| Description | The CD200 molecule is a single-pass type I membrane protein spanning the membrane once, with its N-terminus on the extracellular side of the membrane and subsequent processing results in removal of its signal sequence. Variant 1 produces a protein that is 269 amino acids in length, variant 2 yields a protein that is 294 amino acids, and variant 3 has yet to be experimentally validated for its product. CD200 is a highly conserved member of the immunoglobulin superfamily containing both an Ig-like C2-type (immunoglobulin-like) domain as well as Ig-like V-type (immunoglobulin-like) domain. |
| Expression | CD200 is commonly expressed on cells originating from the hematopoietic cells, specifically those of the myeloid lineage such as macrophages, dendritic cells, neutrophils, mast cells, and eosinophils, yet it can also be expressed on B cells, activated T cells, endothelial neuronal cells and cells of the reproductive organs (ovaries and placental trophoblasts). This molecule exerts its effect by binding to its cognate receptor CD200R (also on chromosome 3 and containing two Ig-like domains) which is expressed on cells specifically derived from the myeloid lineage and certain populations of T cells. This interaction can only occur when the cell carrying the receptor and the cell expressing CD200 are in close contact to one another. Unlike the CD200 molecule itself, the CD200R has 67 amino acids in its cytoplasmic domain compared to 19 for CD200, and it contains tyrosine residues that can be phosphorylated to carry on further signal transduction. A recent review has further summarized the tissue distribution of CD200 and its receptor in rat, mouse and human samples. |
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| | CD200 and membrane protein interactions in the control of myeloid cells.
Neil Barclay, Gavin J. Wrightb, Gary Brooke and Marion H. Brown. Trends in Immunology. Volume 23, Issue 6, 1 June 2002, Pages 285-290. |
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| Localisation | Single-pass type I plasma membrane protein or plasma membrane associated protein. |
| Function | The function of CD200 was orginally identified using mice lacking the CD200 gene where the mice developed an earlier onset of disease in experimental models of both autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA), and autoimmune alopecia. The mice have increased numbers of macrophages in the spleen and after immunological stimulation, these macrophages demonstate a more active phenoype in vivo. These studies demonstrate the importance of CD200 in maintaining self-tolerance and further studies have demonstrated that CD200 acts as an important molecule in controlling autoimmunity, inflammation and adaptive immune responses implicating it as a key immunosuppressive molecule. The CD200-CD200R interaction exerts its inhibitory signal to myeloid cells that suppresses INF (Interferon)-gamma-induced proliferation, activation and secretion of nitrous oxide (NO), IL5, IL13 and IL6. Interestingly, a few phylogenetically distinct viruses including poxviruses and KSHV, the agent that causes Kaposi sarcoma and other human cancers, have been shown to attenuate the host antiviral immune response by expressing a viral CD200 homolog. |
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| Homology | | | | | % Identity | | Homo sapiens | | | Protein | DNA | CD200 | vs. Pan troglodytes (Common Chimpanzee) | CD200 | 99.3 | 99.4 | | | vs. Canis lupus familiaris (Domestic Dog) | CD200 | 77.1 | 82.7 | | | vs. Bos taurus (Domestic Cow) | CD200 | 80.2 | 84.8 | | | vs. Mus musculus (The House Mouse) | CD200 | 77.6 | 81.7 | | | vs. Rattus norvegicus (Norway Rat) | CD200 | 77.2 | 80.7 | | | vs. Gallus gallus (Domesticated Fowl) | CD200 | 36.8 | 51.0 | |
| Entity | Cancer |
| Note | The expression of CD200 has been found in expressed several cancer cell lines or tissues, including ovarian, melanoma, head and neck carcinoma, testicular, malignant mesothelioma, neuroblastoma, renal cell carcinoma, chronic lymphocytic leukemia, prostate, breast and colon cancer. In multiple myeloma (MM) and acute myeloid leukemia (AML) CD200 has been implicated as a prognostic factor. In MM patients, CD200 was expressed in 78% of samples analyzed and for AML patients, in 43% of the patient samples. Patients who demonstrated expression of CD200 on their leukemic cells also demonstrated a decrease in survival overall. With regards to cancer progression, expression of CD200 is associated with metastasis or a relapse in bladder, lung, CML (chronic myeloid leukemia), breast, melanoma and prostate cancers. The expression of CD200 on cancer cells has been linked to the theory of tumor immunity since mice treated wtih a CD200-Fc fusion protein (which blocks function of CD200) were able to clear injected leukemic, cells unlike mice who did not receive the antibody. |
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| Entity | Cancer Stem Cells |
| Note | A relatively new hypothesis about cancer progression has suggested that cancer stem cells (CSCs) mediate solid tumor initiation and progression. The theory suggests that CSCs are only a minor subpopulation of cells (generally <1%) within the tumor that self-renew and also give rise to differentiated tumor cells, while the bulk of tumor cells are highly differentiated, have limited proliferative potential and are non-tumorigenic. Several markers exist to identify CSCs. For example CD44, CD133, α2β1 integrin and flow cytometry-based 'side-populations' are all associated with CSCs. In 2007, CD200 was found to be co-expressed with the CSC markers CD44 and CD133 in a number of cancer cell lines including breast, prostate, brain, colon and melanoma, as well as in normal mesenchymal stem cells. In addition, the expression of CD200 was found to be 3-fold higher in CSCs compared with non-CSCs. This research has supported the theory that expression of CD200 defines a CSC population that can evade the tumor immune responses the host would normally provide (Figure below). |
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| A hypothetical model of how CD200 might be involved in cancer stem cell (CSC) immunoevasion. CD200-expressing CSCs survive immune therapy or a natural immune response and induce a shift away from a Th1 response. These immunosuppressive effects of CD200+ CSCs could be mediated by events such as deviations in cytokine production, increased proliferation and/or induction of regulatory T cells (Treg). The altered immune response to the tumor might indefinitely dampen future immune reactions to the tumor, thus resulting in tumor cells that are resistant and free to proliferate in an immunocompromised tumor microenvironment.
