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Tomasz P. Rygiel - One of the best experts on this subject based on the ideXlab platform.
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The pro-tumor effect of CD200 expression is not mimicked by agonistic CD200R antibodies.
PLOS ONE, 2019Co-Authors: Zofia Pilch, Linde Meyaard, Louis Boon, Katarzyna Tonecka, Marcin Skorzynski, Zuzanna Sas, Agata Braniewska, Tomasz Kryczka, Jakub Golab, Tomasz P. RygielAbstract:Tumor-infiltrating immune cells can impact tumor growth and progression. The inhibitory CD200 receptor (CD200R) suppresses the activation of myeloid cells and lack of this pathway results in a reduction of tumor growth, conversely a tumorigenic effect of CD200R triggering was also described. Here we investigated the role of CD200R activation in syngeneic mouse tumor models. We showed that agonistic CD200R antibody reached tumors, but had no significant impact on tumor growth and minor effect on infiltration of immune myeloid cells. These effects were reproduced using two different anti-CD200R clones. In contrast, we showed that CD200-deficiency did decrease melanoma tumor burden. The presence of either endogenous or tumor-expressed CD200 restored the growth of metastatic melanoma foci. On the basis of these findings, we conclude that blockade of the endogenous ligand CD200 prevented the tumorigenic effect of CD200R-expressing myeloid cells in the tumor microenvironment, whereas agonistic anti-CD200R has no effect on tumor development.
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Antitumor Activity of TLR7 Is Potentiated by CD200R Antibody Leading to Changes in the Tumor Microenvironment
Cancer immunology research, 2018Co-Authors: Zofia Pilch, Linde Meyaard, Louis Boon, Katarzyna Tonecka, Marcin Skorzynski, Zuzanna Sas, Agata Braniewska, Jakub Golab, Tomasz P. RygielAbstract:Stimulation of Toll-like receptor 7 (TLR7) activates myeloid cells and boosts the immune response. Previously, we have shown that stimulation of the inhibitory CD200 receptor (CD200R) suppresses TLR7 signaling and that the absence of CD200R signaling leads to a decreased number of papillomas in mice. Here, we investigated the effects of agonistic anti-CD200R on the antitumor activity of a TLR7 agonist (R848) in a syngeneic mouse tumor model. Intratumoral administration of R848 inhibited the growth of the CT26 colon carcinoma and simultaneously decreased CD200R expression in tumor-infiltrating immune cells. The antitumor effects of R848 were potentiated by anti-CD200R. Successfully treated mice were resistant to rechallenge with the same tumor cells. However, the immediate antitumor effects were independent of lymphocytes, because treatment efficacy was similar in wild-type and Rag1tm1Mom mice. Administration of R848, particularly in combination with anti-CD200R, changed the phenotype of intratumoral myeloid cells. The infiltration with immature MHC-II+ macrophages decreased and in parallel monocytes and immature MHC-II− macrophages increased. Combined treatment decreased the expression of the macrophage markers F4/80, CD206, CD86, CD115, and the ability to produce IL1β, suggesting a shift in the composition of intratumor myeloid cells. Adoptively transferred CD11b+ myeloid cells, isolated from the tumors of mice treated with R848 and anti-CD200R, inhibited tumor outgrowth in recipient mice. We conclude that administration of agonistic anti-CD200R improves the antitumor effects of TLR7 signaling and changes the local tumor microenvironment, which becomes less supportive of tumor progression. Cancer Immunol Res; 6(8); 930–40. ©2018 AACR.
