTOR pathway|PI3K-AKT-GSK3β axis]]. CD19 signaling, independent of BCR functions, increases c-MYC protein stability. Using a loss of function approach, researchers found reduced MYC levels in B cells of CD19 [[Gene knockdown|knockdown]] mice.<ref name="Chung_2012" /> CD19 signaling involves the recruitment and activation of phosphoinositide 3-kinase [[Phosphoinositide 3-kinase|(PI3K]]) and later downstream, the activation of protein kinase B ([[Protein kinase B|Akt]]). The Akt-GSK3β axis is necessary for MYC activation by CD19 in BCR-negative cells, with higher levels of Akt activation corresponding to higher levels of MYC.<ref name="Chung_2012" /><ref name="Poe_2012">{{cite journal | vauthors = Poe JC, Minard-Colin V, Kountikov EI, Haas KM, Tedder TF | title = A c-Myc and surface CD19 signaling amplification loop promotes B cell lymphoma development and progression in mice | journal = Journal of Immunology | volume = 189 | issue = 5 | pages = 2318–25 | date = September 2012 | pmid = 22826319 | doi = 10.4049/jimmunol.1201000 | pmc = 3426298 }}</ref> CD19 is a crucial BCR-independent regulator of MYC-driven neoplastic growth in B cells since the CD19-MYC axis promotes cell expansion ''[[in vitro]]'' and ''in vivo''.<ref name="Chung_2012" /><ref name="Poe_2012" />


As on T cells, several surface molecules form the antigen receptor and form a complex on B lymphocytes.  The (almost) B cell-specific CD19 phosphoglycoprotein is one of these molecules. The others are CD21 and CD81.  These surface immunoglobulin (sIg)-associated molecules facilitate signal transduction. On B cells, anti-immunoglobulin antibody mimicking exogenous antigen causes CD19 to bind to sIg and internalize with it. The reverse process has not been demonstrated, suggesting that formation of this receptor complex is antigen-induced.  This molecular association has been confirmed by chemical studies.
=== CD19/CD21 complex ===
On the cell surface, CD19 is the dominant signaling component of a multimolecular complex including [[Complement receptor 2|CD21]], a complement receptor, CD81, a tetraspanin membrane protein ([[CD81|TAPA-1]]), and CD225.<ref name="Wang_2012" /><ref name="Chung_2012" /> The CD19/CD21 complex arises from [[Complement component 3|C3d]] binding to CD21; however, CD19 does not require CD21 for [[signal transduction]]. CD81, attached to CD19, is a part of the [[Tetraspanin|tetraspanin web]], acts as a [[Chaperone (protein)|chaperone protein]], and provides docking sites for molecules in various different signal transduction pathways.<ref name="Wang_2012" />
 
=== BCR-dependent ===
While colligated with the BCR, the CD19/CD21 complex bound to the antigen-complement complex can decrease the threshold for B cell activation. CD21, complement receptor 2, can bind fragments of C3 that have covalently attached to [[glycoconjugate]]s by [[Complement system|complement activation]].<ref name="Morbach_2016">{{cite journal | vauthors = Morbach H, Schickel JN, Cunningham-Rundles C, Conley ME, Reisli I, Franco JL, Meffre E | title = CD19 controls Toll-like receptor 9 responses in human B cells | journal = The Journal of Allergy and Clinical Immunology | volume = 137 | issue = 3 | pages = 889–98.e6 | date = March 2016 | pmid = 26478008 | doi = 10.1016/j.jaci.2015.08.040 | pmc = 4783287 }}</ref> Recognition of an antigen by the complement system enables the CD19/CD21 complex and associated intracellular signaling molecules to [[Cross-link|crosslink]] to the BCR. This results in phosphorylation of the cytoplasmic tail of CD19 by BCR-associated [[tyrosine kinase]]s, ensuing is the binding of additional [[Src family kinase|Src-family kinases,]] augmentation of signaling through the BCR, and recruitment of PI3K. The localization of PI3K initiates another signaling pathway leading to Akt activation. Varying expression of CD19 on the cell surface modulates tyrosine phosphorylation and Akt kinase signaling and by extension, [[MHC class II]] mediated signaling.<ref name="Wang_2012" />
 
Activated spleen tyrosine kinase ([[Syk]]) leads to phosphorylation of the scaffold protein, [[B-cell linker|BLNK]], which provides multiple sites for tyrosine phosphorylation and recruits SH2-containing enzymes and adaptor proteins that can form various multiprotein signaling complexes. In this way, CD19 can modulate the threshold for B cell activation. This is important during primary immune response, prior to [[affinity maturation]], amplifying the response of low affinity BCRs to low concentrations of antigen.<ref name="Wang_2012" /><ref name="Morbach_2016" />


== Interactions ==
== Interactions ==


CD19 has been shown to [[Protein-protein interaction|interact]] with:
CD19 has been shown to [[Protein-protein interaction|interact]] with:
* [[CD81]],<ref name=pmid1383329/><ref name=pmid9804823/><ref name=pmid7636191/>
* [[CD81]]
* [[CD82 (gene)|CD82]]<ref name="pmid7636191">{{cite journal | vauthors = Imai T, Kakizaki M, Nishimura M, Yoshie O | title = Molecular analyses of the association of CD4 with two members of the transmembrane 4 superfamily, CD81 and CD82 | journal = Journal of Immunology | volume = 155 | issue = 3 | pages = 1229–39 | date = Aug 1995 | pmid = 7636191 | doi =  }}</ref>
* [[CD82 (gene)|CD82]]
* [[Complement receptor 2]],<ref name="pmid1383329">{{cite journal | vauthors = Bradbury LE, Kansas GS, Levy S, Evans RL, Tedder TF | title = The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules | journal = Journal of Immunology | volume = 149 | issue = 9 | pages = 2841–50 | date = Nov 1992 | pmid = 1383329 | doi =  }}</ref><ref name="pmid9804823">{{cite journal | vauthors = Horváth G, Serru V, Clay D, Billard M, Boucheix C, Rubinstein E | title = CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 46 | pages = 30537–43 | date = Nov 1998 | pmid = 9804823 | doi = 10.1074/jbc.273.46.30537 }}</ref> and
* [[Complement receptor 2]]
* [[VAV2]].<ref name="pmid11080163">{{cite journal | vauthors = Doody GM, Billadeau DD, Clayton E, Hutchings A, Berland R, McAdam S, Leibson PJ, Turner M | title = Vav-2 controls NFAT-dependent transcription in B- but not T-lymphocytes | journal = The EMBO Journal | volume = 19 | issue = 22 | pages = 6173–84 | date = Nov 2000 | pmid = 11080163 | pmc = 305817 | doi = 10.1093/emboj/19.22.6173 }}</ref>
* [[VAV2]]


