{"gene":"CD200R1","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2000,"finding":"CD200R (OX2R) is a novel cell-surface receptor restricted to myeloid lineage cells that binds CD200 (OX2) with a dissociation constant of ~2.5 μM and koff 0.8 s⁻¹; pervanadate treatment showed CD200R can be tyrosine-phosphorylated; antibody blockade of OX2-OX2R interaction exacerbated experimental allergic encephalomyelitis, indicating an inhibitory function in myeloid cell regulation.","method":"Surface plasmon resonance (binding kinetics), pervanadate phosphorylation assay, antibody blockade in EAE model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding measurement with kinetics, tyrosine phosphorylation assay, and in vivo functional validation; foundational paper","pmids":["10981966"],"is_preprint":false},{"year":2003,"finding":"Human CD200R (hCD200R) was characterized and shown to bind hCD200; a closely related gene hCD200RLa was identified. Mouse CD200R-related genes (mCD200RLa–d) were identified; mCD200RLa and mCD200RLb pair with the activatory adaptor DAP12 and do not bind CD200, distinguishing them functionally from the inhibitory CD200R. CD200R is most strongly expressed on macrophages and neutrophils but also on monocytes, mast cells, and T lymphocytes.","method":"Quantitative RT-PCR, novel monoclonal antibodies, DAP12 co-precipitation, flow cytometry","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding and co-precipitation with DAP12, replicated across human and mouse; comprehensive receptor family characterization","pmids":["12960329"],"is_preprint":false},{"year":2004,"finding":"Human herpesvirus 8 K14 protein binds human CD200R with an affinity nearly identical to CD200 (KD ≈ 0.5 μM) and, when expressed on cell surfaces, inhibits TNF-α secretion by activated macrophages—an effect relieved by anti-CD200R mAb or soluble CD200. This demonstrates that CD200R-mediated macrophage suppression occurs via direct cell–cell contact and is mimicked by a viral CD200 homologue.","method":"Surface plasmon resonance, cell-surface expression assay, TNF-α secretion assay with blocking antibodies","journal":"Journal of Virology","confidence":"High","confidence_rationale":"Tier 1–2 — quantitative binding kinetics combined with functional cytokine inhibition and specificity controls","pmids":["15220441"],"is_preprint":false},{"year":2005,"finding":"CD200R is expressed on mouse and human mast cells; engagement by agonist antibodies or CD200 ligand potently inhibits mast cell degranulation and cytokine secretion in vitro and in vivo without requiring coligation to FcεRI. CD200R does not contain an ITIM, establishing it as a novel inhibitory receptor class on mast cells.","method":"Flow cytometry, in vitro degranulation and cytokine secretion assays, in vivo mast cell activation model","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays in vitro and in vivo, replicated across species","pmids":["15661892"],"is_preprint":false},{"year":2005,"finding":"Site-directed mutagenesis of the three cytoplasmic tyrosines of CD200R (Y286, Y289, Y297) in mouse mast cells showed Y286 and Y297 are the major phosphorylation sites critical for CD200R-mediated inhibition of mast cell activation; Y289 is dispensable. Y297 resides in an NPxY motif. Src family kinases mediate CD200R and Dok phosphorylation.","method":"Site-directed mutagenesis, tyrosine phosphorylation assays, mast cell activation assays","journal":"Journal of Leukocyte Biology","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis of all three cytoplasmic tyrosines with direct functional readout","pmids":["16330532"],"is_preprint":false},{"year":2009,"finding":"In human myeloid (U937) cells, CD200R inhibitory signaling is mediated through the NPLY (NPxY) motif in its cytoplasmic tail. The adaptor Dok2 binds directly to the phosphorylated NPLY motif with ~10-fold higher affinity (KD ~1 μM at 37°C) than Dok1. Dok2 is phosphorylated upon CD200R engagement and recruits RasGAP. RNAi knockdown of Dok2 and RasGAP abolished CD200R-mediated inhibition, while knockdown of Dok1 and SHIP did not, establishing a Dok2→RasGAP pathway as the primary human CD200R signaling mechanism.","method":"Cytoplasmic tail mutants, direct binding affinity measurement, RNAi knockdown, co-immunoprecipitation","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding kinetics, multiple RNAi knockdowns, and mutagenesis in human cells; comprehensive mechanistic dissection","pmids":["19786546"],"is_preprint":false},{"year":2010,"finding":"CD200R-induced phosphorylation of Dok2 precedes Dok1 phosphorylation. Dok2 recruits RasGAP and the adaptor Nck; Dok1 recruits CrkL (and constitutively binds Crk). Knockdown of Dok1 or CrkL increases Dok2 phosphorylation and RasGAP recruitment, indicating that Dok1 negatively regulates Dok2-mediated CD200R inhibitory signaling via CrkL.","method":"RNAi knockdown, co-immunoprecipitation, phosphorylation time-course assays","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple RNAi conditions with co-IP and phosphorylation readouts establishing opposing roles for Dok1 and Dok2","pmids":["21078907"],"is_preprint":false},{"year":2007,"finding":"CD200 (not normally expressed in myeloid lineage) is strongly upregulated in macrophages at the onset of fusion; CD200R is expressed on osteoclasts and CD4+ T cells. In CD200-knockout mice, osteoclast differentiation is reduced and NF-κB and MAPK signaling downstream of RANK is depressed. A soluble CD200 extracellular domain protein rescued fusion and RANK signaling in CD200-/- macrophages; soluble CD200R extracellular domain or shRNA silencing of CD200R prevented fusion. CD200-/- mice have fewer osteoclasts and accumulate more bone.","method":"CD200-/- mouse model, shRNA silencing, recombinant protein rescue, NF-κB/MAPK signaling assays, bone histology","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1–2 — genetic knockout, shRNA, and recombinant protein rescue with multiple signaling and phenotypic readouts","pmids":["17726108"],"is_preprint":false},{"year":2007,"finding":"Mice lacking CD200R1 (CD200R1-/- generated by deletion of exons encoding extracellular domain) showed loss of FACS staining with anti-CD200R1 mAb on myeloid cells/splenocytes, enhanced LPS-stimulated splenic TNF-α production that was not suppressible by CD200Fc, loss of CD200Fc-mediated modulation of alloreactivity dependent on CD200R1+ stimulatory and T responder cells, and failure of CD200Fc to suppress graft rejection. This defines CD200R1 as the essential receptor mediating CD200-induced immunosuppression in vivo.","method":"CD200R1-/- mouse generation (ES cell targeting), FACS, LPS-TNF assay, mixed leukocyte culture, skin graft rejection model","journal":"Transplantation","confidence":"High","confidence_rationale":"Tier 2 — clean knockout mouse with multiple in vitro and in vivo functional readouts","pmids":["17667818"],"is_preprint":false},{"year":2012,"finding":"CD200R1-/- macrophages showed 70–75% reduction in IL-6 and CCL5 production in response to TLR2 agonist Pam2CSK4 and to HSV-1. CD200R1-/- macrophages could not upregulate TLR2 expression or assemble a functional inflammasome in response to HSV-1. CD200R1-/- mice were protected from HSV-1 infection and showed dysfunctional TLR2 signaling and markedly reduced ability to support HSV-1 replication. This reveals an unanticipated requirement for CD200R1 in 'licensing' pro-inflammatory TLR2 functions.","method":"CD200R1-/- mouse model, cytokine assays, TLR2 expression analysis, inflammasome assembly assay, viral replication assay","journal":"PLoS One","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with multiple orthogonal ex vivo and in vivo readouts; unexpected bidirectional role discovered","pmids":["23082204"],"is_preprint":false},{"year":2012,"finding":"LPS treatment of microglial cells decreases CD200R1 mRNA and protein expression in a C/EBPβ-dependent manner: C/EBPβ binds the CD200R1 promoter in LPS-treated (but not control) glial cells, and C/EBPβ overexpression alone reduces basal CD200R1 expression. HDAC1 co-immunoprecipitates with C/EBPβ and binds the C/EBPβ consensus sequence in the CD200R1 promoter in LPS-treated cells; HDAC1 inhibitors reverse LPS-induced CD200R1 downregulation. This defines a C/EBPβ/HDAC1 transcriptional repression axis for CD200R1.","method":"Primary microglial cultures from wild-type and C/EBPβ-KO mice, BV2 overexpression, quantitative ChIP, co-immunoprecipitation, HDAC inhibitor treatment","journal":"Journal of Neuroinflammation","confidence":"High","confidence_rationale":"Tier 1–2 — qChIP for promoter occupancy, co-IP, KO and overexpression with multiple orthogonal methods","pmids":["22776069"],"is_preprint":false},{"year":2014,"finding":"PPAR-γ agonist 15d-PGJ2 inhibits the pro-inflammatory response in reactive glial cells and prevents LPS/IFN-γ-induced downregulation of CD200R1 and upregulation of CD200. In neuron-microglia co-cultures, 15d-PGJ2 abrogates reactive-microglia-induced neurotoxicity through a CD200-CD200R1-dependent mechanism, placing PPAR-γ upstream of CD200R1 expression regulation.","method":"Primary neuronal and glial cultures, neuron-microglia co-cultures, LPS/IFN-γ stimulation, PPAR-γ agonist treatment, Western blot/qPCR, functional neurotoxicity assay","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 — co-culture functional assay with pharmacological intervention; CD200R1 dependency inferred but not rescued by CD200R1 re-expression","pmids":["24639050"],"is_preprint":false},{"year":2017,"finding":"Exposure to acute stressor reduces CD200R1 expression across hippocampal sub-regions, amygdala, and isolated microglia. The transcriptional suppressor C/EBPβ is induced by stress and inversely correlated with CD200R1 expression. Intracisterna magna administration of soluble CD200 (mCD200Fc) prior to stress blocked stress-induced microglial priming and hippocampal HMGB1 increase; soluble CD200R1Fc recapitulated microglial priming. Glucocorticoids (GCs) mediate stress-induced CD200R1 reduction, as shown by GC receptor blockade (RU486) and adrenalectomy experiments.","method":"In vivo stressor exposure, microglia isolation and ex vivo cytokine assay, pharmacological blockade (RU486), adrenalectomy with CORT replacement, intracisterna magna injection","journal":"Brain, Behavior, and Immunity","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pharmacological and surgical interventions in vivo with defined molecular endpoints; single lab","pmids":["29104062","31078691"],"is_preprint":false},{"year":2014,"finding":"DNA aptamers that bind murine CD200R1 act as agonists in the absence of exogenous CD200, inducing rapid phosphorylation of the CD200R1 cytoplasmic tail and suppressing CTL induction in allogeneic mixed leukocyte cultures. PEGylated aptamers show in vivo immunosuppression and enhance allogeneic skin graft survival comparably to CD200Fc. Suppression is absent in CD200R1-/- responder cells, confirming direct CD200R1 engagement as the mechanism.","method":"SELEX aptamer selection, cytoplasmic tail phosphorylation assay, allogeneic MLC suppression, CD200R1-/- control, in vivo skin graft model","journal":"Molecular Therapy. Nucleic Acids","confidence":"Medium","confidence_rationale":"Tier 2 — phosphorylation assay plus knockout control confirms on-target mechanism; single lab","pmids":["25158092"],"is_preprint":false},{"year":2021,"finding":"In the presence of cleaved p120-RasGAP (generated during mild cellular stress or IFN-α treatment), CD200R loses its capacity to inhibit rpS6 phosphorylation (mTORC1 activity). Furthermore, upon IFN-α pretreatment of human PBMCs, CD200R switches from inhibiting to potentiating TLR7/8-induced IFN-γ gene expression. SLE patients with elevated cleaved p120-RasGAP show similar CD200R signaling reversal. This demonstrates that type I IFN rewires CD200R from inhibitory to pro-inflammatory by altering the availability of the downstream effector p120-RasGAP.","method":"Human PBMC stimulation assays, p120-RasGAP cleavage analysis, rpS6 phosphorylation (mTORC1 readout), IFN-γ mRNA measurement, SLE patient samples","journal":"Science Signaling","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays (signaling pathway, cytokine gene expression, patient validation), mechanistic explanation via RasGAP cleavage","pmids":["34637328"],"is_preprint":false},{"year":2018,"finding":"N-glycosylation of CD200R1 at asparagine 44 (Asn44/N44) is required for CD200-CD200R1 interaction; mutation of N44 disrupts CD200 binding and upregulates pro-inflammatory