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the CD200 CD200 receptor inhibitory axis controls arteriogenesis and local t lymphocyte influx
PLOS ONE, 2014Co-Authors: Pleunie Van Den Borne, Tomasz P. Rygiel, Ayla Hoogendoorn, Geertje H A Westerlaken, Louis Boon, Paul H A Quax, Gerard Pasterkamp, Imo E Hoefer, Linde MeyaardAbstract:The role of the CD200 ligand-CD200 receptor (CD200-CD200R) inhibitory axis is highly important in controlling myeloid cell function. Since the activation of myeloid cells is crucial in arteriogenesis, we hypothesized that disruption of the CD200-CD200R axis promotes arteriogenesis in a murine hindlimb ischemia model. Female CD200−/− and wildtype (C57Bl/6J) mice underwent unilateral femoral artery ligation. Perfusion recovery was monitored over 7 days using Laser-Doppler analysis and was increased in CD200−/− mice at day 3 and 7 after femoral artery ligation, compared to wildtype. Histology was performed on hindlimb muscles at baseline, day 3 and 7 to assess vessel geometry and number and inflammatory cell influx. Vessel geometry in non-ischemic muscles was larger, and vessel numbers in ischemic muscles were increased in CD200−/− mice compared to wildtype. Furthermore, T lymphocyte influx was increased in CD200−/− compared to wildtype. CD200R agonist treatment was performed in male C57Bl/6J mice to validate the role of the CD200-CD200R axis in arteriogenesis. CD200R agonist treatment after unilateral femoral artery ligation resulted in a significant decrease in vessel geometry, perfusion recovery and T lymphocyte influx at day 7 compared to isotype treatment. In this study, we show a causal role for the CD200-CD200R inhibitory axis in arteriogenesis in a murine hindlimb ischemia model. Lack of CD200R signaling is accompanied by increased T lymphocyte recruitment to the collateral vasculature and results in enlargement of preexisting collateral arteries.
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CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor
Oncogene, 2012Co-Authors: Tomasz P. Rygiel, Guruswamy Karnam, G Goverse, A P J Van Der Marel, M J Greuter, R A Van Schaarenburg, W F Visser, A B Brenkman, R Molenaar, R M HoekAbstract:Expression of CD200, the gene encoding the ligand for the inhibitory immune receptor CD200R, is an independent prognostic factor for various forms of leukemia predicting worse overall survival of the patients. The enhanced expression of CD200 on the tumors implies that anti-tumor responses can be enhanced by blockage of the CD200–CD200R interaction. Indeed, antibody-mediated blockade of the CD200-CD200R inhibitory axis is currently evaluated in clinical tests to boost immune responses against CD200-expressing tumors. Here, we show that mice lacking CD200, the exclusive ligand for CD200R, are resistant to chemical skin carcinogenesis. Importantly, CD200R controls tumor outgrowth independently of CD200 expression by the tumor cells themselves. Furthermore, CD200 ^−/− mice do not become tolerant to intranasally administered antigens, suggesting that tumor rejection is normally suppressed through CD200-induced immune tolerance. Decreased tumor outgrowth is accompanied by increased expression of the proinflammatory cytokines interleukin (IL)-1β and IL-6 by the lymph node (LN) dendritic cells. During carcinogenesis, skin-draining LNs of CD200 ^−/− mice contain increased numbers of IL-17-producing FoxP3^+ cells, which preferentially home to the tumors. Thus, the CD200-CD200R axis induces tolerance to external and tumor antigens and influences the T-regulatory/Th17 cell ratio. We demonstrate for the first time that the absence of CD200R signaling inhibits outgrowth of an endogenous tumor irrespective of CD200 expression by the tumor cells. This important paradigm shift leads to a much broader applicability of CD200-blockade in the treatment of tumors.
