OX-2 membrane glycoprotein, also named CD200 (Cluster of Differentiation 200) [5] is a human protein encoded by the CD200 gene. [6] In humans, the CD200 gene is located on chromosome 3 in proximity to genes encoding the other B7 proteins CD80/CD86. In mice, the CD200 gene is located on chromosome 16. [7]
The protein encoded by this gene is a type-1 membrane glycoprotein, which contains two IgSF immunoglobulin domains, transmembrane region and a 19 amino acid long cytoplasmatic domain. CD 200 belongs to the immunoglobulin superfamily, particularly belongs to the B7 receptor family. [7] [6]
CD200 is expressed on dendritic cells, activated B lymphocytes, activated T lymphocytes, thymocytes, endothelial cells, neurons and osteoblast precursors. Moreover, CD200 is expressed on various types of human cancer cells including hairy cell leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, malignant melanoma, multiple myeloma, testicular cancer, renal carcinoma, colon carcinoma and glioblastoma multiforme. [7] [8]
In innate immunity, cellular CD200 expression is induced upon TLR and NLR activation.
At the transcriptional level, CD200 expression is regulated by C/EBP-β. It has been shown that CD200 expression is induced by IFN-γ and TNF-α in a NF-kappaB-, STAT1- and IRF-1-dependent manner. [7]
Soluble CD200 (sCD200) is present in serum. It was shown that elevated levels of serum sCD200 are associated with adverse tumor prognosis in chronic lymphocytic leukemia, glioblastoma multiforme, ependymoma and medulloblastoma. Furthermore, sCD200 is associated with the expansion of myeloid-derived suppressor cells in patients with glioblastoma multiforme. [8]
Truncated CD200 (CD200tr) is a truncated version of CD200 produced by alternative splicing mechanism. CD200tr lacks approximately 30 amino acids in the NH2-terminal sequence. It was shown that CD200tr acts as a competitive inhibitor to the full length CD200. [7]
CD200 interacts with its receptor CD200R and leads to immunosuppressive signaling. CD200R is strongly expressed on macrophages, neutrophils and mast cells as well as on some subtypes of B lymphocytes and T lymphocytes. In the tumor microenvironment CD200R is expressed on tumor-associated myeloid cells, particularly in tumor-associate macrophages, myeloid-derived suppressor cells, tumor-associated dendritic cells and also in regulatory T lymphocytes. [9] [8]
CD200-CD200R engagement inhibits T-cell immune response, shifts cytokine profile towards Th2 type response, decreases NK cell cytotoxic activity, promotes indoleamin-2,3 dioxygenase production in macrophages and triggers regulatory T cell expansion. CD200 on dendritic and lymphoid effector cells modulates the activation threshold of inflammatory response and thus contributes to the maintenance of self-tolerance. [7] [10] Interaction between CD200 and CD200R results in a down-regulation of basophils function and inhibits lytic function of NK cells. In IFN-γ and TNF-α producing macrophages, CD200-CD200R interaction leads to inhibition of function through Dok2 and RasGAP dependent mechanism. Elevated expression of CD200R on macrophages is associated with alternative activation of macrophages to M2 phenotype. [7]
The engagement of CD200 to CD200R leads to tyrosine phosphorylation on CD200R cytomplasmatic PTB domain. This leads to a recruitment of adaptor proteins DOK-1 and DOK-2 that promotes binding of SHIP to DOK-1 and the recruitment of RasGAP which negatively regulates the MAPK/ERK signaling pathway. This signaling leads to the inhibition of proinflammatory cytokine release and inhibition of immune cell activation and suppression of mast cell degranulation. [8]
CD200-encoding gene has been acquired by a number of viruses infecting animals as well as human, for example some human herpesviruses.
KSHV, also known as human herpesvirus-8 is, essential for the development of Kaposi sarcoma. This virus produces an ortholog of CD200, known as viral OX2 (vOX2), a 55 kDa protein. This gene is expressed on the surface of infected cells during viral replicative state. vOX-2 has an approximately 40% sequence similarity with the human gene for CD200 but shares key residues with CD200 in its binding site for CD200R. Due to its ability to engage CD200R, vOX2 can target host immune cells (T lymphocytes, macrophages, neutrophils, basophils) and inhibit anti-viral activity. Particularly, vOX2 is capable of decreasing production of TNF-α, IFN-γ from macrophages and T lymphocytes and the CD170a-dependent activation of NK cells.
