Biology:CD19

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Short description: Biomarker for B cell lineage


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[3][4] Contrary to some early doubts, human plasma cells do express CD19,[5] as confirmed by others.[6] CD19 plays two major roles in human B cells: on the one hand, it acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane; on the other, 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.[7][8] It contains at least fifteen exons, four that encode extracellular domain and nine that encode cytoplasmic domains, with a total of 556 amino acids.[8] Experiments show that there are multiple mRNA transcripts; however, only two have been isolated in vivo.[7]

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.[7][9][10][11] The extracellular C2-type Ig-like domains are divided by a potential disulfide linked non-Ig-like domain and N-linked carbohydrate addition sites.[10][12] The cytoplasmic tail contains at least nine tyrosine residues near the C-terminus.[7][10] Within these residues, Y391, Y482, and Y513 have been shown to be essential to the biological functions of CD19.[13] Phenylalanine substitution for tyrosine at Y482 and Y513 leads to the inhibition of phosphorylation at the other tyrosines.[7][14]

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.[7] CD19 expression in mature B cells is threefold higher than that in immature B cells.[7] CD19 is expressed on all normal, mitogen-stimulated, and malignant B cells, excluding plasma cells[inconsistent]. CD19 expression is even maintained in B lineage cells that undergo neoplastic transformation.[3][14] 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][7]

Function

Role in development & survival

Decisions to live, proliferate, differentiate, or die are continuously being made during B cell development.[15] These decisions are tightly regulated through B cell receptor (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.[10] Essential to the functionality of a BCR is the presence of CD19.[16] 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.[10][17][18] 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.[19] 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.[19][20][21] 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.[19] 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.[19][22] 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.[19][22]

CD19/CD21 complex

On the cell surface, CD19 is the dominant signaling component of a multimolecular complex including CD21 (CR2, a complement receptor), TAPA-1 (a tetraspanin membrane protein), and CD225.[7][19] 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.[7]

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.[23] 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.[7]

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.[7][23]

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.[24][25] Additionally, mutations in CD21 and CD81 can also underlie primary immunodeficiency due to their role in the CD19/CD21 complex formation.[26] These mutations can lead to hypogammaglobulinaemia as a result of poor response to antigen and defective immunological memory.[27] 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.[28] CD19 has also been implicated in autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and may be a useful treatment target.[9][12][29]

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.[17][18] 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.[19]

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.[9][30] 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.[19][22]

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-Hodgkin's Lymphoma (NHL), then against CLL in 2011, and then against ALL in 2013.[4][31][32][33] 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.[34]