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CD200 Receptor Controls Sex-Specific TLR7 Responses to Viral Infection
PLOS Pathogens, 2012Co-Authors: Guruswamy Karnam, Tomasz P. Rygiel, Matthijs Raaben, Guy C. M. Grinwis, Frank E. J. Coenjaerts, Maaike E. Ressing, Peter J. M. Rottier, Cornelis A. M. De Haan, Linde MeyaardAbstract:Immunological checkpoints, such as the inhibitory CD200 receptor (CD200R), play a dual role in balancing the immune system during microbial infection. On the one hand these inhibitory signals prevent excessive immune mediated pathology but on the other hand they may impair clearance of the pathogen. We studied the influence of the inhibitory CD200-CD200R axis on clearance and pathology in two different virus infection models. We find that lack of CD200R signaling strongly enhances type I interferon (IFN) production and viral clearance and improves the outcome of mouse hepatitis corona virus (MHV) infection, particularly in female mice. MHV clearance is known to be dependent on Toll like receptor 7 (TLR7)-mediated type I IFN production and sex differences in TLR7 responses previously have been reported for humans. We therefore hypothesize that CD200R ligation suppresses TLR7 responses and that release of this inhibition enlarges sex differences in TLR7 signaling. This hypothesis is supported by our findings that in vivo administration of synthetic TLR7 ligand leads to enhanced type I IFN production, particularly in female CD200−/− mice and that CD200R ligation inhibits TLR7 signaling in vitro. In influenza A virus infection we show that viral clearance is determined by sex but not by CD200R signaling. However, absence of CD200R in influenza A virus infection results in enhanced lung neutrophil influx and pathology in females. Thus, CD200-CD200R and sex are host factors that together determine the outcome of viral infection. Our data predict a sex bias in both beneficial and pathological immune responses to virus infection upon therapeutic targeting of CD200-CD200R.
Linde Meyaard - One of the best experts on this subject based on the ideXlab platform.
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The pro-tumor effect of CD200 expression is not mimicked by agonistic CD200R antibodies.
PLOS ONE, 2019Co-Authors: Zofia Pilch, Linde Meyaard, Louis Boon, Katarzyna Tonecka, Marcin Skorzynski, Zuzanna Sas, Agata Braniewska, Tomasz Kryczka, Jakub Golab, Tomasz P. RygielAbstract:Tumor-infiltrating immune cells can impact tumor growth and progression. The inhibitory CD200 receptor (CD200R) suppresses the activation of myeloid cells and lack of this pathway results in a reduction of tumor growth, conversely a tumorigenic effect of CD200R triggering was also described. Here we investigated the role of CD200R activation in syngeneic mouse tumor models. We showed that agonistic CD200R antibody reached tumors, but had no significant impact on tumor growth and minor effect on infiltration of immune myeloid cells. These effects were reproduced using two different anti-CD200R clones. In contrast, we showed that CD200-deficiency did decrease melanoma tumor burden. The presence of either endogenous or tumor-expressed CD200 restored the growth of metastatic melanoma foci. On the basis of these findings, we conclude that blockade of the endogenous ligand CD200 prevented the tumorigenic effect of CD200R-expressing myeloid cells in the tumor microenvironment, whereas agonistic anti-CD200R has no effect on tumor development.
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Antitumor Activity of TLR7 Is Potentiated by CD200R Antibody Leading to Changes in the Tumor Microenvironment
Cancer immunology research, 2018Co-Authors: Zofia Pilch, Linde Meyaard, Louis Boon, Katarzyna Tonecka, Marcin Skorzynski, Zuzanna Sas, Agata Braniewska, Jakub Golab, Tomasz P. RygielAbstract:Stimulation of Toll-like receptor 7 (TLR7) activates myeloid cells and boosts the immune response. Previously, we have shown that stimulation of the inhibitory CD200 receptor (CD200R) suppresses TLR7 signaling and that the absence of CD200R signaling leads to a decreased number of papillomas in mice. Here, we investigated the effects of agonistic anti-CD200R on the antitumor activity of a TLR7 agonist (R848) in a syngeneic mouse tumor model. Intratumoral administration of R848 inhibited the growth of the CT26 colon carcinoma and simultaneously decreased CD200R expression in tumor-infiltrating immune cells. The antitumor effects of R848 were potentiated by anti-CD200R. Successfully treated mice were resistant to rechallenge with the same tumor cells. However, the immediate antitumor effects were independent of lymphocytes, because treatment efficacy was similar in wild-type and Rag1tm1Mom mice. Administration of R848, particularly in combination with anti-CD200R, changed the phenotype of intratumoral myeloid cells. The infiltration with immature MHC-II+ macrophages decreased and in parallel monocytes and immature MHC-II− macrophages increased. Combined treatment decreased the expression of the macrophage markers F4/80, CD206, CD86, CD115, and the ability to produce IL1β, suggesting a shift in the composition of intratumor myeloid cells. Adoptively transferred CD11b+ myeloid cells, isolated from the tumors of mice treated with R848 and anti-CD200R, inhibited tumor outgrowth in recipient mice. We conclude that administration of agonistic anti-CD200R improves the antitumor effects of TLR7 signaling and changes the local tumor microenvironment, which becomes less supportive of tumor progression. Cancer Immunol Res; 6(8); 930–40. ©2018 AACR.