==In disease==
==In disease==
Mutations in CD19 are associated with severe immunodeficiency syndromes characterized by diminished antibody production.<ref name="pmid2479707">{{cite journal | vauthors = Pesando JM, Bouchard LS, McMaster BE | title = CD19 is functionally and physically associated with surface immunoglobulin | journal = The Journal of Experimental Medicine | volume = 170 | issue = 6 | pages = 2159–64 | date = Dec 1989 | pmid = 2479707 | pmc = 2189531 | doi = 10.1084/jem.170.6.2159 }}</ref><ref name="pmid16672701">{{cite journal | vauthors = van Zelm MC, Reisli I, van der Burg M, Castaño D, van Noesel CJ, van Tol MJ, Woellner C, Grimbacher B, Patiño PJ, van Dongen JJ, Franco JL | title = An antibody-deficiency syndrome due to mutations in the CD19 gene | journal = The New England Journal of Medicine | volume = 354 | issue = 18 | pages = 1901–12 | date = May 2006 | pmid = 16672701 | doi = 10.1056/NEJMoa051568 }}</ref>


Since CD19 is a hallmark of B-cells, the protein has been used to diagnose cancers that arise from this type of cell - notably [[B-cell lymphomas]].<ref>{{cite journal | vauthors = Scheuermann RH, Racila E | title = CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy | journal = Leukemia & Lymphoma | volume = 18 | issue = 5-6 | pages = 385–97 | date = Aug 1995 | pmid = 8528044 | pmc =  | doi = 10.3109/10428199509059636 }}</ref> Since 2011, [[anti-CD19 immunotoxin]] treatments targeting CD19 have begun to enter trials.<ref>[http://clinicaltrials.gov/ct2/show/NCT01493453 A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy]</ref><ref>{{cite news | title = CAR T cells for leukemia and more? | url = http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=2898&sKey=12cf85b4-2673-4567-86a8-cb21a0e1f2f1&cKey=00df4880-4e2e-4bc1-80e7-4f66437a74c0&mKey=%7b2D8C569E-B72C-4E7D-AB3B-070BEC7EB280%7d | location = AACR Annual Meeting, Chicago, Illinois | agency = [[American Association for Cancer Research]] | date = April 3, 2012 | accessdate = 17 April 2013}}</ref><ref>Coghlan, Andy (26 March 2013) [https://www.newscientist.com/article/mg21729104.100-gene-therapy-cures-leukaemia-in-eight-days.html Gene therapy cures leukaemia in eight days] The New Scientist, Retrieved 15 April 2013</ref><ref>{{Cite web|url=https://www.cancer.gov/publications/dictionaries/cancer-terms?CdrID=543121|title=NCI Dictionary of Cancer Terms|website=National Cancer Institute|language=en|access-date=2017-02-24}}</ref> Most current experimental anti-CD19 drugs in development work by exploiting the presence of CD19 to direct treatment specifically towards B-cell cancers. However, it is now emerging that the protein plays an active role in driving the growth of these cancers, most intriguingly by stabilizing the concentrations of the [[MYC]] oncoprotein. This suggests that CD19 and its downstream signaling may be a more attractive therapeutic target than suspected <ref>{{cite journal | vauthors = Chung EY, Psathas JN, Yu D, Li Y, Weiss MJ, Thomas-Tikhonenko A | title = CD19 is a major B cell receptor-independent activator of MYC-driven B-lymphomagenesis | journal = The Journal of Clinical Investigation | volume = 122 | issue = 6 | pages = 2257–66 | date = Jun 2012 | pmid = 22546857 | pmc = 3366393 | doi = 10.1172/JCI45851 }}</ref><ref>[http://info.cancerresearchuk.org/news/archive/cancernews/2012-05-01-B-cell-lymphoma-discovery-could-lead-to-new-treatments B-cell lymphoma discovery could lead to new treatments] - [[Cancer Research UK]] news article, April 2012</ref>
=== Autoimmunity & immunodeficiency ===
[[Mutation]]s in CD19 are associated with severe [[immunodeficiency]] syndromes characterized by diminished [[antibody]] production.<ref>{{cite journal | vauthors = Pesando JM, Bouchard LS, McMaster BE | title = CD19 is functionally and physically associated with surface immunoglobulin | journal = The Journal of Experimental Medicine | volume = 170 | issue = 6 | pages = 2159–64 | date = December 1989 | pmid = 2479707 | doi = 10.1084/jem.170.6.2159 | pmc = 2189531 }}</ref><ref>{{cite journal | vauthors = van Zelm MC, Reisli I, van der Burg M, Castaño D, van Noesel CJ, van Tol MJ, Woellner C, Grimbacher B, Patiño PJ, van Dongen JJ, Franco JL | title = An antibody-deficiency syndrome due to mutations in the CD19 gene | journal = The New England Journal of Medicine | volume = 354 | issue = 18 | pages = 1901–12 | date = May 2006 | pmid = 16672701 | doi = 10.1056/nejmoa051568 }}</ref> Additionally, mutations in CD21 and CD81 can also underlie primary immunodeficiency due to their role in the CD19/CD21 complex formation.<ref>{{cite journal | vauthors = Carsetti R, Valentini D, Marcellini V, Scarsella M, Marasco E, Giustini F, Bartuli A, Villani A, Ugazio AG | title = Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome | journal = European Journal of Immunology | volume = 45 | issue = 3 | pages = 903–14 | date = March 2015 | pmid = 25472482 | pmc = 4674966 | doi = 10.1002/eji.201445049 }}</ref> These mutations can lead to [[Hypogammaglobulinemia|hypogammaglobulinaemia]] as a result of poor response to antigen and defective [[immunological memory]].<ref>{{cite journal | vauthors = Verstegen RH, Driessen GJ, Bartol SJ, van Noesel CJ, Boon L, van der Burg M, van Dongen JJ, de Vries E, van Zelm MC | display-authors = 6 | title = Defective B-cell memory in patients with Down syndrome | journal = The Journal of Allergy and Clinical Immunology | volume = 134 | issue = 6 | pages = 1346–1353.e9 | date = December 2014 | pmid = 25159464 | doi = 10.1016/j.jaci.2014.07.015 }}</ref> Researchers found changes in the constitution of B lymphocyte population and reduced amounts of switched [[memory B cell]]s with high terminal differentiation potential in patients with Down Syndrome.<ref>{{cite journal | vauthors = Seckin AN, Ozdemir H, Ceylan A, Artac H | title = Age-related alterations of the CD19 complex and memory B cells in children with Down syndrome | journal = Clinical and Experimental Medicine | volume = 18 | issue = 1 | pages = 125–131 | date = February 2018 | pmid = 28197808 | doi = 10.1007/s10238-017-0457-2 }}</ref> CD19 has also been implicated in [[autoimmune disease]]s, including rheumatoid arthritis and multiple sclerosis, and may be a useful treatment target.<ref name="Mei_2012" /><ref name="Tedder_2009" /><ref>{{cite journal | vauthors = Fujimoto M, Sato S | title = B cell signaling and autoimmune diseases: CD19/CD22 loop as a B cell signaling device to regulate the balance of autoimmunity | journal = Journal of Dermatological Science | volume = 46 | issue = 1 | pages = 1–9 | date = April 2007 | pmid = 17223015 | doi = 10.1016/j.jdermsci.2006.12.004 | url = https://kanazawa-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=13096&item_no=1&attribute_id=26&file_no=1 }}</ref>
 