markers iNOS, CD86, IL-1β, and TNF-α in a neuronal-microglia co-culture system.","method":"Site-directed mutagenesis of glycosylation site, neuronal-microglia co-culture, cytokine/marker expression assays","journal":"Journal of Inflammation","confidence":"Medium","confidence_rationale":"Tier 1 — mutagenesis of specific glycosylation site with functional readout; single lab, single method","pmids":["30574022"],"is_preprint":false},{"year":2021,"finding":"miR-129-5p is a posttranscriptional repressor of CD200R1: arsenic exposure demethylates the miR-129-5p promoter, increasing its expression, which represses CD200R1 by binding its 3'-UTR and shuttling CD200R1 mRNA to cytoplasmic processing bodies in microglia. Anti-miR-129 injection in mice restores CD200R1 expression and reduces IL-6 and TNF-α. CD200R1 siRNA loss-of-function confirmed an miR-129-5p → CD200R1 → IL-6/TNF-α axis. Findings were replicated in a human cell line and validated in human samples.","method":"In silico miRNA target prediction, primary neonatal microglia and BV2 assays, methylation analysis, stereotaxic anti-miR injection in mice, CD200R1 siRNA, human cell line validation","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (methylation, RNA localization, anti-miR in vivo, siRNA loss-of-function, human validation) across mouse and human","pmids":["34952004"],"is_preprint":false},{"year":2017,"finding":"CD200R engagement activates STAT6 phosphorylation as a downstream effector; STAT6 activation modulates Foxp3 transcription in microglia. CD200R suppression prevents anti-inflammatory microglial phenotype, while Foxp3 overexpression enhances it. CD200R/Foxp3-mediated signaling enhances hippocampal neuronal viability and confers neuroprotection by counteracting iNOS.","method":"Excitotoxicity hippocampal neuroinflammation model, CD200R suppression, Foxp3 overexpression, STAT6 phosphorylation assay","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 — STAT6 phosphorylation assay with genetic loss/gain of function; single lab","pmids":["27731341"],"is_preprint":false},{"year":2017,"finding":"Anti-inflammatory stimulation of CD200R1 after germinal matrix hemorrhage (GMH) in rat pups activates Dok1 downstream: CD200Fc increases Dok1 expression and decreases IL-1β and TNF-α, whereas CD200R1 siRNA or Dok1 siRNA abolishes these effects. This places Dok1 as a downstream mediator of CD200R1 anti-inflammatory signaling in the neonatal brain.","method":"Neonatal rat GMH model, intracerebroventricular CD200Fc, siRNA knockdown of CD200R1 and Dok1, Western blot for Dok1/cytokines, neurobehavioral assessment","journal":"Journal of Cerebral Blood Flow and Metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA loss-of-function for both receptor and downstream effector with cytokine readouts; single lab","pmids":["28792282"],"is_preprint":false},{"year":2021,"finding":"CD200R expressed on ILC2s inhibits their activation, proliferation, and type 2 cytokine production upon engagement; mechanistically, CD200R engagement inhibits both canonical and non-canonical NF-κB signaling pathways in activated ILC2s. CD200R is also expressed on human ILC2s, and its engagement in humanized mouse models ameliorates airway hyperreactivity.","method":"Mouse and human ILC2 flow cytometry, CD200R engagement assays, NF-κB signaling pathway analysis, in vivo AHR models (preventative and therapeutic)","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — defined signaling pathway (NF-κB) with in vitro and in vivo validation across mouse and human","pmids":["33953190"],"is_preprint":false},{"year":2023,"finding":"A humanized anti-CD200R1 antibody (23ME-00610) blocks CD200 binding to CD200R1 and inhibits recruitment of the downstream adaptor protein DOK2, inducing T-cell cytokine production and enhancing T cell-mediated tumor cell killing in vitro; it inhibits tumor growth in an S91 melanoma model in vivo. Genome-wide association data identified CD200, CD200R1, and DOK2 as a linked immune checkpoint pathway.","method":"High-affinity antibody binding assay (KD <0.1 nM), DOK2 recruitment inhibition assay, T cell cytokine/killing assays, syngeneic tumor model","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 — DOK2 recruitment assay and T cell functional assays confirm mechanism; in vivo validation in single tumor model","pmids":["37288324"],"is_preprint":false},{"year":2015,"finding":"CD200Fc (CD200R1 agonist) in human renal proximal tubular epithelial cells inhibits LPS-induced TLR4 expression and its adapter interactions (MyD88 and phospho-TAK1), abolishes TLR4-MyD88 and TLR4-TAK1 co-immunoprecipitation, and attenuates downstream IκB phosphorylation, NF-κB-p65 nuclear translocation, and ERK1/2/p38/JNK phosphorylation, as well as pro-inflammatory mediator release.","method":"Co-immunoprecipitation, NF-κB nuclear translocation assay, Western blot for phosphorylated signaling intermediates, ELISA for cytokines","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple signaling pathway readouts and co-IP; single lab, non-myeloid cell type","pmids":["25791482"],"is_preprint":false},{"year":2016,"finding":"Novel CD200 homologues iSEC1 and iSEC2, expressed exclusively by secretory cells of the gastrointestinal epithelium, bind CD200R but not other CD200R family members. Binding of iSEC1 to CD200R on intraepithelial lymphocytes suppresses their cytokine production and cytolytic activity, identifying iSEC1 as a previously unrecognized CD200R ligand in gastrointestinal mucosal immunity.","method":"Binding assays across CD200R family members, IEL cytokine and cytolytic activity assays","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 — ligand-receptor binding specificity across receptor family and functional IEL suppression assays","pmids":["27819346"],"is_preprint":false},{"year":2019,"finding":"CD200R-deficient neutrophils display significantly reduced reactive oxygen species (ROS) production; in vivo, CD200R deficiency increases bacterial burden in neutrophils and enhances colonization by Francisella tularensis. Depletion of the neutrophil niche in CD200R-/- mice restores bacterial burden to wild-type levels. This establishes that CD200R promotes antimicrobial ROS production in neutrophils to limit intracellular bacterial proliferation.","method":"CD200R-/- mouse model, ROS production assay, in vitro and in vivo infection assays, neutrophil depletion","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with mechanistic ROS assay and rescue by neutrophil depletion in vivo","pmids":["31073183"],"is_preprint":false},{"year":2021,"finding":"CD200R1 knockout in CAR T cells is detrimental to their metabolic fitness and activity, while a CD200R-CD28 switch receptor (replacing CD200R cytoplasmic tail with CD28 signaling domain) potently enhances CAR T-cell polyfunctionality, cytotoxicity, proliferation, and metabolic fitness in response to CD200+ multiple myeloma cells in vitro and in xenograft models. CD200R dominant-negative provided modest benefit. This demonstrates that the CD200R cytoplasmic signaling domain determines functional outcome and can be rewired to deliver costimulation.","method":"CRISPR-Cas9 knockout, switch receptor engineering, in vitro co-culture killing assays, metabolic assays, murine xenograft models of plasmacytoma and disseminated disease","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — genetic knockout vs. engineered switch receptor comparison with multiple orthogonal assays and in vivo validation","pmids":["37616575"],"is_preprint":false}],"current_model":"CD200R1 is a cell-surface inhibitory receptor on myeloid and lymphoid cells that, upon binding CD200 (or viral CD200 homologues) via its two Ig-like extracellular domains (interaction requiring N-glycosylation at Asn44), undergoes Src-family-kinase-mediated tyrosine phosphorylation at Y286 and Y297 in its cytoplasmic NPxY and juxtamembrane motifs, directly recruiting the adaptor Dok2 (with ~10-fold higher affinity than Dok1), which then recruits RasGAP to suppress Ras/MAPK activation and NF-κB signaling, thereby inhibiting myeloid cell activation, mast cell degranulation, ILC2 type-2 cytokine production, and microglial priming; Dok1/CrkL negatively modulates this pathway, while type I IFN-induced cleavage of p120-RasGAP can switch CD200R1 from inhibitory to pro-inflammatory, and CD200R1 expression is transcriptionally repressed by C/EBPβ/HDAC1 and post-transcriptionally by miR-129-5p under inflammatory conditions."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of CD200R as the myeloid-restricted receptor for CD200 resolved how CD200 delivers its immunosuppressive signal, establishing binding affinity (~2.5 µM), tyrosine-phosphorylation potential, and in vivo inhibitory function in EAE.","evidence":"Surface plasmon resonance, pervanadate phosphorylation, and antibody blockade in murine EAE model","pmids":["10981966"],"confidence":"High","gaps":["Downstream signaling intermediates unknown","Cytoplasmic phosphorylation sites not mapped","Expression on non-myeloid lineages not fully characterized"]},{"year":2003,"claim":"Characterization of the CD200R gene family in human and mouse distinguished the inhibitory CD200R1 (which binds CD200) from activating CD200R-like receptors (which pair with DAP12 and do not bind CD200), clarifying receptor–ligand specificity within the family.","evidence":"DAP12 co-precipitation, quantitative RT-PCR, flow cytometry across human and mouse","pmids":["12960329"],"confidence":"High","gaps":["Signaling pathway downstream of CD200R1 still unresolved","Human CD200R family members less characterized than mouse"]},{"year":2004,"claim":"Demonstration that the viral CD200 homologue HHV-8 K14 engages CD200R with near-native affinity to suppress macrophage TNF-α established that pathogens exploit this checkpoint and confirmed the contact-dependent inhibitory mechanism.","evidence":"Surface plasmon resonance for K14–CD200R binding, TNF-α secretion assay with anti-CD200R blocking antibody","pmids":["15220441"],"confidence":"High","gaps":["Signaling events downstream of viral ligand engagement not compared to endogenous CD200","Scope of viral mimicry across herpesviruses not defined"]},{"year":2005,"claim":"Systematic mutagenesis of the three cytoplasmic tyrosines identified Y286 and Y297 (NPxY motif) as the critical phosphorylation sites for CD200R-mediated mast cell inhibition, and showed Src-family kinases mediate this phosphorylation, defining the proximal signaling code.","evidence":"Site-directed mutagenesis of Y286/Y289/Y297, phosphorylation and mast cell degranulation assays","pmids":["16330532","15661892"],"confidence":"High","gaps":["Identity of the adaptor recruited to phospho-NPxY not yet determined","Relative contribution of each tyrosine in non-mast-cell lineages unknown"]},{"year":2007,"claim":"Generation of CD200R1-knockout mice proved CD200R1 is the essential receptor for CD200-mediated immunosuppression in vivo, as CD200Fc failed to suppress allograft rejection or modulate alloreactivity in CD200R1−/− animals, while a separate study revealed an unexpected positive role for CD200–CD200R in osteoclast fusion and RANK signaling.","evidence":"CD200R1−/− mouse model with skin graft rejection, MLR, LPS-TNF assay; CD200−/− mice with osteoclast differentiation/bone histology and recombinant protein rescue","pmids":["17667818","17726108"],"confidence":"High","gaps":["Mechanism by which CD200R1 promotes RANK signaling in osteoclasts is unclear","Possible CD200R1-independent effects of CD200 not fully excluded"]},{"year":2009,"claim":"Identification of Dok2 as the primary adaptor directly binding the phosphorylated NPxY motif, with ~10-fold higher affinity than Dok1, and its downstream recruitment of RasGAP, established the core inhibitory signaling cascade (CD200R1→Dok2→RasGAP) in human myeloid cells.","evidence":"Direct binding affinity measurements, RNAi knockdown of Dok2/RasGAP vs Dok1/SHIP, co-immunoprecipitation in U937 cells","pmids":["19786546"],"confidence":"High","gaps":["Structural basis of Dok2 selectivity over Dok1 for the NPxY motif unknown","Whether RasGAP enzymatic activity is the sole effector not tested"]},{"year":2010,"claim":"Discovery that Dok1/CrkL negatively regulates CD200R1 signaling by competing with Dok2 for receptor access revealed an internal rheostat that tunes the inhibitory output, explaining why Dok1 knockdown paradoxically enhances inhibition.","evidence":"RNAi knockdown of Dok1/CrkL, phosphorylation time-course, co-immunoprecipitation","pmids":["21078907"],"confidence":"High","gaps":["Stoichiometric