The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD ) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophenotyping of cells. In terms of physiology, CD molecules can act in numerous ways, often acting as receptors or ligands important to the cell. A signal cascade is usually initiated, altering the behavior of the cell (see cell signaling ). Some CD proteins do not play a role in cell signaling, but have other functions, such as cell adhesion . CD for humans is numbered up to 371 (as of 21 April 2016 ).
53-408: 930 12478 ENSG00000177455 ENSMUSG00000030724 P15391 P25918 NM_001178098 NM_001770 NM_001385732 NM_009844 NM_001357091 NP_001171569 NP_001761 NP_033974 NP_001344020 B-lymphocyte antigen CD19 , also known as CD19 molecule ( C luster of D ifferentiation 19 ), B-Lymphocyte Surface Antigen B4 , T-Cell Surface Antigen Leu-12 and CVID3
106-410: A chemokine receptor on the surface of a T helper cell to gain entry. The number of CD4 and CD8 T cells in blood is often used to monitor the progression of HIV infection . While CD molecules are very useful in defining leukocytes, they are not merely markers on the cell surface . Though only a fraction of known CD molecules have been thoroughly characterised, most of them have important functions. In
159-468: A " CD34 +, CD31 −" cell is one that expresses CD34 but not CD31. This CD combination typically corresponds to a stem cell , as opposed to a fully differentiated endothelial cell . Some cell populations can also be defined as , , or (alternatively, , , or ), indicating an overall variability in CD expression , particularly when compared to other cells being studied. A review of the development of T cells in
212-474: 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. This article incorporates text from the United States National Library of Medicine , which is in the public domain . Cluster of differentiation The CD nomenclature was proposed and established in
265-790: A condition or growth that is not cancerous, i.e. does not spread to other parts of the body or invade nearby tissue. Sometimes the term is used to suggest that a condition is not dangerous or serious. Malignancy in cancers is characterized by anaplasia , invasiveness, and metastasis . Malignant tumors are also characterized by genome instability , so that cancers, as assessed by whole genome sequencing , frequently have between 10,000 and 100,000 mutations in their entire genomes. Cancers usually show tumour heterogeneity , containing multiple subclones. They also frequently have reduced expression of DNA repair enzymes due to epigenetic methylation of DNA repair genes or altered microRNAs that control DNA repair gene expression. Tumours can be detected through
318-429: A constant global health concern for a number of years, resulting in significant social and economic impacts on individuals with malignancy and their families. The risk of developing malignancy is 20.2%. In 2018, 18 million patients were diagnosed with a malignant tumour with lung, breast and prostate being the most common form. Additionally, there were approximately 10 million mortalities due to cancer in 2020 and, there
371-491: 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
424-505: A history of cancer in the family. Other risk factors include developing post-transplant malignancy which occurs subsequent to solid organ transplantations . Individuals who undergo organ transplant surgery have an increased risk of developing malignancy in comparison to the general population. The most common form of malignancy being " nonmelanoma skin cancer and, posttransplant lymphoproliferative disorders ". The different types of malignancy developed post-transplant depend on which organ
477-404: A laboratory. If detected as a malignant tumour, treatment is necessary; treatment during early stages is most effective. Forms of treatment include chemotherapy, surgery, photoradiation, and hyperthermia, amongst various others. When malignant cells form, symptoms do not typically appear until there has been a significant growth of the mass. Once signs and symptoms do arise, they are dependent on
530-423: 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
583-476: 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. CD19
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#1732859010606636-405: A role in controlling or reducing malignancy growth rather, they increase the patient's quality of life. Hematoporphyrin derivative (HPD) is a drug which was developed to be absorbed by malignant cells and only becomes active when exposed to light. It is commonly used to identify and localise cancers as when it is under activation of blue light the red fluorescence of the malignant tumour (due to
689-405: A role in the development of malignancy, with agents of infectious disease being able to produce a multitude of malignant cells. These include bacterial causes, fungal and parasitic causes and, viral causes. Bacteria , fungi and similar pathogens have the ability to form an environment within states of chronic inflammation which gives rise to oncogenic potential. Viral agents are able to assist
742-483: 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
795-453: 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 kDa 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. The extracellular C2-type Ig-like domains are divided by
848-443: 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 , 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
901-474: 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. 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
954-447: Is a cytotoxic agent which holds the ability to eradicate malignant cells by preventing both nucleic acid and protein synthesis . The treatment process also utilises HPD's capability of accumulating at higher levels in malignant tissues compared to most other tissues. In the case of deeply pigmented or larger tumours, a stronger course of this treatment process is required in order to be effective. Malignancy can be treated through
1007-504: Is affected indirectly and/or through multiple pathways. The combination of these intracellular changes means there is no specific target of cell death in the hyperthermic process. Chemotherapy is commonly used as either the primary treatment or in conjunction with other treatment forms such as radiotherapy or surgery. It can be administered through "injection, intra-arterial (IA), intraperitoneal (IP), intrathecal (IT), intravenous (IV), topical or oral". The purpose of chemotherapy