Mouse model research shows that CD19 deficiency can lead to hyporesponsiveness to transmembrane signals and weak [[T cell]] dependent [[humoral response]], that in turn leads to an overall impaired humoral immune response.<ref name="Rickert_1995" /><ref name="Engel_1995" /> Additionally CD19 plays a role in modulating MHC Class II expression and signaling, which can be affected by mutations. CD19 deficient B cells exhibit selective growth disadvantage; therefore, it is rare for CD19 to be absent in neoplastic B cells, as it is essential for development.<ref name="Chung_2012" />
 
=== Cancer ===
Since CD19 is a marker of B cells, the protein has been used to diagnose cancers that arise from this type of cell - notably [[B-cell lymphomas|B cell lymphomas]], acute lymphoblastic leukemia ([[Acute lymphoblastic leukemia|ALL]]), and chronic lymphocytic leukemia ([[Chronic lymphocytic leukemia|CLL]]).<ref name="Scheuermann_1995" /> The majority of B cell malignancies express normal to high levels of CD19. The most current experimental [[anti-CD19 immunotoxin]]s in development work by exploiting the widespread presence of CD19 on B cells, with expression highly conserved in most neoplastic B cells, to direct treatment specifically towards B-cell cancers.<ref name="Mei_2012" /><ref>{{cite journal | vauthors = Hiepe F, Dörner T, Hauser AE, Hoyer BF, Mei H, Radbruch A | title = Long-lived autoreactive plasma cells drive persistent autoimmune inflammation | journal = Nature Reviews. Rheumatology | volume = 7 | issue = 3 | pages = 170–8 | date = March 2011 | pmid = 21283146 | doi = 10.1038/nrrheum.2011.1 }}</ref> However, it is now emerging that the protein plays an active role in driving the growth of these cancers, most intriguingly by stabilizing the concentrations of the MYC oncoprotein. This suggests that CD19 and its downstream signaling may be a more attractive therapeutic target than initially suspected.<ref name="Chung_2012" /><ref name="Poe_2012" />


CD19 has also been implicated in autoimmune diseases and may be a useful treatment target.<ref>{{cite journal | vauthors = Fujimoto M, Sato S | title = B cell signaling and autoimmune diseases: CD19/CD22 loop as a B cell signaling device to regulate the balance of autoimmunity | journal = Journal of Dermatological Science | volume = 46 | issue = 1 | pages = 1–9 | date = Apr 2007 | pmid = 17223015 | pmc = | doi = 10.1016/j.jdermsci.2006.12.004 }}</ref>
CD19-targeted therapies based on T cells that express CD19-specific chimeric antigen receptors ([[Chimeric antigen receptor|CARs]]) have been utilized for their antitumor abilities in patients with CD19<sup>+</sup> lymphoma and leukemia, first against Non-Hodgkins Lymphoma (NHL), then against CLL in 2011, and then against ALL in 2013.<ref name="Scheuermann_1995" /><ref>{{cite journal | vauthors = Porter DL, Levine BL, Kalos M, Bagg A, June CH | title = Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia | journal = The New England Journal of Medicine | volume = 365 | issue = 8 | pages = 725–33 | date = August 2011 | pmid = 21830940 | doi = 10.1056/nejmoa1103849 | pmc = 3387277 }}</ref><ref>{{cite journal | vauthors = Sadelain M | title = CD19 CAR T Cells | journal = Cell | volume = 171 | issue = 7 | pages = 1471 | date = December 2017 | pmid = 29245005 | doi = 10.1016/j.cell.2017.12.002 }}</ref><ref>{{ClinicalTrialsGov|NCT01493453|A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy}}</ref> CAR-19 T cells are genetically modified T cells that express a targeting moiety on their surface that confers T cell receptor ([[T-cell receptor|TCR]]) specificity towards CD19<sup>+</sup> cells. CD19 activates the TCR signaling cascade that leads to proliferation, [[cytokine]] production, and ultimately [[lysis]] of the target cells, which in this case are CD19<sup>+</sup> B cells. CAR-19 T cells are more effective than anti-CD19 immunotoxins because they can proliferate and remain in the body for a longer period of time. This comes with a caveat since now CD19<sup>−</sup> immune escape facilitated by splice variants, point mutations, and lineage switching can form as a major form of therapeutic resistance for patients with ALL.<ref>{{cite journal | vauthors = Velasquez MP, Gottschalk S | title = Targeting CD19: the good, the bad, and CD81 | journal = Blood | volume = 129 | issue = 1 | pages = 9–10 | date = January 2017 | pmid = 28057672 | pmc = 5216268 | doi = 10.1182/blood-2016-11-749143 }}</ref>