model of Dok1 vs. Dok2 competition not quantified","Role of Nck recruitment by Dok2 functionally undefined"]},{"year":2012,"claim":"Two parallel discoveries reshaped understanding: (1) C/EBPβ and HDAC1 were shown to co-occupy the CD200R1 promoter upon LPS stimulation, defining the transcriptional repression mechanism that silences CD200R1 during inflammation; (2) CD200R1−/− macrophages failed to upregulate TLR2 or assemble inflammasomes upon HSV-1 infection, revealing an unexpected pro-inflammatory licensing role.","evidence":"Quantitative ChIP, co-IP of C/EBPβ/HDAC1, HDAC inhibitor rescue in microglia; CD200R1−/− macrophage cytokine/TLR2/inflammasome assays and in vivo HSV-1 infection","pmids":["22776069","23082204"],"confidence":"High","gaps":["Direct chromatin remodeling mechanism by HDAC1 at CD200R1 locus not resolved","How CD200R1 licenses TLR2 expression mechanistically is unknown"]},{"year":2016,"claim":"Identification of gastrointestinal epithelial CD200 homologues iSEC1/iSEC2 as additional CD200R ligands expanded the ligand repertoire beyond CD200, with functional suppression of intraepithelial lymphocytes demonstrating mucosal immune regulation.","evidence":"Binding assays across CD200R family, IEL cytokine and cytolytic activity assays","pmids":["27819346"],"confidence":"Medium","gaps":["Structural basis of iSEC1–CD200R interaction vs. CD200–CD200R not compared","In vivo role of iSEC ligands in gut homeostasis not tested with genetic models"]},{"year":2017,"claim":"Acute stress was shown to downregulate CD200R1 in brain regions via glucocorticoid-induced C/EBPβ, and soluble CD200Fc delivery blocked stress-induced microglial priming, linking neuroendocrine regulation to the CD200–CD200R1 checkpoint in the CNS.","evidence":"In vivo stressor model, microglia isolation, RU486 blockade, adrenalectomy with corticosterone replacement, intracisterna magna CD200Fc injection","pmids":["29104062","31078691"],"confidence":"Medium","gaps":["Whether glucocorticoid receptor acts directly on CD200R1 promoter or indirectly through C/EBPβ not distinguished","Translational relevance to human stress responses not established"]},{"year":2018,"claim":"N-glycosylation at Asn44 was shown to be required for CD200 binding; its mutation abolished the interaction and de-repressed microglial pro-inflammatory markers, pinpointing a post-translational determinant of receptor competence.","evidence":"Site-directed mutagenesis of N44 glycosylation site, neuronal-microglia co-culture functional assay","pmids":["30574022"],"confidence":"Medium","gaps":["Other glycosylation sites not systematically tested","Crystal structure of glycosylated CD200R–CD200 complex unavailable"]},{"year":2019,"claim":"CD200R-deficient neutrophils displayed reduced ROS production and increased intracellular bacterial burden in Francisella infection, and neutrophil depletion rescued the phenotype, establishing a non-classical pro-defense role for CD200R in innate antimicrobial killing.","evidence":"CD200R−/− mouse model, ROS assay, in vivo Francisella tularensis infection, neutrophil depletion rescue","pmids":["31073183"],"confidence":"High","gaps":["Mechanism linking CD200R signaling to NADPH oxidase activation unknown","Whether this extends to other intracellular pathogens not tested"]},{"year":2021,"claim":"Three key advances emerged: (a) type I IFN-induced cleavage of p120-RasGAP switches CD200R from inhibitory to pro-inflammatory, explaining the paradoxical IFN-γ potentiation seen in SLE patients; (b) miR-129-5p was identified as a post-transcriptional repressor targeting CD200R1 3′-UTR, silenceable by anti-miR in vivo; (c) CD200R engagement inhibits both canonical and non-canonical NF-κB in ILC2s, expanding the receptor's scope to innate lymphoid regulation of type-2 immunity.","evidence":"Human PBMC signaling assays with p120-RasGAP cleavage analysis and SLE patient samples; primary microglia miR-129-5p/anti-miR experiments with methylation analysis; mouse and human ILC2 NF-κB pathway analysis with in vivo AHR models","pmids":["34637328","34952004","33953190"],"confidence":"High","gaps":["Protease responsible for p120-RasGAP cleavage during IFN signaling not identified","Whether miR-129-5p regulation operates in non-CNS tissues not determined","Structural basis of CD200R non-canonical NF-κB inhibition unknown"]},{"year":2023,"claim":"A therapeutic anti-CD200R1 blocking antibody confirmed the CD200–CD200R1–DOK2 axis as an immune checkpoint in cancer: antibody blockade prevented DOK2 recruitment, enhanced T cell cytotoxicity, and suppressed tumor growth, linking GWAS-identified pathway genes to a druggable target.","evidence":"Humanized antibody binding/DOK2 recruitment assays, T cell killing assays, S91 melanoma syngeneic model, GWAS data","pmids":["37288324"],"confidence":"Medium","gaps":["Efficacy across diverse tumor types not shown","Biomarkers for patient selection not defined","Whether combination with other checkpoint inhibitors is synergistic not tested"]},{"year":null,"claim":"Key unresolved questions include the structural basis of Dok2 selectivity for the CD200R1 NPxY motif, the protease mediating IFN-induced p120-RasGAP cleavage that switches CD200R1 output, the mechanism linking CD200R1 to neutrophil NADPH oxidase activation, and whether the inhibitory-to-activating switch operates in tissue-resident macrophage subsets beyond PBMCs.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of CD200R1 cytoplasmic domain with Dok2","Protease identity for p120-RasGAP cleavage unknown","CD200R1 signaling in tissue-specific macrophage subsets incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3,4,5,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6,14,19]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3,15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,5,8,19,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,6,14,17]}],"complexes":[],"partners":["CD200","DOK2","DOK1","RASA1","CRKL","NCK1"],"other_free_text":[]},"mechanistic_narrative":"CD200R1 is an inhibitory immunoreceptor on myeloid and lymphoid cells that restrains inflammatory activation upon engagement by CD200 or its homologues. Ligation triggers Src-family-kinase-dependent phosphorylation of cytoplasmic tyrosines Y286 and Y297 (the latter within an NPxY motif), directly recruiting the adaptor Dok2, which in turn recruits RasGAP to suppress Ras/MAPK and NF-κB signaling, thereby inhibiting macrophage TNF-α secretion, mast cell degranulation, ILC2 cytokine production, and microglial priming [PMID:19786546, PMID:16330532, PMID:33953190, PMID:15661892]. CD200R1 expression is transcriptionally repressed by a C/EBPβ/HDAC1 complex under inflammatory conditions and post-transcriptionally by miR-129-5p, while type I interferon-induced cleavage of p120-RasGAP can switch CD200R1 signaling from inhibitory to pro-inflammatory, as observed in systemic lupus erythematosus [PMID:22776069, PMID:34952004, PMID:34637328]. Beyond classical inhibition, CD200R1 is required for neutrophil ROS production limiting intracellular bacterial proliferation and for TLR2-dependent inflammasome assembly during herpesvirus infection, revealing context-dependent pro-host-defense functions [PMID:31073183, PMID:23082204]."},"prefetch_data":{"uniprot":{"accession":"Q8TD46","full_name":"Cell surface glycoprotein CD200 receptor 1","aliases":["CD200 cell surface glycoprotein receptor","Cell surface glycoprotein OX2 receptor 1"],"length_aa":348,"mass_kda":39.0,"function":"Inhibitory receptor for the CD200/OX2 cell surface glycoprotein. Limits inflammation by inhibiting the expression of pro-inflammatory molecules including TNF, interferons, and inducible nitric oxide synthase (iNOS) in response to selected stimuli. Also binds to HHV-8 K14 viral CD200 homolog with identical affinity and kinetics as the host CD200","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8TD46/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD200R1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD200R1","total_profiled":1310},"omim":[{"mim_id":"621205","title":"MICRO RNA 129-2; MIR129-2","url":"https://www.omim.org/entry/621205"},{"mim_id":"621204","title":"MICRO RNA 129-1; MIR129-1","url":"https://www.omim.org/entry/621204"},{"mim_id":"607546","title":"CD200 RECEPTOR 1; CD200R1","url":"https://www.omim.org/entry/607546"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":7.5}],"url":"https://www.proteinatlas.org/search/CD200R1"},"hgnc":{"alias_symbol":["OX2R","HCRTR2","CD200R"],"prev_symbol":["MOX2R"]},"alphafold":{"accession":"Q8TD46","domains":[{"cath_id":"2.60.40.10","chopping":"45-151","consensus_level":"high","plddt":94.0242,"start":45,"end":151},{"cath_id":"2.60.40.10","chopping":"155-231","consensus_level":"high","plddt":93.7405,"start":155,"end":231}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TD46","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TD46-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TD46-F1-predicted_aligned_error_v6.png","plddt_mean":74.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD200R1","jax_strain_url":"https://www.jax.org/strain/search?query=CD200R1"},"sequence":{"accession":"Q8TD46","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TD46.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TD46/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TD46"}},"corpus_meta":[{"pmid":"22053982","id":"PMC_22053982","title":"CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease.","date":"2011","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/22053982","citation_count":114,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15187158","id":"PMC_15187158","title":"CD200 is a ligand for all members of the CD200R family of immunoregulatory molecules.","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15187158","citation_count":111,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17714785","id":"PMC_17714785","title":"The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes.","date":"2007","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17714785","citation_count":110,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30367946","id":"PMC_30367946","title":"Role of the CD200-CD200R Axis During Homeostasis and Neuroinflammation.","date":"2018","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30367946","citation_count":95,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33562512","id":"PMC_33562512","title":"CD200:CD200R Interactions and Their Importance in Immunoregulation.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33562512","citation_count":90,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21295135","id":"PMC_21295135","title":"Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK.","date":"2011","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21295135","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22264927","id":"PMC_22264927","title":"CD200R signaling in tumor tolerance and inflammation: A tricky balance.","date":"2012","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22264927","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18164423","id":"PMC_18164423","title":"CNS inflammation and neuronal degeneration is aggravated by impaired CD200-CD200R-mediated macrophage silencing.","date":"2008","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/18164423","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24388216","id":"PMC_24388216","title":"The CD200-CD200R1 inhibitory signaling pathway: immune regulation and host-pathogen interactions.","date":"2014","source":"Advances in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24388216","citation_count":73,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20147531","id":"PMC_20147531","title":"CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20147531","citation_count":71,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17667818","id":"PMC_17667818","title":"Mice lacking CD200R1 show absence of suppression of lipopolysaccharide-induced tumor necrosis factor-alpha and mixed leukocyte culture responses by CD200.","date":"2007","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/17667818","citation_count":68,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16801656","id":"PMC_16801656","title":"A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort.","date":"2006","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/16801656","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24588829","id":"PMC_24588829","title":"Brain