Kawasaki, B.T. et al. (2008) Cancer stem cells, CD200 and immunoevasion. Trends in Iummunology Vol. 29 No. 10 (464-468). |
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| Entity | Experimental autoimmune encephalomyelitis (EAE) |
| Note | EAE is a model of the human disease multiple sclerosis, which results from activation of peripheral T lymphocytes, macrophages, and granulocytes. These activated cells migrate to the Central Nervous System and can lead to microglial activation, tissue damage, and neurological deficits including paralysis. In these EAE mice, loss of CD200 resulted in an increase of disease onset and progression compared to mice expressing the gene. Using cultured rat hippocampal neurons, it was found that if the CD200-CD200R signalling pathway is blocked using an anti-CD200R-Fc antibody, the INF-gamma induced IL6 response of macrophages is increased and macrophage-mediated cell death of the neurons occured. |
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| Entity | Collagen-induced arthritis (CIA) |
| Note | CIA is a model of human rheumatoid arthritis which is an inflammatory autoimmune disease of the joints, and like EAE involves tissue-specific influx of T cells, macrophages, and granulocytes. Disruption of CD200-CD200 receptor interaction using cd200 KO mice increased susceptibility to mice normally resistant to this disease. The animals developed moderate to severe arthritis with synovial inflammation and formation of invasive pannus which results in degradation of cartilage and bone. |
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| Entity | Skin Graft Rejection/Transplantation |
| Note | Experiments from mice have demonstrated that when wild-type tail skin from a male mouse was grafted onto the flank of a strain matched female, the skin was rejected at 59 days. However, if the male skin was CD200-deficient, it was only rejected after only 25 days. |
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| Entity | Alopecia |
| Note | When expression of CD200 is lost from follicular kertainocytes the CD200R-positive cells (Langerhans cells and dendritic cells) switch to having an activated phenotype. Any additional trauma to the skin can initate a full activation of CD200 positive cells and cause folliculocentric inflammation. The chronic inflammation that ensues leads to recruitment and activation of autoreactive T cells which are specific for hair follicles and lead to their destruction. |
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| Entity | Autoimmune uveoretinitis (EAU) |
| Note | EAU is an organ-specific autoimmunity in the eye, a tissue with extensive neuronal and endothelial CD200 expression.One experiment demonstrated that mice lacking CD200 expression had increased numbers of retina-infiltrating macrophages. In addition, these mice displayed an increase in nitric oxide responses. When DX109 (a monoclonal antibody to CD200) was administered, it suppressed EAU despite maintained T-cell proliferation and IFNgamma production and resulted in an earlier resolution of disease. Thus promoting CD200R-mediated signaling can successfully prevent full expression of IFNgamma-mediated macrophage activation and protect against tissue damage during autoimmune responses. |
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| Entity | Recurrent Abortion/Pre-Eclampsia |
| Note | A number of immunoregulatory cells have been shown to help prevent abortions and/or play a role in pre-eclampsia. For CD200, when male lymyphocytes from aborting mice were immunized (inactivated), this stimulated female gdT CD4 cells to secrete Th2 cytokines via a CD200-dependent mechanism and reversed the abortive affects. |
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| Entity | Microglia activation and Parkinsons Disease (PD) |
| Note | A number of studies have demonstrated that CD200 down-regulates microglia activation through binding to CD200R. Microglia are the primary immune cells in the brain and play an important role in the progression of PD. Similar to true myleoid cells, microglia in CD200-deficient mice exhibited more activated characterisitics, such as shorter glial processes and less of a disordered arrangement, as well as an increase in inducible nitric oxide synthetase (specific to immune cells). To further support this, Frank et al. in 2006 demonstrated that expression of CD200 mRNA (measured by PCR) in the hippocampus decreased with increase in aging. Thus, the CD200-CD200R signaling pathway should be considered as target for developing therapies against PD. |