== References ==
== References ==
{{reflist|33em}}
{{reflist|32em}}


== Further reading ==
== Further reading ==
{{refbegin|33em}}
{{refbegin|32em}}
* {{cite book |author1=Goldsby, Richard A. |author2=Kindt, Thomas J. |author3=Osborne, Barbara A. |title=Kuby Immunology |publisher=W. H. Freeman |location=San Francisco |year=2006 |pages= |isbn=0-7167-8590-0 |oclc= |doi=}}
* {{cite book |author1=Goldsby, Richard A. |author2=Kindt, Thomas J. |author3=Osborne, Barbara A. |title=Kuby Immunology |publisher=W. H. Freeman |location=San Francisco |year=2006 |pages= |isbn=978-0-7167-8590-3 |oclc= |doi=}}
* {{cite journal | vauthors = Ishikawa H, Tsuyama N, Mahmoud MS, Fujii R, Abroun S, Liu S, Li FJ, Kawano MM | title = CD19 expression and growth inhibition of tumours in human multiple myeloma | journal = Leukemia & Lymphoma | volume = 43 | issue = 3 | pages = 613–6 | date = Mar 2002 | pmid = 12002767 | doi = 10.1080/10428190290012146 }}
* {{cite journal | vauthors = Ishikawa H, Tsuyama N, Mahmoud MS, Fujii R, Abroun S, Liu S, Li FJ, Kawano MM | title = CD19 expression and growth inhibition of tumours in human multiple myeloma | journal = Leukemia & Lymphoma | volume = 43 | issue = 3 | pages = 613–6 | date = March 2002 | pmid = 12002767 | doi = 10.1080/10428190290012146 }}
* {{cite journal | vauthors = Zhou LJ, Ord DC, Omori SA, Tedder TF | title = Structure of the genes encoding the CD19 antigen of human and mouse B lymphocytes | journal = Immunogenetics | volume = 35 | issue = 2 | pages = 102–11 | year = 1992 | pmid = 1370948 | doi = 10.1007/BF00189519 }}
* {{cite journal | vauthors = Zhou LJ, Ord DC, Omori SA, Tedder TF | title = Structure of the genes encoding the CD19 antigen of human and mouse B lymphocytes | journal = Immunogenetics | volume = 35 | issue = 2 | pages = 102–11 | year = 1992 | pmid = 1370948 | doi = 10.1007/BF00189519 }}
* {{cite journal | vauthors = Carter RH, Fearon DT | title = CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes | journal = Science | volume = 256 | issue = 5053 | pages = 105–7 | date = Apr 1992 | pmid = 1373518 | doi = 10.1126/science.1373518 }}
* {{cite journal | vauthors = Carter RH, Fearon DT | title = CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes | journal = Science | volume = 256 | issue = 5053 | pages = 105–7 | date = April 1992 | pmid = 1373518 | doi = 10.1126/science.1373518 }}
* {{cite journal | vauthors = Kozmik Z, Wang S, Dörfler P, Adams B, Busslinger M | title = The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP | journal = Molecular and Cellular Biology | volume = 12 | issue = 6 | pages = 2662–72 | date = Jun 1992 | pmid = 1375324 | pmc = 364460 | doi = 10.1128/mcb.12.6.2662}}
* {{cite journal | vauthors = Kozmik Z, Wang S, Dörfler P, Adams B, Busslinger M | title = The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP | journal = Molecular and Cellular Biology | volume = 12 | issue = 6 | pages = 2662–72 | date = June 1992 | pmid = 1375324 | pmc = 364460 | doi = 10.1128/mcb.12.6.2662 }}
* {{cite journal | vauthors = Bradbury LE, Kansas GS, Levy S, Evans RL, Tedder TF | title = The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules | journal = Journal of Immunology | volume = 149 | issue = 9 | pages = 2841–50 | date = Nov 1992 | pmid = 1383329 | doi =  }}
* {{cite journal | vauthors = Bradbury LE, Kansas GS, Levy S, Evans RL, Tedder TF | title = The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules | journal = Journal of Immunology | volume = 149 | issue = 9 | pages = 2841–50 | date = November 1992 | pmid = 1383329 | doi =  }}
* {{cite journal | vauthors = Matsumoto AK, Kopicky-Burd J, Carter RH, Tuveson DA, Tedder TF, Fearon DT | title = Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19 | journal = The Journal of Experimental Medicine | volume = 173 | issue = 1 | pages = 55–64 | date = Jan 1991 | pmid = 1702139 | pmc = 2118751 | doi = 10.1084/jem.173.1.55 }}
* {{cite journal | vauthors = Matsumoto AK, Kopicky-Burd J, Carter RH, Tuveson DA, Tedder TF, Fearon DT | title = Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19 | journal = The Journal of Experimental Medicine | volume = 173 | issue = 1 | pages = 55–64 | date = January 1991 | pmid = 1702139 | pmc = 2118751 | doi = 10.1084/jem.173.1.55 }}
* {{cite journal | vauthors = Zhou LJ, Ord DC, Hughes AL, Tedder TF | title = Structure and domain organization of the CD19 antigen of human, mouse, and guinea pig B lymphocytes. Conservation of the extensive cytoplasmic domain | journal = Journal of Immunology | volume = 147 | issue = 4 | pages = 1424–32 | date = Aug 1991 | pmid = 1714482 | doi =  }}
* {{cite journal | vauthors = Zhou LJ, Ord DC, Hughes AL, Tedder TF | title = Structure and domain organization of the CD19 antigen of human, mouse, and guinea pig B lymphocytes. Conservation of the extensive cytoplasmic domain | journal = Journal of Immunology | volume = 147 | issue = 4 | pages = 1424–32 | date = August 1991 | pmid = 1714482 | doi =  }}
* {{cite journal | vauthors = Stamenkovic I, Seed B | title = CD19, the earliest differentiation antigen of the B cell lineage, bears three extracellular immunoglobulin-like domains and an Epstein-Barr virus-related cytoplasmic tail | journal = The Journal of Experimental Medicine | volume = 168 | issue = 3 | pages = 1205–10 | date = Sep 1988 | pmid = 2459292 | pmc = 2189043 | doi = 10.1084/jem.168.3.1205 }}
* {{cite journal | vauthors = Stamenkovic I, Seed B | title = CD19, the earliest differentiation antigen of the B cell lineage, bears three extracellular immunoglobulin-like domains and an Epstein-Barr virus-related cytoplasmic tail | journal = The Journal of Experimental Medicine | volume = 168 | issue = 3 | pages = 1205–10 | date = September 1988 | pmid = 2459292 | pmc = 2189043 | doi = 10.1084/jem.168.3.1205 }}
* {{cite journal | vauthors = Ord DC, Edelhoff S, Dushkin H, Zhou LJ, Beier DR, Disteche C, Tedder TF | title = CD19 maps to a region of conservation between human chromosome 16 and mouse chromosome 7 | journal = Immunogenetics | volume = 39 | issue = 5 | pages = 322–8 | year = 1994 | pmid = 7513297 | doi = 10.1007/BF00189228 }}
* {{cite journal | vauthors = Ord DC, Edelhoff S, Dushkin H, Zhou LJ, Beier DR, Disteche C, Tedder TF | title = CD19 maps to a region of conservation between human chromosome 16 and mouse chromosome 7 | journal = Immunogenetics | volume = 39 | issue = 5 | pages = 322–8 | year = 1994 | pmid = 7513297 | doi = 10.1007/BF00189228 }}
* {{cite journal | vauthors = Weng WK, Jarvis L, LeBien TW | title = Signaling through CD19 activates Vav/mitogen-activated protein kinase pathway and induces formation of a CD19/Vav/phosphatidylinositol 3-kinase complex in human B cell precursors | journal = The Journal of Biological Chemistry | volume = 269 | issue = 51 | pages = 32514–21 | date = Dec 1994 | pmid = 7528218 | doi =  }}