innate immunity in the regulation of neuroinflammation: therapeutic strategies by modulating CD200-CD200R interaction involve the cannabinoid system.","date":"2014","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/24588829","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22575528","id":"PMC_22575528","title":"Characterization and functionality of the CD200-CD200R system during mesenchymal stromal cell interactions with T-lymphocytes.","date":"2012","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/22575528","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29104062","id":"PMC_29104062","title":"Stress disinhibits microglia via down-regulation of CD200R: A mechanism of neuroinflammatory priming.","date":"2017","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/29104062","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22020332","id":"PMC_22020332","title":"CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22020332","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17726108","id":"PMC_17726108","title":"CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17726108","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16774153","id":"PMC_16774153","title":"Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy: anti-Hcrt system antibody in narcolepsy.","date":"2006","source":"Sleep","url":"https://pubmed.ncbi.nlm.nih.gov/16774153","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32473633","id":"PMC_32473633","title":"The CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity after stroke.","date":"2020","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/32473633","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15880066","id":"PMC_15880066","title":"Augmented Induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R.","date":"2005","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/15880066","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32030689","id":"PMC_32030689","title":"CD200-CD200R Pathway in the Regulation of Tumor Immune Microenvironment and Immunotherapy.","date":"2020","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/32030689","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22696929","id":"PMC_22696929","title":"CD200/CD200R paired potent inhibitory molecules regulating immune and inflammatory responses; Part I: CD200/CD200R structure, activation, and function.","date":"2012","source":"Acta medica (Hradec Kralove)","url":"https://pubmed.ncbi.nlm.nih.gov/22696929","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18040859","id":"PMC_18040859","title":"CD200-CD200R regulation of microglia activation in the pathogenesis of Parkinson's disease.","date":"2007","source":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18040859","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28164283","id":"PMC_28164283","title":"Monocytes, microglia, and CD200-CD200R1 signaling are essential in the transmission of inflammation from the periphery to the central nervous system.","date":"2017","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28164283","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16330532","id":"PMC_16330532","title":"Identification of tyrosine residues crucial for CD200R-mediated inhibition of mast cell activation.","date":"2005","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/16330532","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22652455","id":"PMC_22652455","title":"OX2R activation induces PKC-mediated ERK and CREB phosphorylation.","date":"2012","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/22652455","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22323214","id":"PMC_22323214","title":"The immune inhibitory complex CD200/CD200R is developmentally regulated in the mouse brain.","date":"2012","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/22323214","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24639050","id":"PMC_24639050","title":"CD200R1 and CD200 expression are regulated by PPAR-γ in activated glial cells.","date":"2014","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/24639050","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32829711","id":"PMC_32829711","title":"The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours.","date":"2020","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/32829711","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26891688","id":"PMC_26891688","title":"CD200R1 agonist attenuates glial activation, inflammatory reactions, and hypersensitivity immediately after its intrathecal application in a rat neuropathic pain model.","date":"2016","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/26891688","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20688107","id":"PMC_20688107","title":"Expression of orexin receptors 1 (OX1R) and 2 (OX2R) in the porcine ovary during the oestrous cycle.","date":"2010","source":"Regulatory peptides","url":"https://pubmed.ncbi.nlm.nih.gov/20688107","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15729177","id":"PMC_15729177","title":"Augmented induction of CD4+CD25+ Treg using monoclonal antibodies to CD200R.","date":"2005","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/15729177","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22776069","id":"PMC_22776069","title":"Inhibition of CD200R1 expression by C/EBP β in reactive microglial cells.","date":"2012","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/22776069","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32257540","id":"PMC_32257540","title":"Disease Progression-Dependent Expression of CD200R1 and CX3CR1 in Mouse Models of Parkinson's Disease.","date":"2020","source":"Aging and disease","url":"https://pubmed.ncbi.nlm.nih.gov/32257540","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30777093","id":"PMC_30777093","title":"CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke.","date":"2019","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/30777093","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33953190","id":"PMC_33953190","title":"CD200-CD200R immune checkpoint engagement regulates ILC2 effector function and ameliorates lung inflammation in asthma.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33953190","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18399985","id":"PMC_18399985","title":"Haplotype analysis confirms the association between the HCRTR2 gene and cluster headache.","date":"2008","source":"Headache","url":"https://pubmed.ncbi.nlm.nih.gov/18399985","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37903272","id":"PMC_37903272","title":"Dysregulated CD200-CD200R signaling in early diabetes modulates microglia-mediated retinopathy.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37903272","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22995645","id":"PMC_22995645","title":"The differential effects of OX1R and OX2R selective antagonists on morphine conditioned place preference in naïve versus morphine-dependent mice.","date":"2012","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/22995645","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29870752","id":"PMC_29870752","title":"CD200 modulates spinal cord injury neuroinflammation and outcome through CD200R1.","date":"2018","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/29870752","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24496593","id":"PMC_24496593","title":"Decreased CD200R expression on monocyte-derived macrophages correlates with Th17/Treg imbalance and disease activity in rheumatoid arthritis patients.","date":"2014","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/24496593","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29318394","id":"PMC_29318394","title":"Genetic association of HCRTR2, ADH4 and CLOCK genes with cluster headache: a Chinese population-based case-control study.","date":"2018","source":"The journal of headache and pain","url":"https://pubmed.ncbi.nlm.nih.gov/29318394","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25791482","id":"PMC_25791482","title":"CD200R1 agonist attenuates LPS-induced inflammatory response in human renal proximal tubular epithelial cells by regulating TLR4-MyD88-TAK1-mediated NF-κB and MAPK pathway.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25791482","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28106273","id":"PMC_28106273","title":"The immunoglobulin superfamily member CD200R identifies cells involved in type 2 immune responses.","date":"2017","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/28106273","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20610868","id":"PMC_20610868","title":"Expression of orexin receptors 1 (OX1R) and 2 (OX2R) in the porcine hypothalamus during the oestrous cycle.","date":"2010","source":"Journal of physiology and pharmacology : an official journal of the Polish Physiological Society","url":"https://pubmed.ncbi.nlm.nih.gov/20610868","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24376396","id":"PMC_24376396","title":"Kinetic properties of \"dual\" orexin receptor antagonists at OX1R and OX2R orexin receptors.","date":"2013","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24376396","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27385779","id":"PMC_27385779","title":"A Critical Role for CD200R Signaling in Limiting the Growth and Metastasis of CD200+ Melanoma.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27385779","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26690123","id":"PMC_26690123","title":"Reduced Dendritic Cells Expressing CD200R1 in Children with Inflammatory Bowel Disease: Correlation with Th17 and Regulatory T Cells.","date":"2015","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26690123","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19394166","id":"PMC_19394166","title":"Expression of orexin receptors 1 (OX1R) and 2 (OX2R) in the porcine pituitary during the oestrous cycle.","date":"2009","source":"Animal reproduction science","url":"https://pubmed.ncbi.nlm.nih.gov/19394166","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29101312","id":"PMC_29101312","title":"Gingival Tissue Inflammation Promotes Increased Matrix Metalloproteinase-12 Production by CD200Rlow Monocyte-Derived Cells in Periodontitis.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29101312","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30006626","id":"PMC_30006626","title":"CD200-CD200R imbalance correlates with microglia and pro-inflammatory activation in rat spinal cords exposed to amniotic fluid in retinoic acid-induced spina bifida.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30006626","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31513876","id":"PMC_31513876","title":"Neurogenesis promoted by the CD200/CD200R signaling pathway following treadmill exercise enhances post-stroke functional recovery in rats.","date":"2019","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/31513876","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32664639","id":"PMC_32664639","title":"Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200-CD200R and CX3CL1-CX3CR1 Systems.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32664639","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33823877","id":"PMC_33823877","title":"The CD200R1 microglial inhibitory receptor as a therapeutic target in the MPTP model of Parkinson's disease.","date":"2021","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/33823877","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23541619","id":"PMC_23541619","title":"The role of CD200-CD200R in tumor immune evasion.","date":"2013","source":"Journal of theoretical biology","url":"https://pubmed.ncbi.nlm.nih.gov/23541619","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25239810","id":"PMC_25239810","title":"Both Ox1r and Ox2r orexin receptors contribute to the cardiovascular and locomotor components of the novelty stress response in the rat.","date":"2014","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25239810","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34183355","id":"PMC_34183355","title":"The CD200-CD200R Axis Promotes Squamous Cell Carcinoma Metastasis via Regulation of Cathepsin K.