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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''. In humans, CD19 is expressed in all B lineage cells. Contrary to some early doubts, human plasma cells do express CD19, as confirmed by others. 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 In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.


Structure

In humans, CD19 is encoded by the 7.41 kilobase ''CD19'' gene located on the short arm of chromosome 16. It contains at least fifteen exons, four that encode extracellular domain and nine that encode cytoplasmic domains, with a total of 556 amino acids. Experiments show that there are multiple mRNA transcripts; however, only two have been isolated '' in vivo''. CD19 is a 95 kd Type I transmembrane
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as g ...
in the immunoglobulin superfamily ( IgSF) with two extracellular C2-set Ig-like domains and a relatively large, 240
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
, cytoplasmic tail that is highly conserved among mammalian species. The extracellular C2-type Ig-like domains are divided by a potential disulfide linked non-Ig-like domain and N-linked carbohydrate addition sites. The cytoplasmic tail contains at least nine tyrosine residues near the C-terminus. Within these residues, Y391, Y482, and Y513 have been shown to be essential to the biological functions of CD19. Phenylalanine substitution for tyrosine at Y482 and Y513 leads to the inhibition of phosphorylation at the other tyrosines.


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. Throughout development, the surface density of CD19 is highly regulated. CD19 expression in mature B cells is threefold higher than that in immature B cells. 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. Because of its ubiquity on all B cells, it can function as a B cell
marker The term Marker may refer to: Common uses * Marker (linguistics), a morpheme that indicates some grammatical function * Marker (telecommunications), a special-purpose computer * Boundary marker, an object that identifies a land boundary * Marke ...
and a target for immunotherapies targeting neoplastic lymphocytes.


Function


Role in development & survival

Decisions to live, proliferate, differentiate, or die are continuously being made during B cell development. 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. Essential to the functionality of a BCR is the presence of CD19. 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. Analysis of mixed bone marrow chimeras suggest that prior to an initial antigen encounter, CD19 promotes the survival of
naive Naivety (also spelled naïvety), naiveness, or naïveté is the state of being naive. It refers to an apparent or actual lack of experience and sophistication, often describing a neglect of pragmatism in favor of moral idealism. A ''naïve'' ma ...
recirculating B cells and increases the in vivo life span of B cells in the peripheral B cell compartment. 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. 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 Knockdown or knock-down may refer to: * Knockdown, a situation in full-contact combat sports where a fighter is down or vulnerable, often preliminary to a knockout * "Knockdown" (Castle), the thirteenth episode of the third season of the TV serie ...
mice. 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. 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 ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...
'' and ''in vivo''.


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. The CD19/CD21 complex arises from
C3d C3D Toolkit is a geometric modeling kit originally developed by ASCON Group, now by C3D Labs, using C++ and written in Visual Studio. C3D Toolkit responsible for constructing and editing geometric models. It can be licensed by other companies ...
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.


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 The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...
. 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 kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cl ...
s, ensuing is the binding of additional
Src-family kinases Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs in ...
, 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. Activated spleen tyrosine kinase ( Syk) leads to phosphorylation of the scaffold protein,
BLNK The B-cell linker protein is encoded by the ''BLNK'' gene and is an adaptor protein also known as SLP-65, BASH, and BCA. BLNK is expressed in B cells and macrophages and plays a large role in B cell receptor signalling, in a fashion analogous to ...
, 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.


Interactions

CD19 has been shown to interact with: * CD81 * CD82 *
Complement receptor 2 Complement receptor type 2 (CR2), also known as complement C3d receptor, Epstein-Barr virus receptor, and CD21 (cluster of differentiation 21), is a protein that in humans is encoded by the CR2 gene. CR2 is involved in the complement system. I ...
* VAV2


In disease


Autoimmunity & immunodeficiency

Mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s in CD19 are associated with severe immunodeficiency syndromes characterized by diminished
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique m ...
production. Additionally, mutations in CD21 and CD81 can also underlie primary immunodeficiency due to their role in the CD19/CD21 complex formation. These mutations can lead to
hypogammaglobulinaemia Hypogammaglobulinemia is a problem with the immune system in which not enough gamma globulins are produced in the blood (thus '' hypo-'' + ''gamma'' + '' globulin'' + '' -emia''). This results in a lower antibody count, which impairs the immune ...
as a result of poor response to antigen and defective immunological memory. 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. CD19 has also been implicated in autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and may be a useful treatment target. Mouse model research shows that CD19 deficiency can lead to hyporesponsiveness to transmembrane signals and weak T cell dependent
humoral response Humoral immunity is the aspect of immunity that is mediated by macromolecules - including secreted antibodies, complement proteins, and certain antimicrobial peptides - located in extracellular fluids. Humoral immunity is named so because it invo ...
, that in turn leads to an overall impaired humoral immune response. 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.


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). The majority of B cell malignancies express normal to high levels of CD19. The most current experimental
anti-CD19 immunotoxin Anti-CD19 immunotoxin is a monoclonal antibody linked to a toxic substance. It is being studied in the treatment of some types of B-cell cancer. Anti-CD19 immunotoxin is made in the laboratory. It binds to CD19, a protein on the surface of normal B ...
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. 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. 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. 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 Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in a ...
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.


References


Further reading

* * * * * * * * * * * * * * * * * * * *


External links


Mouse CD Antigen Chart


* {{Immunoglobulin superfamily immune receptors Clusters of differentiation Biomarkers