References

  1. "Entrez Gene: CD19 CD19 molecule". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=930. 
  2. "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. July 1989. doi:10.4049/jimmunol.143.2.712. PMID 2472450. 
  3. 3.0 3.1 Schroeder, Harry W; Rich, Robert R. (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 "CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy". Leukemia & Lymphoma 18 (5–6): 385–97. August 1995. doi:10.3109/10428199509059636. PMID 8528044. 
  5. "Bcl-2+ tonsillar plasma cells are rescued from apoptosis by bone marrow fibroblasts". The Journal of Experimental Medicine 183 (1): 227–36. January 1996. doi:10.1084/jem.183.1.227. PMID 8551226. 
  6. "Neural cell adhesion molecule expression in plasma cells in bone marrow biopsies and aspirates allows discrimination between multiple myeloma, monoclonal gammopathy of uncertain significance and polyclonal plasmacytosis". Histopathology 44 (4): 375–80. April 2004. doi:10.1111/j.1365-2559.2004.01834.x. PMID 15049904. 
  7. 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 "CD19: a biomarker for B cell development, lymphoma diagnosis and therapy". Experimental Hematology & Oncology 1 (1): 36. November 2012. doi:10.1186/2162-3619-1-36. PMID 23210908. 
  8. 8.0 8.1 "Structure of the genes encoding the CD19 antigen of human and mouse B lymphocytes". Immunogenetics 35 (2): 102–11. 1992. doi:10.1007/bf00189519. PMID 1370948. 
  9. 9.0 9.1 9.2 "Rationale of anti-CD19 immunotherapy: an option to target autoreactive plasma cells in autoimmunity". Arthritis Research & Therapy 14 Suppl 5 (5): S1. November 2012. doi:10.1186/ar3909. PMID 23281743. 
  10. 10.0 10.1 10.2 10.3 10.4 Haas, Karen M.; Tedder, Thomas F. (2005). "Role of the CD19 and CD21/35 Receptor Complex in Innate Immunity, Host Defense and Autoimmunity". 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. 
  11. "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. July 1989. doi:10.4049/jimmunol.143.2.712. PMID 2472450. 
  12. 12.0 12.1 "CD19: a promising B cell target for rheumatoid arthritis". Nature Reviews. Rheumatology 5 (10): 572–7. October 2009. doi:10.1038/nrrheum.2009.184. PMID 19798033. 
  13. "CD19 function in central and peripheral B-cell development". Immunologic Research 31 (2): 119–31. 2005. doi:10.1385/IR:31:2:119. PMID 15778510. 
  14. 14.0 14.1 "Role of CD19 signal transduction in B cell biology". Immunologic Research 26 (1–3): 45–54. 2002. doi:10.1385/IR:26:1-3:045. PMID 12403344. 
  15. "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. January 2003. doi:10.4049/jimmunol.170.1.73. PMID 12496385. 
  16. "CD19 is a central response regulator of B lymphocyte signaling thresholds governing autoimmunity". Journal of Dermatological Science 22 (1): 1–10. December 1999. doi:10.1016/s0923-1811(99)00043-2. PMID 10651223. 
  17. 17.0 17.1 "Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice". Nature 376 (6538): 352–5. July 1995. doi:10.1038/376352a0. PMID 7543183. Bibcode1995Natur.376..352R. 
  18. 18.0 18.1 "Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule". Immunity 3 (1): 39–50. July 1995. doi:10.1016/1074-7613(95)90157-4. PMID 7542548. 
  19. 19.0 19.1 19.2 19.3 19.4 19.5 19.6 19.7 "CD19 is a major B cell receptor-independent activator of MYC-driven B-lymphomagenesis". The Journal of Clinical Investigation 122 (6): 2257–66. June 2012. doi:10.1172/jci45851. PMID 22546857. 
  20. "ITAM-mediated tonic signalling through pre-BCR and BCR complexes". Nature Reviews. Immunology 6 (4): 283–94. April 2006. doi:10.1038/nri1808. PMID 16557260. 
  21. "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. October 2003. doi:10.1093/nar/gkg785. PMID 14500810. 
  22. 22.0 22.1 22.2 "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. September 2012. doi:10.4049/jimmunol.1201000. PMID 22826319. 
  23. 23.0 23.1 "CD19 controls Toll-like receptor 9 responses in human B cells". The Journal of Allergy and Clinical Immunology 137 (3): 889–98.e6. March 2016. doi:10.1016/j.jaci.2015.08.040. PMID 26478008. 
  24. "CD19 is functionally and physically associated with surface immunoglobulin". The Journal of Experimental Medicine 170 (6): 2159–64. December 1989. doi:10.1084/jem.170.6.2159. PMID 2479707. 
  25. "An antibody-deficiency syndrome due to mutations in the CD19 gene". The New England Journal of Medicine 354 (18): 1901–12. May 2006. doi:10.1056/nejmoa051568. PMID 16672701. 
  26. "Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome". European Journal of Immunology 45 (3): 903–14. March 2015. doi:10.1002/eji.201445049. PMID 25472482. 
  27. "Defective B-cell memory in patients with Down syndrome". The Journal of Allergy and Clinical Immunology 134 (6): 1346–1353.e9. December 2014. doi:10.1016/j.jaci.2014.07.015. PMID 25159464. 
  28. "Age-related alterations of the CD19 complex and memory B cells in children with Down syndrome". Clinical and Experimental Medicine 18 (1): 125–131. February 2018. doi:10.1007/s10238-017-0457-2. PMID 28197808. 
  29. "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. April 2007. doi:10.1016/j.jdermsci.2006.12.004. PMID 17223015. https://kanazawa-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=13096&item_no=1&attribute_id=26&file_no=1. 
  30. "Long-lived autoreactive plasma cells drive persistent autoimmune inflammation". Nature Reviews. Rheumatology 7 (3): 170–8. March 2011. doi:10.1038/nrrheum.2011.1. PMID 21283146. 
  31. "Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia". The New England Journal of Medicine 365 (8): 725–33. August 2011. doi:10.1056/nejmoa1103849. PMID 21830940. 
  32. "CD19 CAR T Cells". Cell 171 (7): 1471. December 2017. doi:10.1016/j.cell.2017.12.002. PMID 29245005. 
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  34. "Targeting CD19: the good, the bad, and CD81". Blood 129 (1): 9–10. January 2017. doi:10.1182/blood-2016-11-749143. PMID 28057672. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.