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34183355","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31993106","id":"PMC_31993106","title":"CD200-CD200R signaling and diseases: a potential therapeutic target?","date":"2019","source":"International journal of physiology, pathophysiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31993106","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31073183","id":"PMC_31073183","title":"CD200R deletion promotes a neutrophil niche for Francisella tularensis and increases infectious burden and mortality.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31073183","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28792282","id":"PMC_28792282","title":"Anti-inflammation conferred by stimulation of CD200R1 via Dok1 pathway in rat microglia after germinal matrix hemorrhage.","date":"2017","source":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/28792282","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24333170","id":"PMC_24333170","title":"Elevated serum soluble CD200 and CD200R as surrogate markers of bone loss under bed rest conditions.","date":"2013","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/24333170","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31078691","id":"PMC_31078691","title":"Glucocorticoids mediate stress induction of the alarmin HMGB1 and reduction of the microglia checkpoint receptor CD200R1 in limbic brain structures.","date":"2019","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/31078691","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30021725","id":"PMC_30021725","title":"Antitumor Activity of TLR7 Is Potentiated by CD200R Antibody Leading to Changes in the Tumor Microenvironment.","date":"2018","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/30021725","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24166280","id":"PMC_24166280","title":"Cure of metastatic growth of EMT6 tumor cells in mice following manipulation of CD200:CD200R signaling.","date":"2013","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/24166280","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37902837","id":"PMC_37902837","title":"Activation of the CD200/CD200R1 axis attenuates neuroinflammation and improves postoperative cognitive dysfunction via the PI3K/Akt/NF-κB signaling pathway in aged mice.","date":"2023","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/37902837","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23082204","id":"PMC_23082204","title":"CD200R1 supports HSV-1 viral replication and licenses pro-inflammatory signaling functions of TLR2.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23082204","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28522962","id":"PMC_28522962","title":"Alterations in CD200-CD200R1 System during EAE Already Manifest at Presymptomatic Stages.","date":"2017","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28522962","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27929051","id":"PMC_27929051","title":"Reduced expression of monocyte CD200R is associated with enhanced proinflammatory cytokine production in sarcoidosis.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27929051","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25261692","id":"PMC_25261692","title":"Aberrant CD200/CD200R1 expression and its potential role in Th17 cell differentiation, chemotaxis and osteoclastogenesis in rheumatoid arthritis.","date":"2014","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25261692","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36756156","id":"PMC_36756156","title":"Cancel cancer: The immunotherapeutic potential of CD200/CD200R blockade.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36756156","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30800162","id":"PMC_30800162","title":"Interaction of CD200 Overexpression on Tumor Cells with CD200R1 Overexpression on Stromal Cells: An Escape from the Host Immune Response in Rectal Cancer Patients.","date":"2019","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30800162","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30652302","id":"PMC_30652302","title":"Analysis of HCRTR2 Gene Variants and Cluster Headache in Sweden.","date":"2019","source":"Headache","url":"https://pubmed.ncbi.nlm.nih.gov/30652302","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35589803","id":"PMC_35589803","title":"Orexin 2 receptor (OX2R) protein distribution measured by autoradiography using radiolabeled OX2R-selective antagonist EMPA in rodent brain and peripheral tissues.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35589803","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27731341","id":"PMC_27731341","title":"CD200R/Foxp3-mediated signalling regulates microglial activation.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27731341","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20735439","id":"PMC_20735439","title":"CD200R1 regulates the severity of arthritis but has minimal impact on the adaptive immune response.","date":"2010","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20735439","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38137547","id":"PMC_38137547","title":"CD200/CD200R: Bidirectional Role in Cancer Progression and Immunotherapy.","date":"2023","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/38137547","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37616575","id":"PMC_37616575","title":"Exploiting the CD200-CD200R immune checkpoint axis in multiple myeloma to enhance CAR T-cell therapy.","date":"2024","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/37616575","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23101267","id":"PMC_23101267","title":"CD200/CD200R paired potent inhibitory molecules regulating immune and inflammatory responses; Part II: CD200/CD200R potential clinical applications.","date":"2012","source":"Acta medica (Hradec Kralove)","url":"https://pubmed.ncbi.nlm.nih.gov/23101267","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16530849","id":"PMC_16530849","title":"A role for the immunomodulatory molecules CD200 and CD200R in regulating bone formation.","date":"2006","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/16530849","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19967353","id":"PMC_19967353","title":"Heterogeneity in the CD200R paired receptor family.","date":"2009","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19967353","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25158092","id":"PMC_25158092","title":"Agonistic CD200R1 DNA Aptamers Are Potent Immunosuppressants That Prolong Allogeneic Skin Graft Survival.","date":"2014","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/25158092","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21186399","id":"PMC_21186399","title":"Elevated expression of orexin receptor 2 (HCRTR2) in benign prostatic hyperplasia is accompanied by lowered serum orexin A concentrations.","date":"2010","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21186399","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26555080","id":"PMC_26555080","title":"Absence of mutations in HCRT, HCRTR1 and HCRTR2 in patients with ROHHAD.","date":"2015","source":"Respiratory physiology & neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26555080","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29280053","id":"PMC_29280053","title":"CD200Fc Attenuates Retinal Glial Responses and RGCs Apoptosis After Optic Nerve Crush by Modulating CD200/CD200R1 Interaction.","date":"2017","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/29280053","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24969517","id":"PMC_24969517","title":"Is HCRTR2 a genetic risk factor for Alzheimer's disease?","date":"2014","source":"Dementia and geriatric cognitive disorders","url":"https://pubmed.ncbi.nlm.nih.gov/24969517","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37288324","id":"PMC_37288324","title":"23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function.","date":"2023","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/37288324","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30574022","id":"PMC_30574022","title":"The role of N-glycosylation of CD200-CD200R1 interaction in classical microglial activation.","date":"2018","source":"Journal of inflammation (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/30574022","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23178470","id":"PMC_23178470","title":"Effect of CD200 and CD200R1 expression within tissue grafts on increased graft survival in allogeneic recipients.","date":"2012","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/23178470","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26923638","id":"PMC_26923638","title":"Constitutively expressed Siglec-9 inhibits LPS-induced CCR7, but enhances IL-4-induced CD200R expression in human macrophages.","date":"2016","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26923638","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20548263","id":"PMC_20548263","title":"Potent immunosuppression by a bivalent molecule binding to CD200R and TGF-betaR.","date":"2010","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/20548263","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31768945","id":"PMC_31768945","title":"Analysis of HCRTR2, GNB3, and ADH4 Gene Polymorphisms in a Southeastern European Caucasian Cluster Headache Population.","date":"2019","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/31768945","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17645762","id":"PMC_17645762","title":"The 1246G-->A polymorphism of the HCRTR2 gene is not associated with migraine.","date":"2007","source":"Cephalalgia : an international journal of headache","url":"https://pubmed.ncbi.nlm.nih.gov/17645762","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27819346","id":"PMC_27819346","title":"Novel CD200 homologues iSEC1 and iSEC2 are gastrointestinal secretory cell-specific ligands of inhibitory receptor CD200R.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27819346","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34952004","id":"PMC_34952004","title":"MicroRNA-129-5p-regulated microglial expression of the surface receptor CD200R1 controls neuroinflammation.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34952004","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35296683","id":"PMC_35296683","title":"Altered expression of the immunoregulatory ligand-receptor pair CD200-CD200R1 in the brain of Parkinson's disease patients.","date":"2022","source":"NPJ Parkinson's disease","url":"https://pubmed.ncbi.nlm.nih.gov/35296683","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34637328","id":"PMC_34637328","title":"Signaling by the inhibitory receptor CD200R is rewired by type I interferon.","date":"2021","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/34637328","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37011735","id":"PMC_37011735","title":"Jingfang Granule alleviates bleomycin-induced acute lung injury via CD200-CD200R immunoregulatory pathway.","date":"2023","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37011735","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34540085","id":"PMC_34540085","title":"The CD200/CD200R mechanism in mesenchymal stem cells' regulation of dendritic cells.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/34540085","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30195773","id":"PMC_30195773","title":"A Synthetic Cross-Species CD200R1 Agonist Suppresses Inflammatory Immune Responses In Vivo.","date":"2018","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/30195773","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32606391","id":"PMC_32606391","title":"Parkinsonian neurotoxicants impair the anti-inflammatory response induced by IL4 in glial cells: involvement of the CD200-CD200R1 ligand-receptor pair.