* {{cite journal | vauthors = Weng WK, Jarvis L, LeBien TW | title = Signaling through CD19 activates Vav/mitogen-activated protein kinase pathway and induces formation of a CD19/Vav/phosphatidylinositol 3-kinase complex in human B cell precursors | journal = The Journal of Biological Chemistry | volume = 269 | issue = 51 | pages = 32514–21 | date = December 1994 | pmid = 7528218 | doi =  }}
* {{cite journal | vauthors = Myers DE, Jun X, Waddick KG, Forsyth C, Chelstrom LM, Gunther RL, Tumer NE, Bolen J, Uckun FM | title = Membrane-associated CD19-LYN complex is an endogenous p53-independent and Bc1-2-independent regulator of apoptosis in human B-lineage lymphoma cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 21 | pages = 9575–9 | date = Oct 1995 | pmid = 7568175 | pmc = 40844 | doi = 10.1073/pnas.92.21.9575 }}
* {{cite journal | vauthors = Myers DE, Jun X, Waddick KG, Forsyth C, Chelstrom LM, Gunther RL, Tumer NE, Bolen J, Uckun FM | title = Membrane-associated CD19-LYN complex is an endogenous p53-independent and Bc1-2-independent regulator of apoptosis in human B-lineage lymphoma cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 21 | pages = 9575–9 | date = October 1995 | pmid = 7568175 | pmc = 40844 | doi = 10.1073/pnas.92.21.9575 }}
* {{cite journal | vauthors = Chalupny NJ, Aruffo A, Esselstyn JM, Chan PY, Bajorath J, Blake J, Gilliland LK, Ledbetter JA, Tepper MA | title = Specific binding of Fyn and phosphatidylinositol 3-kinase to the B cell surface glycoprotein CD19 through their src homology 2 domains | journal = European Journal of Immunology | volume = 25 | issue = 10 | pages = 2978–84 | date = Oct 1995 | pmid = 7589101 | doi = 10.1002/eji.1830251040 }}
* {{cite journal | vauthors = Chalupny NJ, Aruffo A, Esselstyn JM, Chan PY, Bajorath J, Blake J, Gilliland LK, Ledbetter JA, Tepper MA | title = Specific binding of Fyn and phosphatidylinositol 3-kinase to the B cell surface glycoprotein CD19 through their src homology 2 domains | journal = European Journal of Immunology | volume = 25 | issue = 10 | pages = 2978–84 | date = October 1995 | pmid = 7589101 | doi = 10.1002/eji.1830251040 }}
* {{cite journal | vauthors = Tuscano JM, Engel P, Tedder TF, Agarwal A, Kehrl JH | title = Involvement of p72syk kinase, p53/56lyn kinase and phosphatidyl inositol-3 kinase in signal transduction via the human B lymphocyte antigen CD22 | journal = European Journal of Immunology | volume = 26 | issue = 6 | pages = 1246–52 | date = Jun 1996 | pmid = 8647200 | doi = 10.1002/eji.1830260610 }}
* {{cite journal | vauthors = Tuscano JM, Engel P, Tedder TF, Agarwal A, Kehrl JH | title = Involvement of p72syk kinase, p53/56lyn kinase and phosphatidyl inositol-3 kinase in signal transduction via the human B lymphocyte antigen CD22 | journal = European Journal of Immunology | volume = 26 | issue = 6 | pages = 1246–52 | date = June 1996 | pmid = 8647200 | doi = 10.1002/eji.1830260610 }}
* {{cite journal | vauthors = Carter RH, Doody GM, Bolen JB, Fearon DT | title = Membrane IgM-induced tyrosine phosphorylation of CD19 requires a CD19 domain that mediates association with components of the B cell antigen receptor complex | journal = Journal of Immunology | volume = 158 | issue = 7 | pages = 3062–9 | date = Apr 1997 | pmid = 9120258 | doi =  }}
* {{cite journal | vauthors = Carter RH, Doody GM, Bolen JB, Fearon DT | title = Membrane IgM-induced tyrosine phosphorylation of CD19 requires a CD19 domain that mediates association with components of the B cell antigen receptor complex | journal = Journal of Immunology | volume = 158 | issue = 7 | pages = 3062–9 | date = April 1997 | pmid = 9120258 | doi =  }}
* {{cite journal | vauthors = Husson H, Mograbi B, Schmid-Antomarchi H, Fischer S, Rossi B | title = CSF-1 stimulation induces the formation of a multiprotein complex including CSF-1 receptor, c-Cbl, PI 3-kinase, Crk-II and Grb2 | journal = Oncogene | volume = 14 | issue = 19 | pages = 2331–8 | date = May 1997 | pmid = 9178909 | doi = 10.1038/sj.onc.1201074 }}
* {{cite journal | vauthors = Husson H, Mograbi B, Schmid-Antomarchi H, Fischer S, Rossi B | title = CSF-1 stimulation induces the formation of a multiprotein complex including CSF-1 receptor, c-Cbl, PI 3-kinase, Crk-II and Grb2 | journal = Oncogene | volume = 14 | issue = 19 | pages = 2331–8 | date = May 1997 | pmid = 9178909 | doi = 10.1038/sj.onc.1201074 }}
* {{cite journal | vauthors = Khine AA, Firtel M, Lingwood CA | title = CD77-dependent retrograde transport of CD19 to the nuclear membrane: functional relationship between CD77 and CD19 during germinal center B-cell apoptosis | journal = Journal of Cellular Physiology | volume = 176 | issue = 2 | pages = 281–92 | date = Aug 1998 | pmid = 9648915 | doi = 10.1002/(SICI)1097-4652(199808)176:2<281::AID-JCP6>3.0.CO;2-K }}
* {{cite journal | vauthors = Khine AA, Firtel M, Lingwood CA | title = CD77-dependent retrograde transport of CD19 to the nuclear membrane: functional relationship between CD77 and CD19 during germinal center B-cell apoptosis | journal = Journal of Cellular Physiology | volume = 176 | issue = 2 | pages = 281–92 | date = August 1998 | pmid = 9648915 | doi = 10.1002/(SICI)1097-4652(199808)176:2<281::AID-JCP6>3.0.CO;2-K }}
* {{cite journal | vauthors = Thunberg U, Gidlöf C, Bånghagen M, Sällström JF, Sundström C, Tötterman T | title = HpaII polymerase chain reaction restriction fragment length polymorphism in the human CD19 gene on 16p11 | journal = Human Heredity | volume = 48 | issue = 4 | pages = 230–1 | year = 1998 | pmid = 9694255 | doi = 10.1159/000022806 }}
* {{cite journal | vauthors = Thunberg U, Gidlöf C, Bånghagen M, Sällström JF, Sundström C, Tötterman T | title = HpaII polymerase chain reaction restriction fragment length polymorphism in the human CD19 gene on 16p11 | journal = Human Heredity | volume = 48 | issue = 4 | pages = 230–1 | year = 1998 | pmid = 9694255 | doi = 10.1159/000022806 }}
* {{cite journal | vauthors = Horváth G, Serru V, Clay D, Billard M, Boucheix C, Rubinstein E | title = CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 46 | pages = 30537–43 | date = Nov 1998 | pmid = 9804823 | doi = 10.1074/jbc.273.46.30537 }}
* {{cite journal | vauthors = Horváth G, Serru V, Clay D, Billard M, Boucheix C, Rubinstein E | title = CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 46 | pages = 30537–43 | date = November 1998 | pmid = 9804823 | doi = 10.1074/jbc.273.46.30537 }}
* {{cite journal | vauthors = Buhl AM, Cambier JC | title = Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase | journal = Journal of Immunology | volume = 162 | issue = 8 | pages = 4438–46 | date = Apr 1999 | pmid = 10201980 | doi =  }}
* {{cite journal | vauthors = Buhl AM, Cambier JC | title = Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase | journal = Journal of Immunology | volume = 162 | issue = 8 | pages = 4438–46 | date = April 1999 | pmid = 10201980 | doi =  }}
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Latest revision as of 03:09, 11 January 2019