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the CD200 CD200 receptor inhibitory axis controls arteriogenesis and local t lymphocyte influx
PLOS ONE, 2014Co-Authors: Pleunie Van Den Borne, Tomasz P. Rygiel, Ayla Hoogendoorn, Geertje H A Westerlaken, Louis Boon, Paul H A Quax, Gerard Pasterkamp, Imo E Hoefer, Linde MeyaardAbstract:The role of the CD200 ligand-CD200 receptor (CD200-CD200R) inhibitory axis is highly important in controlling myeloid cell function. Since the activation of myeloid cells is crucial in arteriogenesis, we hypothesized that disruption of the CD200-CD200R axis promotes arteriogenesis in a murine hindlimb ischemia model. Female CD200−/− and wildtype (C57Bl/6J) mice underwent unilateral femoral artery ligation. Perfusion recovery was monitored over 7 days using Laser-Doppler analysis and was increased in CD200−/− mice at day 3 and 7 after femoral artery ligation, compared to wildtype. Histology was performed on hindlimb muscles at baseline, day 3 and 7 to assess vessel geometry and number and inflammatory cell influx. Vessel geometry in non-ischemic muscles was larger, and vessel numbers in ischemic muscles were increased in CD200−/− mice compared to wildtype. Furthermore, T lymphocyte influx was increased in CD200−/− compared to wildtype. CD200R agonist treatment was performed in male C57Bl/6J mice to validate the role of the CD200-CD200R axis in arteriogenesis. CD200R agonist treatment after unilateral femoral artery ligation resulted in a significant decrease in vessel geometry, perfusion recovery and T lymphocyte influx at day 7 compared to isotype treatment. In this study, we show a causal role for the CD200-CD200R inhibitory axis in arteriogenesis in a murine hindlimb ischemia model. Lack of CD200R signaling is accompanied by increased T lymphocyte recruitment to the collateral vasculature and results in enlargement of preexisting collateral arteries.
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CD200 Receptor Controls Sex-Specific TLR7 Responses to Viral Infection
PLOS Pathogens, 2012Co-Authors: Guruswamy Karnam, Tomasz P. Rygiel, Matthijs Raaben, Guy C. M. Grinwis, Frank E. J. Coenjaerts, Maaike E. Ressing, Peter J. M. Rottier, Cornelis A. M. De Haan, Linde MeyaardAbstract:Immunological checkpoints, such as the inhibitory CD200 receptor (CD200R), play a dual role in balancing the immune system during microbial infection. On the one hand these inhibitory signals prevent excessive immune mediated pathology but on the other hand they may impair clearance of the pathogen. We studied the influence of the inhibitory CD200-CD200R axis on clearance and pathology in two different virus infection models. We find that lack of CD200R signaling strongly enhances type I interferon (IFN) production and viral clearance and improves the outcome of mouse hepatitis corona virus (MHV) infection, particularly in female mice. MHV clearance is known to be dependent on Toll like receptor 7 (TLR7)-mediated type I IFN production and sex differences in TLR7 responses previously have been reported for humans. We therefore hypothesize that CD200R ligation suppresses TLR7 responses and that release of this inhibition enlarges sex differences in TLR7 signaling. This hypothesis is supported by our findings that in vivo administration of synthetic TLR7 ligand leads to enhanced type I IFN production, particularly in female CD200−/− mice and that CD200R ligation inhibits TLR7 signaling in vitro. In influenza A virus infection we show that viral clearance is determined by sex but not by CD200R signaling. However, absence of CD200R in influenza A virus infection results in enhanced lung neutrophil influx and pathology in females. Thus, CD200-CD200R and sex are host factors that together determine the outcome of viral infection. Our data predict a sex bias in both beneficial and pathological immune responses to virus infection upon therapeutic targeting of CD200-CD200R.