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32606391","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12960329","id":"PMC_12960329","title":"Characterization of the CD200 receptor family in mice and humans and their interactions with CD200.","date":"2003","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/12960329","citation_count":367,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12072366","id":"PMC_12072366","title":"CD200 and membrane protein interactions in the control of myeloid cells.","date":"2002","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12072366","citation_count":336,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10981966","id":"PMC_10981966","title":"Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function.","date":"2000","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10981966","citation_count":327,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12975309","id":"PMC_12975309","title":"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.","date":"2003","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/12975309","citation_count":285,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17207965","id":"PMC_17207965","title":"hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes.","date":"2007","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17207965","citation_count":222,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11260322","id":"PMC_11260322","title":"The unusual distribution of the neuronal/lymphoid cell surface CD200 (OX2) glycoprotein is conserved in humans.","date":"2001","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11260322","citation_count":184,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19151626","id":"PMC_19151626","title":"Distribution of the immune inhibitory molecules CD200 and CD200R in the normal central nervous system and multiple sclerosis lesions suggests neuron-glia and glia-glia interactions.","date":"2009","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/19151626","citation_count":159,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19786546","id":"PMC_19786546","title":"Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19786546","citation_count":124,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22566634","id":"PMC_22566634","title":"The genetic architecture of economic and political preferences.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22566634","citation_count":121,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23382219","id":"PMC_23382219","title":"Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23382219","citation_count":121,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15661892","id":"PMC_15661892","title":"The CD200 receptor is a novel and potent regulator of murine and human mast cell function.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/15661892","citation_count":94,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15220441","id":"PMC_15220441","title":"Human herpesvirus 8 K14 protein mimics CD200 in down-regulating macrophage activation through CD200 receptor.","date":"2004","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15220441","citation_count":93,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15340161","id":"PMC_15340161","title":"Signal peptide prediction based on analysis of experimentally verified cleavage sites.","date":"2004","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/15340161","citation_count":92,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35922511","id":"PMC_35922511","title":"A physical wiring diagram for the human immune system.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35922511","citation_count":92,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16177086","id":"PMC_16177086","title":"Down-regulation of basophil function by human CD200 and human herpesvirus-8 CD200.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16177086","citation_count":88,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15070969","id":"PMC_15070969","title":"Expression of human prepro-orexin and signaling characteristics of orexin receptors in the male reproductive system.","date":"2004","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/15070969","citation_count":87,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32822567","id":"PMC_32822567","title":"A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions.","date":"2020","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/32822567","citation_count":81,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11133863","id":"PMC_11133863","title":"Distribution of OX2 antigen and OX2 receptor within retina.","date":"2001","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/11133863","citation_count":66,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21078907","id":"PMC_21078907","title":"Downstream of tyrosine kinase 1 and 2 play opposing roles in CD200 receptor signaling.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21078907","citation_count":58,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22363701","id":"PMC_22363701","title":"CD200 positive human mesenchymal stem cells suppress TNF-alpha secretion from CD200 receptor positive macrophage-like cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22363701","citation_count":54,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21982860","id":"PMC_21982860","title":"A secreted protein microarray platform for extracellular protein interaction discovery.","date":"2011","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21982860","citation_count":53,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29042364","id":"PMC_29042364","title":"A CD200R-CD28 fusion protein appropriates an inhibitory signal to enhance T-cell function and therapy of murine leukemia.","date":"2017","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/29042364","citation_count":52,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22491458","id":"PMC_22491458","title":"Suppression of antigen-specific T cell responses by the Kaposi's sarcoma-associated herpesvirus viral OX2 protein and its cellular orthologue, CD200.","date":"2012","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/22491458","citation_count":38,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22496920","id":"PMC_22496920","title":"Chronic infection drives expression of the inhibitory receptor CD200R, and its ligand CD200, by mouse and human CD4 T cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22496920","citation_count":36,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22621248","id":"PMC_22621248","title":"Aberrant CD200/CD200R1 expression and function in systemic lupus erythematosus contributes to abnormal T-cell responsiveness and dendritic cell activity.","date":"2012","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/22621248","citation_count":34,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52713,"output_tokens":5942,"usd":0.123634},"stage2":{"model":"claude-opus-4-6","input_tokens":9678,"output_tokens":3497,"usd":0.203723},"total_usd":0.708395,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":65716,"output_tokens":7225,"usd":0.152761},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":11242,"output_tokens":3839,"usd":0.228277}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"CD200R contains three cytoplasmic tyrosine residues (Y286, Y289, Y297); site-directed mutagenesis showed Y286 and Y297 are the major phosphorylation sites critical for CD200R-mediated inhibition of mast cell activation, while Y289 is dispensable. Engagement of CD200R induces tyrosine phosphorylation and recruitment of inhibitory adaptor proteins Dok1 and Dok2, leading to inhibition of Ras/MAPK activation. Src family kinase may mediate CD200R phosphorylation.\",\n      \"method\": \"Site-directed mutagenesis of cytoplasmic tyrosine residues in mouse mast cells; functional inhibition assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with functional readout, multiple tyrosine residues systematically tested\",\n      \"pmids\": [\"16330532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD200 serves as a ligand for all members of the CD200R family (CD200R1–R4 isoforms), as demonstrated by FITC-labeled CD200Fc binding to COS7 cells transfected with each isoform; functional consequences differ between isoforms—anti-CD200R1/R4 mAbs altered IL-2/IL-4 cytokine production and suppressed CTL responses more potently than anti-CD200R2/R3.\",\n      \"method\": \"FACS binding assay with FITC-labeled CD200Fc on transfected COS7 cells; cytokine and CTL functional assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay with functional follow-up, single lab\",\n      \"pmids\": [\"15187158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD200R1 knockout mice lack suppression of LPS-induced TNF-α production and mixed leukocyte culture responses by CD200Fc, establishing that CD200R1 is the receptor required for CD200-mediated immunosuppression in myeloid cells and for modulation of alloreactivity in vivo, including graft rejection.\",\n      \"method\": \"CD200R1 knockout mice (ES cell-based genomic deletion); FACS, ELISA, mixed leukocyte culture, skin graft rejection\",\n      \"journal\": \"Transplantation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined phenotypic readouts\",\n      \"pmids\": [\"17667818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD200R1 is expressed on osteoclast precursors and macrophages; CD200 engagement of CD200R1 at the initiation of macrophage fusion regulated osteoclast differentiation via downstream NF-κB and MAP kinase signaling pathways. Soluble CD200 extracellular domain rescued fusion of CD200−/− macrophages; soluble CD200R extracellular domain or CD200R shRNA prevented fusion. CD200−/− mice had fewer osteoclasts and accumulated more bone.\",\n      \"method\": \"CD200−/− mice; recombinant soluble proteins; shRNA knockdown; NF-κB/MAPK pathway activation assays; bone histomorphometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — KO mice, reconstitution with recombinant protein, shRNA, and signaling pathway assays in one study\",\n      \"pmids\": [\"17726108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD200R1 is required for TLR2-mediated pro-inflammatory signaling in macrophages; CD200R1−/− peritoneal macrophages showed 70–75% reduction in IL-6 and CCL5 production in response to TLR2 agonist Pam2CSK4 and HSV-1, could not upregulate TLR2 expression or assemble a functional inflammasome in response to HSV-1, and showed markedly reduced ability to support HSV-1 replication. CD200R1−/− mice were protected from HSV-1 infection.\",\n      \"method\": \"CD200R1−/− mice; peritoneal macrophage stimulation assays; inflammasome assembly assessment; viral replication assay; in vivo infection model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with multiple orthogonal in vitro and in vivo readouts in one study\",\n      \"pmids\": [\"23082204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD200R1 expression in microglial cells is transcriptionally repressed by C/EBPβ in response to LPS. C/EBPβ binds to the CD200R1 promoter in LPS-treated glial cells; HDAC1 co-immunoprecipitates with C/EBPβ and binds a C/EBPβ consensus sequence of the CD200R1 promoter under inflammatory conditions. HDAC1 inhibitors reversed LPS-induced CD200R1 downregulation.\",\n      \"method\": \"Quantitative ChIP; co-immunoprecipitation; C/EBPβ-deficient mouse primary microglia; BV2 cells overexpressing C/EBPβ; HDAC inhibitor treatment\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP, co-IP, KO cells, and overexpression with functional readout\",\n      \"pmids\": [\"22776069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD200R1 signaling inhibits TLR4-MyD88-TAK1-mediated NF-κB and MAPK pathways; CD200Fc inhibited LPS-induced TLR4 and MyD88 expression, phosphorylation of TAK1, phosphorylation of IκB, NF-κB-p65 nuclear translocation, and ERK1/2/p38/JNK phosphorylation in human renal proximal tubular epithelial cells.\",\n      \"method\": \"CD200Fc treatment of hRPTECs; western blot for pathway components; co-immunoprecipitation of TLR4-MyD88/TAK1 interactions; ELISA for cytokines\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pathway components measured, single lab\",\n      \"pmids\": [\"25791482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD200R1 activates anti-inflammatory signaling through the Dok1 pathway after germinal matrix hemorrhage; CD200Fc treatment increased Dok1 expression and decreased IL-1β and TNF-α; knockdown of CD200R1 or Dok1 with siRNA abolished the anti-inflammatory effects of CD200Fc, establishing a CD200R1/Dok1 signaling axis.\",\n      \"method\": \"CD200Fc treatment; CD200R1 siRNA and Dok1 siRNA intracerebroventricular injection; western blot; neonatal rat GMH model\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown of both receptor and adapter with functional readout, single lab\",\n      \"pmids\": [\"28792282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD200R signaling on ILC2s inhibits activation, proliferation, and type 2 cytokine production; CD200R engagement inhibits both canonical and non-canonical NF-κB signaling pathways in activated ILC2s, and CD200R is expressed on mouse and human ILC2s.