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B-lymphocyte antigen CD19, also known as CD19 molecule (Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD19.[1][2] In humans, CD19 is expressed in all B lineage cells, except for plasma cells, and in follicular dendritic cells.[3][4] CD19 plays two major roles in human B cells. It acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane and it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.[4]

Structure

In humans, CD19 is encoded by the 7.41 kilobase CD19 gene located on the short arm of chromosome 16.[5][6] It contains at least fifteen exons, four that encode extracellular domain and nine that encode cytoplasmic domains, with a total of 556 amino acids.[6] Experiments show that there are multiple mRNA transcripts; however, only two have been isolated in vivo.[5]

CD19 is a 95 kd Type I transmembrane glycoprotein in the immunoglobulin superfamily (IgSF) with two extracellular C2-set Ig-like domains and a relatively large, 240 amino acid, cytoplasmic tail that is highly conserved among mammalian species.[5][7][8][9] The extracellular C2-type Ig-like domains are divided by a potential disulfide linked non-Ig-like domain and N-linked carbohydrate addition sites.[8][10] The cytoplasmic tail contains at least nine tyrosine residues near the C-terminus.[5][8] Within these residues, Y391, Y482, and Y513 have been shown to be essential to the biological functions of CD19.[11] Phenylalanine substitution for tyrosine at Y482 and Y513 leads to the inhibition of phosphorylation at the other tyrosines.[5][12]

Expression

CD19 is widely expressed during all phases of B cell development until terminal differentiation into plasma cells. During B cell lymphopoiesis, CD19 surface expression starts during immunoglobulin (Ig) gene rearrangement, which coincides during B lineage commitment from hematopoietic stem cell.[4] Throughout development, the surface density of CD19 is highly regulated.[5] CD19 expression in mature B cells is three fold higher than that in immature B cells.[5] CD19 is expressed on all normal, mitogen-stimulated, and malignant B cells, excluding plasma cells. CD19 expression is even maintained in B lineage cells that undergo neoplastic transformation.[3][12] Because of its ubiquity on all B cells, it can function as a B cell marker and a target for immunotherapies targeting neoplastic lymphocytes.[4][5]

Function

Role in development & survival

Decisions to live, proliferate, differentiate, or die are continuously being made during B cell development.[13] These decisions are tightly regulated through BCR interactions and signaling. The presence of a functional BCR is necessary during antigen-dependent differentiation and for continued survival in the peripheral immune system.[8] Essential to the functionality of a BCR is the presence of CD19.[14] Experiments using CD19 knockout mice found that CD19 is essential for B cell differentiative events including the formation of B-1, germinal center, and marginal zone (MZ) B cells.[8][15][16] Analysis of mixed bone marrow chimeras suggest that prior to an initial antigen encounter, CD19 promotes the survival of naive recirculating B cells and increases the in vivo life span of B cells in the peripheral B cell compartment.[17] Ultimately, CD19 expression is integral to the propagation of BCR-induced survival signals and the maintenance of homeostasis through tonic signaling.

BCR-independent

Paired box transcription factor 5 (PAX5) plays a major role in B cell differentiation from pro B cell to mature B cell, the point at which the expression of non-B-lineage genes is permanently blocked.[17][18][19] Part of B cell differentiation is controlling c-MYC protein stability and steady-state levels through CD19, which acts as a PAX5 target and downstream effector of the PI3K-AKT-GSK3β axis. CD19 signaling, independent of BCR functions, increases c-MYC protein stability. Using a loss of function approach, researchers found reduced MYC levels in B cells of CD19 knockdown mice.[17] CD19 signaling involves the recruitment and activation of phosphoinositide 3-kinase (PI3K) and later downstream, the activation of protein kinase B (Akt). The Akt-GSK3β axis is necessary for MYC activation by CD19 in BCR-negative cells, with higher levels of Akt activation corresponding to higher levels of MYC.[17][20] CD19 is a crucial BCR-independent regulator of MYC-driven neoplastic growth in B cells since the CD19-MYC axis promotes cell expansion in vitro and in vivo.[17][20]

CD19/CD21 complex

On the cell surface, CD19 is the dominant signaling component of a multimolecular complex including CD21, a complement receptor, CD81, a tetraspanin membrane protein (TAPA-1), and CD225.[5][17] The CD19/CD21 complex arises from C3d binding to CD21; however, CD19 does not require CD21 for signal transduction. CD81, attached to CD19, is a part of the tetraspanin web, acts as a chaperone protein, and provides docking sites for molecules in various different signal transduction pathways.[5]