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CD200R signaling in tumor tolerance and inflammation: A tricky balance.
Current Opinion in Immunology, 2012Co-Authors: Tomasz P. Rygiel, Linde MeyaardAbstract:The inhibitory CD200-CD200 receptor (CD200R) interaction is essential to prevent massive inflammatory responses and immune pathology during microbial infection. Since CD200 expression on human malignancies is associated with tumor progression, CD200 blocking antibodies are currently tested in clinical trials to boost anti-tumor responses. Here we discuss that CD200-mediated suppression of anti-tumor responses may not only be mediated by the tumor itself, but also by CD200 expressed on healthy tissue. However, in cancers that benefit from inflammation, the blockade of CD200 could result in enhanced tumor growth. We conclude that CD200 blockade forms a potential therapeutic option to strengthen anti-tumor responses which is not restricted to treatment of CD200 expressing tumors.
A. Neil Barclay - One of the best experts on this subject based on the ideXlab platform.
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Dissection of Agonistic and Blocking Effects of CD200 Receptor Antibodies
PLOS ONE, 2013Co-Authors: Munir Akkaya, Marie-laure Aknin, Billur Akkaya, A. Neil BarclayAbstract:The CD200 receptor (CD200R) is present mainly on myeloid cells and gives inhibitory signals when engaged by its ligand CD200. The interaction is currently of therapeutic interest in cancer and inflammation. However functional effects are complicated by the fact that CD200R is itself polymorphic and also a member of a paired receptor family with four closely related gene products in mice called CD200RLa etc. We show that a second allele of CD200R (termed CD200R(2)) that differs in 7 amino acids also binds CD200 but did not react with the widely used CD200R antibody OX110. Biochemical and functional analysis showed that the CD200/CD200R interaction was blocked by the OX131, mAb that recognises both CD200R(1) and CD200R(2), but not by OX110 mAb. Both mAb can give agonistic inhibitory signals but functional analysis shows OX131 mAb also has the potential to block inhibition by preventing the ligand-receptor interaction and hence gives opposing effects. Although OX131 mAb cross-reacts with the activating receptor CD200RLe, it is specific for CD200R in C57BL/6 whilst OX110 mAb cross-reacts on CD200RLc. The results show the importance of the repertoire of paired receptors in strains or individuals and mAb used with implications for paired receptor analysis and therapeutics.
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Structures of CD200/CD200 Receptor Family and Implications for Topology, Regulation, and Evolution
Structure, 2013Co-Authors: Deborah Hatherley, Susan M. Lea, Steven Johnson, A. Neil BarclayAbstract:CD200 is a widely distributed membrane glycoprotein that regulates myeloid cell activity through its interaction with an inhibitory receptor (CD200R). The interaction is of interest as a target for treating excessive inflammation and for treating leukemia. There are closely related proteins to CD200R that give activating signals making this a “paired receptor.” We report X-ray crystallography structures for the inhibitory CD200R, the activating receptor CD200RLa, and a complex between CD200R and CD200. Both CD200 and CD200R contain two Ig-like domains and interact through their NH2 terminal domains compatible with immunological synapse-like interactions occurring between myeloid cells and other CD200-expressing cells. The failure of the activating receptor to bind CD200 resides in subtle changes around the interface. CD200 has been acquired by herpes viruses to mimic the host interaction. CD200R has evolved rapidly presumably driven by pathogen pressure but it may also be important in homeostasis through interactions with commensal bacteria.