\",\n      \"method\": \"Flow cytometry for CD200R expression; functional assays of ILC2 activation/proliferation/cytokine production; NF-κB pathway analysis; humanized mouse models of AHR\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional and signaling readouts, single lab\",\n      \"pmids\": [\"33953190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD200R signaling operates through adaptor protein DOK2 and GTPase activating protein p120-RasGAP. In the presence of cleaved p120-RasGAP (induced by type I IFN), CD200R lost its capacity to inhibit rpS6 phosphorylation (mTORC1 activity) and switched from inhibiting to potentiating TLR7/8-induced IFN-γ expression. SLE patients had increased cleaved p120-RasGAP, causing proinflammatory rewiring of CD200R signaling.\",\n      \"method\": \"PBMC treatment with IFN-α; western blot for cleaved p120-RasGAP and rpS6; TLR7/8 stimulation assays; primary cells from SLE patients\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with multiple orthogonal methods and patient validation\",\n      \"pmids\": [\"34637328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD200R1 blockade in vivo can attenuate high glucose-induced inflammation and phagocytosis in retinal microglia; CD200-CD200R1 signaling between amacrine cells and microglia is dysregulated in early diabetic retinopathy, and targeting CD200R prevented visual dysfunction and retinal inflammation in diabetic mice.\",\n      \"method\": \"CD200R antibody treatment in type I diabetes mouse model; microglial ablation; transcriptome analysis; flow cytometry; behavioral visual function testing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO/blockade with functional readouts, single lab\",\n      \"pmids\": [\"37903272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Novel CD200 homologues iSEC1 and iSEC2 bind CD200R (but not other CD200R family members); binding of iSEC1 to CD200R on intraepithelial lymphocytes suppressed cytokine production and cytolytic activity, demonstrating CD200R-mediated inhibition of mucosal immune responses.\",\n      \"method\": \"Binding assays with recombinant iSEC1/iSEC2 and CD200R family members; functional assays of IEL cytokine production and cytolytic activity\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding and functional assays, single lab\",\n      \"pmids\": [\"27819346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-129-5p post-transcriptionally represses CD200R1 expression by binding to its 3'-UTR and shuttling CD200R1 mRNA to cytoplasmic processing bodies; arsenic demethylates the miR-129-5p promoter, increasing miR-129-5p expression, which reduces CD200R1 and increases IL-6 and TNF-α. An miR-129-5p→CD200R1→IL-6/TNF-α signaling axis was confirmed by anti-miR-129 rescue and CD200R1 siRNA loss-of-function experiments.\",\n      \"method\": \"In silico prediction; primary neonatal microglia and BV2 cells; anti-miR-129 stereotaxic injection in mice; CD200R1 siRNA mouse model; human cell line validation; 3'-UTR reporter assay implied\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vivo rescue, single lab\",\n      \"pmids\": [\"34952004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"N-glycosylation of CD200R1 at asparagine 44 (Asn44) is required for CD200-CD200R1 interaction; mutation of Asn44 disrupted CD200-CD200R1 binding and upregulated pro-inflammatory markers (iNOS, CD86, IL-1β, TNF-α) in a neuronal-microglia co-culture system.\",\n      \"method\": \"Site-directed mutagenesis of CD200R1 glycosylation site; neuronal-microglia co-culture; cytokine expression assays\",\n      \"journal\": \"Journal of inflammation (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"30574022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD200R1 agonist aptamers induced rapid phosphorylation of the CD200R1 cytoplasmic tail, initiating immune inhibitory signaling, suppressed CTL induction in allogeneic mixed leukocyte cultures, and prolonged allogeneic skin graft survival in vivo; effects were absent in CD200R1−/− responder cells, confirming on-target mechanism.\",\n      \"method\": \"DNA aptamer SELEX; CD200R1 cytoplasmic tail phosphorylation assay; allogeneic MLCs with CD200R1−/− cells; in vivo skin graft model\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor phosphorylation confirmed, KO control used, in vivo validation\",\n      \"pmids\": [\"25158092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD200R/CD200R1 signaling promotes expression of Foxp3 in microglia; phosphorylation of STAT6 (a downstream effector of CD200R) modulated Foxp3 transcription; over-expression of Foxp3 enhanced anti-inflammatory microglial phenotype, and CD200R/Foxp3-mediated signaling enhanced hippocampal neuronal viability by counteracting iNOS.\",\n      \"method\": \"CD200R suppression and Foxp3 overexpression in microglia; STAT6 phosphorylation assay; excitotoxicity-induced hippocampal neuroinflammation model; neuronal viability assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — signaling pathway dissection with functional readout, single lab\",\n      \"pmids\": [\"27731341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD200R1 deficiency in neutrophils leads to significantly reduced reactive oxygen species (ROS) production, resulting in enhanced bacterial burden of Francisella tularensis in neutrophils; depleting the neutrophil niche in CD200R−/− mice restored infection levels to wild-type, establishing that CD200R promotes antimicrobial ROS production in neutrophils.\",\n      \"method\": \"CD200R−/− mice; in vitro and in vivo F. tularensis infection; ROS measurement; neutrophil depletion; bacterial burden quantification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with mechanistic ROS readout and depletion rescue experiment\",\n      \"pmids\": [\"31073183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD200 expressed on tumor cells engages CD200R on infiltrating CD11B+ myeloid cells to induce cathepsin K (Ctsk) expression; Ctsk was upregulated in CD200R+ myeloid cells from CD200+ tumors, induction was dependent on CD200-CD200R engagement in coculture, and Ctsk inhibition (but not MMP inhibition) blocked tumor cell migration and metastasis.\",\n      \"method\": \"RNA sequencing of CD11B+CD200R+ cells from CD200+ vs CD200-null tumors; CD200-CD200R coculture system; Ctsk inhibitors; in vivo metastasis model with CD200 disruption\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAseq, coculture mechanistic validation, pharmacologic and genetic in vivo confirmation\",\n      \"pmids\": [\"34183355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD200R1 signaling is regulated by PPAR-γ; the PPAR-γ endogenous ligand 15d-PGJ2 prevented CD200R1 downregulation in reactive glial cells and abrogated reactive-microglia-induced neurotoxicity through a CD200-CD200R1-dependent mechanism.\",\n      \"method\": \"Mouse primary neuronal and glial cultures; 15d-PGJ2 treatment with LPS/IFN-γ stimulation; neuron-microglia cocultures; CD200R1 expression by qPCR/western blot\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacologic and blocking-antibody approaches with functional readouts, single lab\",\n      \"pmids\": [\"24639050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"23ME-00610, a humanized antibody targeting CD200R1, blocked CD200 binding and inhibited recruitment of DOK2 (the downstream adaptor); it induced T-cell cytokine production and enhanced T cell-mediated tumor cell killing in vitro and inhibited tumor growth in vivo.\",\n      \"method\": \"Binding affinity measurement (KD <0.1 nM); DOK2 recruitment assay; T-cell killing assays; S91 melanoma mouse model\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding and DOK2 recruitment mechanistic data with in vitro and in vivo functional validation\",\n      \"pmids\": [\"37288324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD200R expressed on CAR T cells, when engaged by CD200 on myeloma cells, suppresses CAR T-cell polyfunctionality, proliferation, and metabolism. A CD200R-CD28 switch receptor converted CD200-mediated inhibitory signaling into CD28 co-stimulatory signaling, potently enhancing CAR T-cell cytotoxicity and metabolic fitness; CD200R knockout was detrimental to CAR T-cell activity, adversely affecting metabolism.\",\n      \"method\": \"CRISPR-Cas9 CD200R knockout; CD200R-CD28 switch receptor engineering; CAR T-cell functional and metabolic assays; murine xenograft plasmacytoma models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — CRISPR KO, receptor engineering, multiple functional/metabolic readouts, in vivo models\",\n      \"pmids\": [\"37616575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Stress reduces CD200R expression in hippocampus and amygdala microglia; C/EBPβ (induced by stress) is inversely associated with CD200R expression; soluble CD200Fc administered intracisternally blocked stress-induced microglial priming and the stress-induced increase in hippocampal HMGB1, while CD200R1Fc (decoy receptor) recapitulated stress effects on microglial priming.\",\n      \"method\": \"Acute stressor (inescapable tailshock) in rats; intracisterna magna injection of CD200Fc or CD200R1Fc; hippocampal microglial isolation; ex vivo microglial priming assay; HMGB1 measurement\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacologic gain- and loss-of-function with mechanistic HMGB1 readout, single lab\",\n      \"pmids\": [\"29104062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Glucocorticoids (GCs) mediate stress-induced reduction of CD200R1 expression in limbic brain microglia; pharmacological GC receptor blockade (RU486) and adrenalectomy with basal corticosterone replacement mitigated stress effects on CD200R1; exogenous corticosterone was sufficient to reduce CD200R1 in vivo and directly in primary microglia cultures.\",\n      \"method\": \"RU486 pharmacological blockade; adrenalectomy with CORT replacement; exogenous CORT administration; primary microglial cultures; CD200R1 expression by western blot/qPCR\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacologic and surgical approaches, single lab\",\n      \"pmids\": [\"31078691\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD200R1 is an inhibitory immunoreceptor expressed on myeloid cells, microglia, and some lymphoid cells that, upon engagement by CD200 (or novel ligands iSEC1/iSEC2), undergoes Src kinase-mediated tyrosine phosphorylation at Y286 and Y297 in its cytoplasmic tail, recruits adaptor proteins Dok1/Dok2, and activates p120-RasGAP to suppress Ras/MAPK and NF-κB signaling; this inhibitory axis can be rewired to proinflammatory signaling by type I IFN-mediated cleavage of p120-RasGAP, its expression is transcriptionally repressed by C/EBPβ/HDAC1 and post-transcriptionally by miR-129-5p, and N-glycosylation at Asn44 is required for CD200 binding.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"CD200R (OX2R) is a novel cell-surface receptor restricted to myeloid lineage cells that binds CD200 (OX2) with a dissociation constant of ~2.5 μM and koff 0.8 s⁻¹; pervanadate treatment showed CD200R can be tyrosine-phosphorylated; antibody blockade of OX2-OX2R interaction exacerbated experimental allergic encephalomyelitis, indicating an inhibitory function in myeloid cell regulation.\",\n      \"method\": \"Surface plasmon resonance (binding kinetics), pervanadate phosphorylation assay, antibody blockade in EAE model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding measurement with kinetics, tyrosine phosphorylation assay, and in vivo functional validation; foundational paper\",\n      \"pmids\": [\"10981966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human CD200R (hCD200R) was characterized and shown to bind hCD200; a closely related gene hCD200RLa was identified. Mouse CD200R-related genes (mCD200RLa–d) were identified; mCD200RLa and mCD200RLb pair with the activatory adaptor DAP12 and do not bind CD200, distinguishing them functionally from the inhibitory CD200R. CD200R is most strongly expressed on macrophages and neutrophils but also on monocytes, mast cells, and T lymphocytes.\",\n      \"method\": \"Quantitative RT-PCR, novel monoclonal antibodies, DAP12 co-precipitation, flow cytometry\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding and co-precipitation with DAP12, replicated across human and mouse; comprehensive receptor family characterization\",\n      \"pmids\": [\"12960329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human herpesvirus 8 K14 protein binds human CD200R with an affinity nearly identical to CD200 (KD ≈ 0.5 μM) and, when expressed on cell surfaces, inhibits TNF-α secretion by activated macrophages—an effect relieved by anti-CD200R mAb or soluble CD200. This demonstrates that CD200R-mediated macrophage suppression occurs via direct cell–cell contact and is mimicked by a viral CD200 homologue.