BCR-dependent

While colligated with the BCR, the CD19/CD21 complex bound to the antigen-complement complex can decrease the threshold for B cell activation. CD21, complement receptor 2, can bind fragments of C3 that have covalently attached to glycoconjugates by complement activation.[21] Recognition of an antigen by the complement system enables the CD19/CD21 complex and associated intracellular signaling molecules to crosslink to the BCR. This results in phosphorylation of the cytoplasmic tail of CD19 by BCR-associated tyrosine kinases, ensuing is the binding of additional Src-family kinases, augmentation of signaling through the BCR, and recruitment of PI3K. The localization of PI3K initiates another signaling pathway leading to Akt activation. Varying expression of CD19 on the cell surface modulates tyrosine phosphorylation and Akt kinase signaling and by extension, MHC class II mediated signaling.[5]

Activated spleen tyrosine kinase (Syk) leads to phosphorylation of the scaffold protein, BLNK, which provides multiple sites for tyrosine phosphorylation and recruits SH2-containing enzymes and adaptor proteins that can form various multiprotein signaling complexes. In this way, CD19 can modulate the threshold for B cell activation. This is important during primary immune response, prior to affinity maturation, amplifying the response of low affinity BCRs to low concentrations of antigen.[5][21]

Interactions

CD19 has been shown to interact with:

In disease

Autoimmunity & immunodeficiency

Mutations in CD19 are associated with severe immunodeficiency syndromes characterized by diminished antibody production.[22][23] Additionally, mutations in CD21 and CD81 can also underlie primary immunodeficiency due to their role in the CD19/CD21 complex formation.[24] These mutations can lead to hypogammaglobulinaemia as a result of poor response to antigen and defective immunological memory.[25] Researchers found changes in the constitution of B lymphocyte population and reduced amounts of switched memory B cells with high terminal differentiation potential in patients with Down Syndrome.[26] CD19 has also been implicated in autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and may be a useful treatment target.[7][10][27]

Mouse model research shows that CD19 deficiency can lead to hyporesponsiveness to transmembrane signals and weak T cell dependent humoral response, that in turn leads to an overall impaired humoral immune response.[15][16] Additionally CD19 plays a role in modulating MHC Class II expression and signaling, which can be affected by mutations. CD19 deficient B cells exhibit selective growth disadvantage; therefore, it is rare for CD19 to be absent in neoplastic B cells, as it is essential for development.[17]

Cancer

Since CD19 is a marker of B cells, the protein has been used to diagnose cancers that arise from this type of cell - notably B cell lymphomas, acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL).[4] The majority of B cell malignancies express normal to high levels of CD19. The most current experimental anti-CD19 immunotoxins in development work by exploiting the widespread presence of CD19 on B cells, with expression highly conserved in most neoplastic B cells, to direct treatment specifically towards B-cell cancers.[7][28] However, it is now emerging that the protein plays an active role in driving the growth of these cancers, most intriguingly by stabilizing the concentrations of the MYC oncoprotein. This suggests that CD19 and its downstream signaling may be a more attractive therapeutic target than initially suspected.[17][20]

CD19-targeted therapies based on T cells that express CD19-specific chimeric antigen receptors (CARs) have been utilized for their antitumor abilities in patients with CD19+ lymphoma and leukemia, first against Non-Hodgkins Lymphoma (NHL), then against CLL in 2011, and then against ALL in 2013.[4][29][30][31] CAR-19 T cells are genetically modified T cells that express a targeting moiety on their surface that confers T cell receptor (TCR) specificity towards CD19+ cells. CD19 activates the TCR signaling cascade that leads to proliferation, cytokine production, and ultimately lysis of the target cells, which in this case are CD19+ B cells. CAR-19 T cells are more effective than anti-CD19 immunotoxins because they can proliferate and remain in the body for a longer period of time. This comes with a caveat since now CD19− immune escape facilitated by splice variants, point mutations, and lineage switching can form as a major form of therapeutic resistance for patients with ALL.[32]