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Essential Roles for Dok2 and RasGAP in CD200 Receptor-Mediated Regulation of Human Myeloid Cells
Journal of Immunology, 2009Co-Authors: Robin Mihrshahi, A. Neil Barclay, Marion H. BrownAbstract:The CD200 receptor (CD200R) acts as a negative regulator of myeloid cells by interacting with its widely expressed ligand CD200. Using mutants expressed in U937 cells, we show that inhibition is mediated by the PTB domain binding motif (NPLY) in the receptor’s cytoplasmic region. The adaptor protein downstream of tyrosine kinase 2 (Dok2) bound directly to the phosphorylated NPLY motif with a 10-fold higher affinity (KD of ∼1 μM at 37°C) than the closely related Dok1. Both of these proteins have been suggested to play a role in CD200R signaling in murine cells. Dok2 was phosphorylated in response to CD200R engagement and recruited RAS p21 protein activator 1 (RasGAP). Knockdown of Dok2 and RasGAP by RNA interference revealed that these proteins are required for CD200R signaling, while knockdown of Dok1 and the inositol 5-phosphatase SHIP did not affect CD200R-mediated inhibition. We conclude that CD200R inhibits the activation of human myeloid cells through direct recruitment of Dok2 and subsequent activation of RasGAP, which distinguishes this receptor from the majority of inhibitory receptors that utilize ITIMs and recruit phosphatases.
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A critical function for CD200 in lung immune homeostasis and the severity of influenza infection.
Nature Immunology, 2008Co-Authors: Robert J. Snelgrove, Jonathon D Sedgwick, A. Neil Barclay, John Goulding, Arnaud Didierlaurent, Daphne Lyonga, Seema Vekaria, Lorna Edwards, Emily Gwyer, Tracy HussellAbstract:The lung must maintain a high threshold of immune 'ignorance' to innocuous antigens to avoid inflammatory disease that depends on the balance of positive inflammatory signals and repressor pathways. We demonstrate here that airway macrophages had higher expression of the negative regulator CD200 receptor (CD200R) than did their systemic counterparts. Lung macrophages were restrained by CD200 expressed on airway epithelium. Mice lacking CD200 had more macrophage activity and enhanced sensitivity to influenza infection, which led to delayed resolution of inflammation and, ultimately, death. The administration of agonists that bind CD200R, however, prevented inflammatory lung disease. Thus, CD200R is critical for lung macrophage immune homeostasis in the resting state and limits inflammatory amplitude and duration during pulmonary influenza infection.
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Recombinant CD200 Protein Does Not Bind Activating Proteins Closely Related to CD200 Receptor
Journal of Immunology, 2005Co-Authors: Deborah Hatherley, Holly Cherwinski, Mehrdad Moshref, A. Neil BarclayAbstract:CD200 (OX2) is a cell surface glycoprotein that interacts with a structurally related receptor (CD200R) expressed mainly on myeloid cells and is involved in regulation of macrophage and mast cell function. In mouse there are up to five genes related to CD200R with conflicting data as to whether they bind CD200. We show that mouse CD200 binds the inhibitory receptor CD200R with a comparable affinity (Kd = 4 microM) to those found for the rat and human CD200 CD200R interactions. CD200 gave negligible binding to the activating receptors, CD200RLa, CD200RLb, and CD200RLc, by direct analysis at the protein level using recombinant monomeric and dimeric fusion proteins or to CD200RLa and CD200RLb when expressed at the cell surface. An additional potential activating gene, CD200RLe, found in only some mouse strains also did not bind CD200. Thus, the CD200 receptor family consists of both activatory and inhibitory members like several other paired ligand receptors, such as signal regulatory protein, killer cell Ig-like receptor/KAR, LY49, dendritic cell immunoreceptor/dendritic cell immunoactivating receptor, and paired Ig-like type 2 receptor. Although the ligand for the inhibitory product is a widely distributed host protein, the ligands of the activating forms remain to be identified, and one possibility is that they are pathogen components.
Carmen Farid - One of the best experts on this subject based on the ideXlab platform.
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CD200/CD200 receptor axis in psoriasis vulgaris.