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| Down-regulation of the macrophage lineage through interaction with OX2 (CD200). |
| Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, Blom B, Homola ME, Streit WJ, Brown MH, Barclay AN, Sedgwick JD. |
| Science. 2000 Dec 1;290(5497):1768-71. |
| PMID 11099416 |
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| CD200 and membrane protein interactions in the control of myeloid cells. |
| Barclay AN, Wright GJ, Brooke G, Brown MH. |
| Trends Immunol. 2002 Jun;23(6):285-90. Review |
| PMID 12072366 |
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| Structural and functional heterogeneity in the CD200R family of immunoregulatory molecules and their expression at the feto-maternal interface. |
| Gorczynski RM, Chen Z, Clark DA, Kai Y, Lee L, Nachman J, Wong S, Marsden P. |
| Am J Reprod Immunol. 2004 Aug;52(2):147-63. |
| PMID 15274657 |
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| mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. |
| Frank MG, Barrientos RM, Biedenkapp JC, Rudy JW, Watkins LR, Maier SF. |
| Neurobiol Aging. 2006 May;27(5):717-22. |
| PMID 15890435 |
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| CD200 is a new prognostic factor in multiple myeloma. |
| Moreaux J, Hose D, Reme T, Jourdan E, Hundemer M, Legouffe E, Moine P, Bourin P, Moos M, Corre J, Mohler T, De Vos J, Rossi JF, Goldschmidt H, Klein B. |
| Blood. 2006 Dec 15;108(13):4194-7. Epub 2006 Aug 31. |
| PMID 16946299 |
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| CD200, a "no danger" signal for hair follicles. |
| Rosenblum MD, Yancey KB, Olasz EB, Truitt RL. |
| J Dermatol Sci. 2006 Mar;41(3):165-74. Epub 2006 Jan 4. Review |
| PMID 16386879 |
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| Immunological analogy between allograft rejection, recurrent abortion and pre-eclampsia - the same basic mechanism? |
| Wilczynski JR. |
| Hum Immunol. 2006 Jul;67(7):492-511. Epub 2006 May 4. Review |
| PMID 16829304 |
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| Co-expression of the toleragenic glycoprotein, CD200, with markers for cancer stem cells. |
| Kawasaki BT, Mistree T, Hurt EM, Kalathur M, Farrar WL. |
| Biochem Biophys Res Commun. 2007 Dec 28;364(4):778-82. Epub 2007 Oct 25. |
| PMID 17964286 |
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| The biology of cancer stem cells. |
| Lobo NA, Shimono Y, Qian D, Clarke MF. |
| Annu Rev Cell Dev Biol. 2007;23:675-99. |
| PMID 17645413 |
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| CD200 as a prognostic factor in acute myeloid leukaemia. |
| Tonks A, Hills R, White P, Rosie B, Mills KI, Burnett AK, Darley RL. |
| Leukemia. 2007 Mar;21(3):566-8. Epub 2007 Jan 25. |
| PMID 17252007 |
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| CD200-CD200R regulation of microglia activation in the pathogenesis of Parkinson's disease. |
| Wang XJ, Ye M, Zhang YH, Chen SD. |
| J Neuroimmune Pharmacol. 2007 Sep;2(3):259-64. Epub 2007 May 18. |
| PMID 18040859 |
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| Cancer stem cells, CD200 and immunoevasion. |
| Kawasaki BT, Farrar WL. |
| Trends Immunol. 2008 Oct;29(10):464-8. Epub 2008 Sep 3. |
| PMID 18775673 |
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| CNS inflammation and neuronal degeneration is aggravated by impaired CD200-CD200R-mediated macrophage silencing. |
| Meuth SG, Simon OJ, Grimm A, Melzer N, Herrmann AM, Spitzer P, Landgraf P, Wiendl H. |
| J Neuroimmunol. 2008 Feb;194(1-2):62-9. |
| PMID 18164423 |
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| Prostate cell cultures as in vitro models for the study of normal stem cells and cancer stem cells. |
| Miki J, Rhim JS. |
| Prostate Cancer Prostatic Dis. 2008;11(1):32-9. Epub 2007 Nov 6. Review |
| PMID 17984999 |
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| CD200: a putative therapeutic target in cancer. |
| Moreaux J, Veyrune JL, Reme T, De Vos J, Klein B. |
| Biochem Biophys Res Commun. 2008 Feb 1;366(1):117-22. Epub 2007 Dec 4. |
| PMID 18060862 |
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| Immune modulation by melanoma and ovarian tumor cells through expression of the immunosuppressive molecule CD200. |
| Siva A, Xin H, Qin F, Oltean D, Bowdish KS, Kretz-Rommel A. |
| Cancer Immunol Immunother. 2008 Jul;57(7):987-96. |
| PMID 18060403 |
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