References

  1. ↑ "Entrez Gene: CD19 CD19 molecule".
  2. ↑ Tedder TF, Isaacs CM (July 1989). "Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily". Journal of Immunology. 143 (2): 712–7. PMID 2472450.
  3. ↑ 3.0 3.1 Schroeder HW, Rich RR (2013). "Chapter 4: Antigen receptor genes, gene products, and co-receptors". Clinical immunology: Principles and Practice (4th ed.). London. pp. 47–51. ISBN 978-0-7234-3691-1. OCLC 823736017.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Scheuermann RH, Racila E (August 1995). "CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy". Leukemia & Lymphoma. 18 (5–6): 385–97. doi:10.3109/10428199509059636. PMID 8528044.
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 Wang K, Wei G, Liu D (November 2012). "CD19: a biomarker for B cell development, lymphoma diagnosis and therapy". Experimental Hematology & Oncology. 1 (1): 36. doi:10.1186/2162-3619-1-36. PMC 3520838. PMID 23210908.
  6. ↑ 6.0 6.1 Zhou LJ, Ord DC, Omori SA, Tedder TF (1992). "Structure of the genes encoding the CD19 antigen of human and mouse B lymphocytes". Immunogenetics. 35 (2): 102–11. PMID 1370948.
  7. ↑ 7.0 7.1 7.2 Mei HE, Schmidt S, Dörner T (November 2012). "Rationale of anti-CD19 immunotherapy: an option to target autoreactive plasma cells in autoimmunity". Arthritis Research & Therapy. 14 Suppl 5 (5): S1. doi:10.1186/ar3909. PMC 3535716. PMID 23281743.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Haas KM, Tedder TF (2005). Mechanisms of Lymphocyte Activation and Immune Regulation X. Advances in Experimental Medicine and Biology. 560. Springer, Boston, MA. pp. 125–139. doi:10.1007/0-387-24180-9_16. ISBN 978-0-387-24188-3. PMID 15934172.
  9. ↑ Tedder TF, Isaacs CM (July 1989). "Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily". Journal of Immunology. 143 (2): 712–7. PMID 2472450.
  10. ↑ 10.0 10.1 Tedder TF (October 2009). "CD19: a promising B cell target for rheumatoid arthritis". Nature Reviews. Rheumatology. 5 (10): 572–7. doi:10.1038/nrrheum.2009.184. PMID 19798033.
  11. ↑ Del Nagro CJ, Otero DC, Anzelon AN, Omori SA, Kolla RV, Rickert RC (2005). "CD19 function in central and peripheral B-cell development". Immunologic Research. 31 (2): 119–31. doi:10.1385/IR:31:2:119. PMID 15778510.
  12. ↑ 12.0 12.1 Carter RH, Wang Y, Brooks S (2002). "Role of CD19 signal transduction in B cell biology". Immunologic Research. 26 (1–3): 45–54. doi:10.1385/IR:26:1-3:045. PMID 12403344.
  13. ↑ Otero DC, Anzelon AN, Rickert RC (January 2003). "CD19 function in early and late B cell development: I. Maintenance of follicular and marginal zone B cells requires CD19-dependent survival signals". Journal of Immunology. 170 (1): 73–83. PMID 12496385.
  14. ↑ Sato S (December 1999). "CD19 is a central response regulator of B lymphocyte signaling thresholds governing autoimmunity". Journal of Dermatological Science. 22 (1): 1–10. doi:10.1016/s0923-1811(99)00043-2. PMID 10651223.
  15. ↑ 15.0 15.1 Rickert RC, Rajewsky K, Roes J (July 1995). "Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice". Nature. 376 (6538): 352–5. doi:10.1038/376352a0. PMID 7543183.
  16. ↑ 16.0 16.1 Engel P, Zhou LJ, Ord DC, Sato S, Koller B, Tedder TF (July 1995). "Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule". Immunity. 3 (1): 39–50. doi:10.1016/1074-7613(95)90157-4. PMID 7542548.
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 Chung EY, Psathas JN, Yu D, Li Y, Weiss MJ, Thomas-Tikhonenko A (June 2012). "CD19 is a major B cell receptor-independent activator of MYC-driven B-lymphomagenesis". The Journal of Clinical Investigation. 122 (6): 2257–66. doi:10.1172/jci45851. PMC 3366393. PMID 22546857.
  18. ↑ Monroe JG (April 2006). "ITAM-mediated tonic signalling through pre-BCR and BCR complexes". Nature Reviews. Immunology. 6 (4): 283–94. doi:10.1038/nri1808. PMID 16557260.
  19. ↑ Maier H, Ostraat R, Parenti S, Fitzsimmons D, Abraham LJ, Garvie CW, Hagman J (October 2003). "Requirements for selective recruitment of Ets proteins and activation of mb-1/Ig-alpha gene transcription by Pax-5 (BSAP)". Nucleic Acids Research. 31 (19): 5483–9. doi:10.1093/nar/gkg785. PMC 206479. PMID 14500810.
  20. ↑ 20.0 20.1 20.2 Poe JC, Minard-Colin V, Kountikov EI, Haas KM, Tedder TF (September 2012). "A c-Myc and surface CD19 signaling amplification loop promotes B cell lymphoma development and progression in mice". Journal of Immunology. 189 (5): 2318–25. doi:10.4049/jimmunol.1201000. PMC 3426298. PMID 22826319.
  21. ↑ 21.0 21.1 Morbach H, Schickel JN, Cunningham-Rundles C, Conley ME, Reisli I, Franco JL, Meffre E (March 2016). "CD19 controls Toll-like receptor 9 responses in human B cells". The Journal of Allergy and Clinical Immunology. 137 (3): 889–98.e6. doi:10.1016/j.jaci.2015.08.040. PMC 4783287. PMID 26478008.
  22. ↑ Pesando JM, Bouchard LS, McMaster BE (December 1989). "CD19 is functionally and physically associated with surface immunoglobulin". The Journal of Experimental Medicine. 170 (6): 2159–64. doi:10.1084/jem.170.6.2159. PMC 2189531. PMID 2479707.
  23. ↑ van Zelm MC, Reisli I, van der Burg M, Castaño D, van Noesel CJ, van Tol MJ, Woellner C, Grimbacher B, Patiño PJ, van Dongen JJ, Franco JL (May 2006). "An antibody-deficiency syndrome due to mutations in the CD19 gene". The New England Journal of Medicine. 354 (18): 1901–12. doi:10.1056/nejmoa051568. PMID 16672701.
  24. ↑ Carsetti R, Valentini D, Marcellini V, Scarsella M, Marasco E, Giustini F, Bartuli A, Villani A, Ugazio AG (March 2015). "Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome". European Journal of Immunology. 45 (3): 903–14. doi:10.1002/eji.201445049. PMC 4674966. PMID 25472482.
  25. ↑ Verstegen RH, Driessen GJ, Bartol SJ, van Noesel CJ, Boon L, van der Burg M, et al. (December 2014). "Defective B-cell memory in patients with Down syndrome". The Journal of Allergy and Clinical Immunology. 134 (6): 1346–1353.e9. doi:10.1016/j.jaci.2014.07.015. PMID 25159464.
  26. ↑ Seckin AN, Ozdemir H, Ceylan A, Artac H (February 2018). "Age-related alterations of the CD19 complex and memory B cells in children with Down syndrome". Clinical and Experimental Medicine. 18 (1): 125–131. doi:10.1007/s10238-017-0457-2. PMID 28197808.
  27. ↑ Fujimoto M, Sato S (April 2007). "B cell signaling and autoimmune diseases: CD19/CD22 loop as a B cell signaling device to regulate the balance of autoimmunity". Journal of Dermatological Science. 46 (1): 1–9. doi:10.1016/j.jdermsci.2006.12.004. PMID 17223015.
  28. ↑ Hiepe F, Dörner T, Hauser AE, Hoyer BF, Mei H, Radbruch A (March 2011). "Long-lived autoreactive plasma cells drive persistent autoimmune inflammation". Nature Reviews. Rheumatology. 7 (3): 170–8. doi:10.1038/nrrheum.2011.1. PMID 21283146.
  29. ↑ Porter DL, Levine BL, Kalos M, Bagg A, June CH (August 2011). "Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia". The New England Journal of Medicine. 365 (8): 725–33. doi:10.1056/nejmoa1103849. PMC 3387277. PMID 21830940.
  30. ↑ Sadelain M (December 2017). "CD19 CAR T Cells". Cell. 171 (7): 1471. doi:10.1016/j.cell.2017.12.002. PMID 29245005.
  31. ↑ Clinical trial number NCT01493453 for "A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy" at ClinicalTrials.gov
  32. ↑ Velasquez MP, Gottschalk S (January 2017). "Targeting CD19: the good, the bad, and CD81". Blood. 129 (1): 9–10. doi:10.1182/blood-2016-11-749143. PMC 5216268. PMID 28057672.

Further reading

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