1060-459: Is an overall trend which demonstrated that malignant mortality has increased by 28% over the past 15 years. Lung cancer has the highest mortality rate in comparison to other forms of cancer, with the leading cause of development due to smoking. The number of smokers in China is rapidly increasing with tobacco killing approximately 3000 people each day. The diagnosis of lung cancer is most common within
1113-400: Is assigned a CD number once two specific monoclonal antibodies are shown to bind to the molecule. If the molecule has not been well characterized or has only one mAb, it is usually given the provisional indicator "w" (as in " CDw186 "). For instance, CD2 mAbs are reagents that react with a 50‐kDa transmembrane glycoprotein expressed on T cells . The CD designations were used to describe
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#17328590106061166-479: Is rare for CD19 to be absent in neoplastic B cells, as it is essential for development. 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 immunotoxins in development work by exploiting
1219-501: Is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer . A malignant tumor contrasts with a non-cancerous benign tumor in that a malignancy is not self-limited in its growth, is capable of invading into adjacent tissues, and may be capable of spreading to distant tissues. A benign tumor has none of those properties, but may still be harmful to health. The term benign in more general medical use characterizes
1272-623: 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 and a target for immunotherapies targeting neoplastic lymphocytes . 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
1325-464: Is to use cytotoxic agents which kill rapidly dividing cells within the body. It targets the cellular mechanisms which allow the development of malignancy throughout the body. There are no specific areas which are targeted and so, there is a lack of differentiation between normal and malignant cells, resulting in a range of side effects. This includes bone marrow suppression , gastrointestinal problems and alopecia . Some side effects are specific to
1378-635: Is uncommon (though a few examples exist), combining markers has allowed for cell types with very specific definitions within the immune system. CD molecules are utilized in cell sorting using various methods, including flow cytometry . Two commonly used CD molecules are CD4 and CD8 , which are, in general, used as markers for helper and cytotoxic T cells, respectively. These molecules are defined in combination with CD3+, as some other leukocytes also express these CD molecules (some macrophages express low levels of CD4; dendritic cells express high levels of CD8). Human immunodeficiency virus binds CD4 and
1431-403: 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
1484-519: The thymus uses this nomenclature to identify cells transitioning from CD4 /CD8 double-positive cells to CD4 /CD8 . Since 1982 there have been nine Human Leukocyte Differentiation Antigen Workshops culminating in a conference. The CD system is commonly used as cell markers in immunophenotyping , allowing cells to be defined based on what molecules are present on their surface. These markers are often used to associate cells with certain immune functions . While using one CD molecule to define populations
1537-564: The 1st International Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA), held in Paris in 1982. This system was intended for the classification of the many monoclonal antibodies (mAbs) generated by different laboratories around the world against epitopes on the surface molecules of leukocytes (white blood cells). Since then, its use has expanded to many other cell types, and more than 370 CD unique clusters and subclusters have been identified. The proposed surface molecule
1590-499: 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 . Recognition of an antigen by the complement system enables the CD19/CD21 complex and associated intracellular signaling molecules to crosslink to
1643-556: 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. Activated spleen tyrosine kinase ( Syk ) leads to phosphorylation of
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1696-486: The CD19/CD21 complex formation. These mutations can lead to hypogammaglobulinaemia 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
1749-467: The HPD) can be observed easily. The combination of HPD with red light (photoradiation) has been used on various malignant tumours including malignant melanomas and carcinomas on a range of different organs including the breast and colon. This form of treatment produces a singlet oxygen through the photodynamic process; where the oxygen molecule exists in an electronically excited state. The singlet oxygen
1802-714: The anticancer drug used, the most common being bone marrow suppression as bone marrow has the ability to divide rapidly due to high growth fraction. This is because anticancer drugs have the highest activity in high growth fraction tissues. Alkylating agents are used in chemotherapy as these are chemically reactive drugs which form covalent bonds when reacting with DNA. This results in breaks within DNA strands causing either inter-strand or intra-strand DNA cross-linking. The sub-classes of alkylating agents are " nitrogen mustards , oxazaphosphorines, alkyl alkane, sulphonates, nitrosoureas , tetrazines and aziridines ." Malignancy has been
1855-518: 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 . 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. While colligated with
1908-544: The disease has usually progressed for a number of years before detection. Surgery can help manage or treat malignancy by either removing the tumour, localising it and/or determining whether there has been a spread to other organs. When undertaking surgery for malignancy, there are six major objectives which are considered. These include "prevention of cancer, diagnosis and staging of disease, disease cure, tumour debulking, symptom palliation and patient rehabilitation". Surgical prevention of cancer largely consists of removing