PLOS ONE, 2020Co-Authors: Aisha A. Ismail, Hanaa M. Donia, Hafsa M. Ghatesh, Carmen FaridAbstract:Background Psoriasis is a chronic inflammatory multisystem disease with imbalance between the Th17 and T regulatory sub-populations. CD200/CD200R is an anti-inflammatory/immune-suppressive axis that might contribute to its pathogenesis given its relation to the Tregs induction. The current study aimed to investigate the status of the CD200/CD200R axis in the blood of psoriasis vulgaris patients versus healthy controls. Methods In this comparative cross sectional study, the blood levels of sCD200 and CD200R levels were measured in 25 psoriasis vulgaris patients and an age and sex matched 25 healthy controls using ELISA and flow-cytometry respectively. Their levels were tested for correlation to disease severity. Results sCD200 was significantly higher while CD200R was significantly lower in psoriasis vulgaris patients than in controls. They did not correlate to each other or to psoriasis severity although they differed significantly among cases of different severities. Conclusion Aberrant expression of CD200/CD200R might play a role in psoriasis vulgaris pathophysiology and disease severity. It might constitute a future target of therapy, but cannot be used as a marker of disease severity.
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CD200 CD200 receptor axis in psoriasis vulgaris
PLOS ONE, 2020Co-Authors: Aisha A. Ismail, Hanaa M. Donia, Hafsa M. Ghatesh, Carmen FaridAbstract:Background Psoriasis is a chronic inflammatory multisystem disease with imbalance between the Th17 and T regulatory sub-populations. CD200/CD200R is an anti-inflammatory/immune-suppressive axis that might contribute to its pathogenesis given its relation to the Tregs induction. The current study aimed to investigate the status of the CD200/CD200R axis in the blood of psoriasis vulgaris patients versus healthy controls. Methods In this comparative cross sectional study, the blood levels of sCD200 and CD200R levels were measured in 25 psoriasis vulgaris patients and an age and sex matched 25 healthy controls using ELISA and flow-cytometry respectively. Their levels were tested for correlation to disease severity. Results sCD200 was significantly higher while CD200R was significantly lower in psoriasis vulgaris patients than in controls. They did not correlate to each other or to psoriasis severity although they differed significantly among cases of different severities. Conclusion Aberrant expression of CD200/CD200R might play a role in psoriasis vulgaris pathophysiology and disease severity. It might constitute a future target of therapy, but cannot be used as a marker of disease severity.
Neil A Barclay - One of the best experts on this subject based on the ideXlab platform.
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rabbit CD200r binds host CD200 but not CD200 like proteins from poxviruses
Virology, 2016Co-Authors: Munir Akkaya, D Hatherley, Laishan Kwong, Erdem Akkaya, Neil A BarclayAbstract:CD200 is a widely distributed membrane protein that gives inhibitory signals through its receptor (CD200R) on myeloid cells. CD200 has been acquired by herpesviruses where it has been shown to interact with host CD200R and downmodulate the immune system. It has been hypothesized that poxviruses have acquired CD200; but the potential orthologues show less similarity to their hosts. Myxoma virus M141 protein is a potential CD200 orthologue with a potent immune modulatory function in rabbits. Here, we characterized the rabbit CD200, CD200R and tested the CD200-like sequences for binding CD200R. No binding could be detected using soluble recombinant proteins, full length protein expressed on cells or myxoma virus infected cells. Finally, using knockdown models, we showed that the inhibitory effect of M141 on RAW 264.7 cells upon myxoma virus infection is not due to CD200R. We conclude that the rabbit poxvirus CD200-like proteins cause immunomodulation without utilizing CD200R.
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structures of CD200 CD200 receptor family and implications for topology regulation and evolution
Structure, 2013Co-Authors: Deborah Hatherley, Susan M. Lea, Steven Johnson, Neil A BarclayAbstract:CD200 is a widely distributed membrane glycoprotein that regulates myeloid cell activity through its interaction with an inhibitory receptor (CD200R). The interaction is of interest as a target for treating excessive inflammation and for treating leukemia. There are closely related proteins to CD200R that give activating signals making this a “paired receptor.” We report X-ray crystallography structures for the inhibitory CD200R, the activating receptor CD200RLa, and a complex between CD200R and CD200. Both CD200 and CD200R contain two Ig-like domains and interact through their NH2 terminal domains compatible with immunological synapse-like interactions occurring between myeloid cells and other CD200-expressing cells. The failure of the activating receptor to bind CD200 resides in subtle changes around the interface. CD200 has been acquired by herpes viruses to mimic the host interaction. CD200R has evolved rapidly presumably driven by pathogen pressure but it may also be important in homeostasis through interactions with commensal bacteria.