Leishmania amazonensis induces expression of CD200 in the bone marrow macrophages a thus inhibits neighboring macrophages expressing CD200R that inhibits NO production during infection. Infection with Taenia crassiceps and Trypanosoma brucei brucei leads to an overexpression of CD200R on M2 macrophages and consequently to the inhibition of innate immunity response. [7]
Rat cytomegalovirus also express CD200 ortholog known as e127 protein interacts with CD200R. e127 protein is expressed on the surface of infected cells. [8]
CD200 is overexpressed in cancer cells in a number of human tumors including melanoma, ovarian cancer, some B-cell malignances and small cell lung carcinoma. In the tumor microenvironment CD200 is also expressed in endothelial cells and activated T lymphocytes, B lymhocytes and myeloid cells. These cells can thus interact with cells expressing CD200R such as T regulatory cells, tumor-associated dendritic cells, tumor associated macrophages and myeloid derived suppressor cells (MDSC). It was shown that CD200 expressed on tumor cells promotes expansion of MDSCs that are capable of inhibiting anti-tumor immune response. CD200 blockade inhibits tumor growth and decreases number of MDSCs in tumor tissue. [7]
The exact relationship between CD200 and cancer development, as well as its impact on disease prognosis, remains unclear and appears to vary depending on the type of tumor. [9]
It was shown that in animal models CD200 prolongs allograft survival. This effect is associated with polarization of cytokine response towards increased production of type-2 cytokines and decreased production of type-1 cytokines. In in vitro experiments, allostimulated cells in the presence of CD200 decreased their cytotoxic function in TGF-β and IL-10 dependent mechanism. [7]
Samalizumab, recombinant humanized monoclonal antibody targeting CD200 was tested in patients with chronic lymphocytic leukemia (CLL) and multiple myeloma as a phase I study. Samalizumab treatments showed a dose-dependent decrease in CD200 expression on CLL cells and decreased frequencies of circulating CD200+ CD4+ T lymphocytes in a majority of CLL patients and in multiple myeloma patients. [10]
Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.
Integrin alpha M (ITGAM) is one protein subunit that forms heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3). ITGAM is also known as CR3A, and cluster of differentiation molecule 11B (CD11B). The second chain of αMβ2 is the common integrin β2 subunit known as CD18, and integrin αMβ2 thus belongs to the β2 subfamily integrins.
Receptor activator of nuclear factor kappa-Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.
Chemokine ligand 18 (CCL18) is a small cytokine belonging to the CC chemokine family. The functions of CCL18 have been well studied in laboratory settings, however the physiological effects of the molecule in living organisms have been difficult to characterize because there is no similar protein in rodents that can be studied. The receptor for CCL18 has been identified in humans only recently, which will help scientists understand the molecule's role in the body.
Chemokine ligand 9 (CCL9) is a small cytokine belonging to the CC chemokine family. It is also called macrophage inflammatory protein-1 gamma (MIP-1γ), macrophage inflammatory protein-related protein-2 (MRP-2) and CCF18, that has been described in rodents. CCL9 has also been previously designated CCL10, although this name is no longer in use. It is secreted by follicle-associated epithelium (FAE) such as that found around Peyer's patches, and attracts dendritic cells that possess the cell surface molecule CD11b and the chemokine receptor CCR1. CCL9 can activate osteoclasts through its receptor CCR1 suggesting an important role for CCL9 in bone resorption. CCL9 is constitutively expressed in macrophages and myeloid cells. The gene for CCL9 is located on chromosome 11 in mice.
Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.
CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.
5′-nucleotidase (5′-NT), also known as ecto-5′-nucleotidase or CD73, is an enzyme that in humans is encoded by the NT5E gene. CD73 commonly serves to convert AMP to adenosine.
CD226, PTA1 or DNAM-1 is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.
Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3) gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.
Macrophage receptor with collagenous structure (MARCO) is a protein that in humans is encoded by the MARCO gene. MARCO is a class A scavenger receptor that is found on particular subsets of macrophages. Scavenger receptors are pattern recognition receptors (PRRs) found most commonly on immune cells. Their defining feature is that they bind to polyanions and modified forms of a type of cholesterol called low-density lipoprotein (LDL). MARCO is able to bind and phagocytose these ligands and pathogen-associated molecular patterns (PAMPs), leading to the clearance of pathogens and cell signaling events that lead to inflammation. As part of the innate immune system, MARCO clears, or scavenges, pathogens, which leads to inflammatory responses. The scavenger receptor cysteine-rich (SRCR) domain at the end of the extracellular side of MARCO binds ligands to activate the subsequent immune responses. MARCO expression on macrophages has been associated with tumor development and also with Alzheimer's disease, via decreased responses of cells when ligands bind to MARCO.
Cell surface transmembrane glycoprotein CD200 receptor 1 is a protein that in humans is encoded by the CD200R1 gene. CD200R1 is expressed on the surface of myeloid cells and CD4+ T cells. It interacts with CD200 transmembrane glycoprotein that can be expressed on variety of cells including neurons, epithelial cells, endothelial cells, fibroblasts, and lymphoid cells.
Signaling lymphocytic activation molecule (SLAM) is a family of genes. Homophilic binding between SLAMs is involved in cell-to-cell adhesion during antigen presentation.
Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.
Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes or yolk sac progenitors, but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.
The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue and the extracellular matrix. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. The tumor microenvironment is in constant change because of the tumor's ability to influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.
Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage.
Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.
Bacterial therapy is the therapeutic use of bacteria to treat diseases. Bacterial therapeutics are living medicines, and may be wild type bacteria or bacteria that have been genetically engineered to possess therapeutic properties that is injected into a patient. Other examples of living medicines include cellular therapeutics, activators of anti-tumor immunity, or synergizing with existing tools and approaches. and phage therapeutics, or as delivery vehicles for treatment, diagnosis, or imaging, complementing or synergizing with existing tools and approaches.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.