1961-491: The example of CD4 and CD8, these molecules are critical in antigen recognition. Others (e.g., CD135 ) act as cell surface receptors for growth factors . Recently, the marker CD47 was found to have anti- phagocytic signals to macrophages and inhibit natural killer (NK) cells. This enabled researchers to apply CD47 as a potential target to attenuate immune rejection . Malignancy Malignancy (from Latin male 'badly' and -gnus 'born')
2014-405: The formation of a lump . Signs and symptoms specific to males include pain or growths in the scrotum or difficulty urinating. Malignant cells often evolve due to a combination of reasons rather than one definitive reason. Reasons which can explain their development include genetics and family history, triggers such as infectious diseases, and exposure to risk factors. Infectious diseases play
2067-423: The formation of malignant tumours due to a mechanism of cell transformation. This cell transformation can occur through either "DNA integration or cellular-DNA alteration of growth regulator genes". Inflammation can also play a role in triggering malignancy as it can promote stages of tumour formation. The main purpose of inflammation is to repair tissue, defend the body against pathogens and regenerate cells. At
2120-677: The location, size and type of malignancy. Usually, it is quite general and can be associated with other illnesses or diseases and thus, can be difficult to diagnose or can be misdiagnosed. Signs include observable or measurable aspects such as weight loss (without trying), a fever or unusual bleeding. On the other hand, symptoms are felt internally by the individual such as fatigue or changes in appetite. A general list of common signs and symptoms includes pain (headaches or bone aches), skin changes (new moles or bumps), coughing and unusual bleeding. There are also signs and symptoms specific to females including belly pain and bloating or breast changes i.e.,
2173-444: The malignant tumour has only invaded one area of the body. The objective is to remove the entirety of the malignant cells without violating the tumour; if the tumour is violated, the risk of both tumour spillage and wound implantation would increase. The surgical procedure of tumour debulking can be undertaken to increase the effectiveness of postoperative forms of treatment. Symptom palliation and patient rehabilitation do not play
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2226-626: The organ at risk of developing malignancy. This would occur if an individual is predisposed to the formation of malignant cells as a result of inherited genetic mutations and, acquired diseases. Surgical diagnosis of malignancy involves completing a biopsy . This process requires a sufficient amount of tissue to make a confident diagnosis and, the handling of specimen to expand information provided from testing. Biopsies are categorised into four different processes: "fine-needle aspirate (FNA), core needle, incisional and, excisional". Curative surgery (also known as primary surgery) can be conducted when
2279-541: 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 mice. CD19 signaling involves
2332-408: The recognized molecules but had to be clarified by attaching the term antigen or molecule to the designation (e.g., CD2 molecule). Currently, "CD2" is generally used to designate the molecule, and "CD2 antibody " is used to designate the antibody. Cell populations are usually defined using a '+' or a '−' symbol to indicate whether a certain cell fraction expresses or lacks a CD molecule. For example,
2385-566: 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 and in vivo . On
2438-502: The same time, inflammatory cells can also interact with malignant cells to form an inflammatory tumour microenvironment . This environment increases the likelihood of forming malignant cells through blockage of anti-tumour immunity. Once this occurs, the inflammatory tumour microenvironment begins to send out tumour-promoting signals to epithelial cells, triggering the formation of malignant cells. Traditional risk factors of developing malignancy include smoking, sun exposure and, having
2491-804: 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. CD19 has been shown to interact with: Mutations in CD19 are associated with severe immunodeficiency syndromes characterized by diminished antibody production. Additionally, mutations in CD21 and CD81 can also underlie primary immunodeficiency due to their role in
2544-405: The survival of naive 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. Paired box transcription factor 5 ( PAX5 ) plays a major role in B cell differentiation from pro B cell to mature B cell,
2597-456: 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 . 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
2650-407: The use of hyperthermia by applying either surgical perfusion or interstitial techniques to the body. The use of this treatment type largely depends on the fact that malignant and normal cells have differing responses to the energy source used. This dependency is due to the intracellular changes which occur during hyperthermia; as the nucleic acids , cell membrane and cytoskeleton within each cell
2703-408: The visualisation or sensation of a lump on the body. In cases where there is no obvious representation of a lump, a mammogram or an MRI test can be used to determine the presence of a tumour. In the case of an existing tumour, a biopsy would then be required to make a diagnosis and distinguish whether the tumour is malignant or benign. This involves examination of a small sample of the tissue in
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#17328590106062756-449: 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
2809-617: Was transplanted. This is linked to recipients being at a higher risk when exposed to traditional risk factors as well as, the type and intensity of the operation, the duration of their immunosuppression post-operation and, the risk of developing oncogenic viral infections. There are various treatment forms available to help manage malignancy. Common treatments include chemotherapy , radiation and surgical procedures. Photoradiation and hyperthermia are also used as treatment forms to kill or reduce malignant cells. A large portion of patients are at risk of death when diagnosed with malignancy as
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