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immune inhibitory ligand CD200 induction by tlrs and nlrs limits macrophage activation to protect the host from meningococcal septicemia
Cell Host & Microbe, 2010Co-Authors: Subhankar Mukhopadhyay, Marie-laure Aknin, Audrey Varin, Annette Pluddemann, Claire J Hoe, Kevin J Williams, Katherine Makepeace, Dawn M E Bowdish, Stephen T Smale, Neil A BarclayAbstract:Macrophage activation is essential for protection against bacterial pathogens but needs to be regulated to prevent damage to the host. We show a key role for the immune inhibitory receptor CD200R and its ligand CD200 in the context of infection with the Gram-negative human pathogen Neisseria meningitidis. N. meningitidis induced CD200 but downregulated CD200R on macrophages in a manner dependent on Neisserial lipopolysaccharide, Toll-like receptor-4 (TLR-4), and the MyD88 pathway but independent of a known Neisserial receptor, scavenger receptor A (SR-A). Agonists of the pattern-recognition receptors nucleotide oligomerization domain 2 (NOD2) and NACHT-LRR protein 3 (NALP3) also induced CD200. The NF-κB member c-Rel was essential for TLR-, NOD2-, and NALP3-mediated induction of CD200. CD200(-/-) animals showed higher lethality in response to experimental meningococcal septicemia, induced higher levels of proinflammatory cytokines, and recruited increased numbers of activated leukocytes, despite comparable bacterial clearance. Thus CD200 is induced by TLR-, NOD2-, and NALP3-mediated pathways, limiting their function and protecting the host from excessive inflammation.
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essential roles for dok2 and rasgap in CD200 receptor mediated regulation of human myeloid cells
Journal of Immunology, 2009Co-Authors: Robin Mihrshahi, Neil A Barclay, Marion H. BrownAbstract:The CD200 receptor (CD200R) acts as a negative regulator of myeloid cells by interacting with its widely expressed ligand CD200. Using mutants expressed in U937 cells, we show that inhibition is mediated by the PTB domain binding motif (NPLY) in the receptor's cytoplasmic region. The adaptor protein downstream of tyrosine kinase 2 (Dok2) bound directly to the phosphorylated NPLY motif with a 10-fold higher affinity (K(D) of approximately 1 microM at 37 degrees C) than the closely related Dok1. Both of these proteins have been suggested to play a role in CD200R signaling in murine cells. Dok2 was phosphorylated in response to CD200R engagement and recruited RAS p21 protein activator 1 (RasGAP). Knockdown of Dok2 and RasGAP by RNA interference revealed that these proteins are required for CD200R signaling, while knockdown of Dok1 and the inositol 5-phosphatase SHIP did not affect CD200R-mediated inhibition. We conclude that CD200R inhibits the activation of human myeloid cells through direct recruitment of Dok2 and subsequent activation of RasGAP, which distinguishes this receptor from the majority of inhibitory receptors that utilize ITIMs and recruit phosphatases.
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the CD200 and CD200 receptor cell surface proteins interact through their n terminal immunoglobulin like domains
European Journal of Immunology, 2004Co-Authors: D Hatherley, Neil A BarclayAbstract:CD200 (OX2) is a broadly distributed cell surface glycoprotein that interacts with a receptor on myeloid cells (CD200R) involved in regulation of macrophage function. Both CD200 and CD200R contain two Ig superfamily domains like many other leukocyte membrane proteins. Site-directed mutagenesis of CD200R showed that, like CD200, it interacted through its N-terminal domain. This indicated that the cell-cell interaction spans four Ig superfamily domains and this distance is similar to many interactions found between T cells and antigen-presenting cells. This suggests that this topology is also important in interactions of CD200 on a variety of cells with CD200R on myeloid cells, and comparable contact sites may be important mediating regulation in other cell-cell interactions. The mutagenesis showed that the binding involved the predicted GFCC′ face of its N-terminal domain, like that of CD200, suggesting that the interaction evolved from a homotypic interaction.