\",\n      \"method\": \"Surface plasmon resonance, cell-surface expression assay, TNF-α secretion assay with blocking antibodies\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — quantitative binding kinetics combined with functional cytokine inhibition and specificity controls\",\n      \"pmids\": [\"15220441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD200R is expressed on mouse and human mast cells; engagement by agonist antibodies or CD200 ligand potently inhibits mast cell degranulation and cytokine secretion in vitro and in vivo without requiring coligation to FcεRI. CD200R does not contain an ITIM, establishing it as a novel inhibitory receptor class on mast cells.\",\n      \"method\": \"Flow cytometry, in vitro degranulation and cytokine secretion assays, in vivo mast cell activation model\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in vitro and in vivo, replicated across species\",\n      \"pmids\": [\"15661892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Site-directed mutagenesis of the three cytoplasmic tyrosines of CD200R (Y286, Y289, Y297) in mouse mast cells showed Y286 and Y297 are the major phosphorylation sites critical for CD200R-mediated inhibition of mast cell activation; Y289 is dispensable. Y297 resides in an NPxY motif. Src family kinases mediate CD200R and Dok phosphorylation.\",\n      \"method\": \"Site-directed mutagenesis, tyrosine phosphorylation assays, mast cell activation assays\",\n      \"journal\": \"Journal of Leukocyte Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis of all three cytoplasmic tyrosines with direct functional readout\",\n      \"pmids\": [\"16330532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In human myeloid (U937) cells, CD200R inhibitory signaling is mediated through the NPLY (NPxY) motif in its cytoplasmic tail. The adaptor Dok2 binds directly to the phosphorylated NPLY motif with ~10-fold higher affinity (KD ~1 μM at 37°C) than Dok1. Dok2 is phosphorylated upon CD200R engagement and recruits RasGAP. RNAi knockdown of Dok2 and RasGAP abolished CD200R-mediated inhibition, while knockdown of Dok1 and SHIP did not, establishing a Dok2→RasGAP pathway as the primary human CD200R signaling mechanism.\",\n      \"method\": \"Cytoplasmic tail mutants, direct binding affinity measurement, RNAi knockdown, co-immunoprecipitation\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding kinetics, multiple RNAi knockdowns, and mutagenesis in human cells; comprehensive mechanistic dissection\",\n      \"pmids\": [\"19786546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD200R-induced phosphorylation of Dok2 precedes Dok1 phosphorylation. Dok2 recruits RasGAP and the adaptor Nck; Dok1 recruits CrkL (and constitutively binds Crk). Knockdown of Dok1 or CrkL increases Dok2 phosphorylation and RasGAP recruitment, indicating that Dok1 negatively regulates Dok2-mediated CD200R inhibitory signaling via CrkL.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation, phosphorylation time-course assays\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple RNAi conditions with co-IP and phosphorylation readouts establishing opposing roles for Dok1 and Dok2\",\n      \"pmids\": [\"21078907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD200 (not normally expressed in myeloid lineage) is strongly upregulated in macrophages at the onset of fusion; CD200R is expressed on osteoclasts and CD4+ T cells. In CD200-knockout mice, osteoclast differentiation is reduced and NF-κB and MAPK signaling downstream of RANK is depressed. A soluble CD200 extracellular domain protein rescued fusion and RANK signaling in CD200-/- macrophages; soluble CD200R extracellular domain or shRNA silencing of CD200R prevented fusion. CD200-/- mice have fewer osteoclasts and accumulate more bone.\",\n      \"method\": \"CD200-/- mouse model, shRNA silencing, recombinant protein rescue, NF-κB/MAPK signaling assays, bone histology\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic knockout, shRNA, and recombinant protein rescue with multiple signaling and phenotypic readouts\",\n      \"pmids\": [\"17726108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mice lacking CD200R1 (CD200R1-/- generated by deletion of exons encoding extracellular domain) showed loss of FACS staining with anti-CD200R1 mAb on myeloid cells/splenocytes, enhanced LPS-stimulated splenic TNF-α production that was not suppressible by CD200Fc, loss of CD200Fc-mediated modulation of alloreactivity dependent on CD200R1+ stimulatory and T responder cells, and failure of CD200Fc to suppress graft rejection. This defines CD200R1 as the essential receptor mediating CD200-induced immunosuppression in vivo.\",\n      \"method\": \"CD200R1-/- mouse generation (ES cell targeting), FACS, LPS-TNF assay, mixed leukocyte culture, skin graft rejection model\",\n      \"journal\": \"Transplantation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean knockout mouse with multiple in vitro and in vivo functional readouts\",\n      \"pmids\": [\"17667818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD200R1-/- macrophages showed 70–75% reduction in IL-6 and CCL5 production in response to TLR2 agonist Pam2CSK4 and to HSV-1. CD200R1-/- macrophages could not upregulate TLR2 expression or assemble a functional inflammasome in response to HSV-1. CD200R1-/- mice were protected from HSV-1 infection and showed dysfunctional TLR2 signaling and markedly reduced ability to support HSV-1 replication. This reveals an unanticipated requirement for CD200R1 in 'licensing' pro-inflammatory TLR2 functions.\",\n      \"method\": \"CD200R1-/- mouse model, cytokine assays, TLR2 expression analysis, inflammasome assembly assay, viral replication assay\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with multiple orthogonal ex vivo and in vivo readouts; unexpected bidirectional role discovered\",\n      \"pmids\": [\"23082204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LPS treatment of microglial cells decreases CD200R1 mRNA and protein expression in a C/EBPβ-dependent manner: C/EBPβ binds the CD200R1 promoter in LPS-treated (but not control) glial cells, and C/EBPβ overexpression alone reduces basal CD200R1 expression. HDAC1 co-immunoprecipitates with C/EBPβ and binds the C/EBPβ consensus sequence in the CD200R1 promoter in LPS-treated cells; HDAC1 inhibitors reverse LPS-induced CD200R1 downregulation. This defines a C/EBPβ/HDAC1 transcriptional repression axis for CD200R1.\",\n      \"method\": \"Primary microglial cultures from wild-type and C/EBPβ-KO mice, BV2 overexpression, quantitative ChIP, co-immunoprecipitation, HDAC inhibitor treatment\",\n      \"journal\": \"Journal of Neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — qChIP for promoter occupancy, co-IP, KO and overexpression with multiple orthogonal methods\",\n      \"pmids\": [\"22776069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PPAR-γ agonist 15d-PGJ2 inhibits the pro-inflammatory response in reactive glial cells and prevents LPS/IFN-γ-induced downregulation of CD200R1 and upregulation of CD200. In neuron-microglia co-cultures, 15d-PGJ2 abrogates reactive-microglia-induced neurotoxicity through a CD200-CD200R1-dependent mechanism, placing PPAR-γ upstream of CD200R1 expression regulation.\",\n      \"method\": \"Primary neuronal and glial cultures, neuron-microglia co-cultures, LPS/IFN-γ stimulation, PPAR-γ agonist treatment, Western blot/qPCR, functional neurotoxicity assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-culture functional assay with pharmacological intervention; CD200R1 dependency inferred but not rescued by CD200R1 re-expression\",\n      \"pmids\": [\"24639050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Exposure to acute stressor reduces CD200R1 expression across hippocampal sub-regions, amygdala, and isolated microglia. The transcriptional suppressor C/EBPβ is induced by stress and inversely correlated with CD200R1 expression. Intracisterna magna administration of soluble CD200 (mCD200Fc) prior to stress blocked stress-induced microglial priming and hippocampal HMGB1 increase; soluble CD200R1Fc recapitulated microglial priming. Glucocorticoids (GCs) mediate stress-induced CD200R1 reduction, as shown by GC receptor blockade (RU486) and adrenalectomy experiments.\",\n      \"method\": \"In vivo stressor exposure, microglia isolation and ex vivo cytokine assay, pharmacological blockade (RU486), adrenalectomy with CORT replacement, intracisterna magna injection\",\n      \"journal\": \"Brain, Behavior, and Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological and surgical interventions in vivo with defined molecular endpoints; single lab\",\n      \"pmids\": [\"29104062\", \"31078691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DNA aptamers that bind murine CD200R1 act as agonists in the absence of exogenous CD200, inducing rapid phosphorylation of the CD200R1 cytoplasmic tail and suppressing CTL induction in allogeneic mixed leukocyte cultures. PEGylated aptamers show in vivo immunosuppression and enhance allogeneic skin graft survival comparably to CD200Fc. Suppression is absent in CD200R1-/- responder cells, confirming direct CD200R1 engagement as the mechanism.\",\n      \"method\": \"SELEX aptamer selection, cytoplasmic tail phosphorylation assay, allogeneic MLC suppression, CD200R1-/- control, in vivo skin graft model\",\n      \"journal\": \"Molecular Therapy. Nucleic Acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phosphorylation assay plus knockout control confirms on-target mechanism; single lab\",\n      \"pmids\": [\"25158092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In the presence of cleaved p120-RasGAP (generated during mild cellular stress or IFN-α treatment), CD200R loses its capacity to inhibit rpS6 phosphorylation (mTORC1 activity). Furthermore, upon IFN-α pretreatment of human PBMCs, CD200R switches from inhibiting to potentiating TLR7/8-induced IFN-γ gene expression. SLE patients with elevated cleaved p120-RasGAP show similar CD200R signaling reversal. This demonstrates that type I IFN rewires CD200R from inhibitory to pro-inflammatory by altering the availability of the downstream effector p120-RasGAP.\",\n      \"method\": \"Human PBMC stimulation assays, p120-RasGAP cleavage analysis, rpS6 phosphorylation (mTORC1 readout), IFN-γ mRNA measurement, SLE patient samples\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays (signaling pathway, cytokine gene expression, patient validation), mechanistic explanation via RasGAP cleavage\",\n      \"pmids\": [\"34637328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"N-glycosylation of CD200R1 at asparagine 44 (Asn44/N44) is required for CD200-CD200R1 interaction; mutation of N44 disrupts CD200 binding and upregulates pro-inflammatory markers iNOS, CD86, IL-1β, and TNF-α in a neuronal-microglia co-culture system.\",\n      \"method\": \"Site-directed mutagenesis of glycosylation site, neuronal-microglia co-culture, cytokine/marker expression assays\",\n      \"journal\": \"Journal of Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of specific glycosylation site with functional readout; single lab, single method\",\n      \"pmids\": [\"30574022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-129-5p is a posttranscriptional repressor of CD200R1: arsenic exposure demethylates the miR-129-5p promoter, increasing its expression, which represses CD200R1 by binding its 3'-UTR and shuttling CD200R1 mRNA to cytoplasmic processing bodies in microglia. Anti-miR-129 injection in mice restores CD200R1 expression and reduces IL-6 and TNF-α. CD200R1 siRNA loss-of-function confirmed an miR-129-5p → CD200R1 → IL-6/TNF-α axis. Findings were replicated in a human cell line and validated in human samples.\",\n      \"method\": \"In silico miRNA target prediction, primary neonatal microglia and BV2 assays, methylation analysis, stereotaxic anti-miR injection in mice, CD200R1 siRNA, human cell line validation\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (methylation, RNA localization, anti-miR in vivo, siRNA loss-of-function, human validation) across mouse and human\",\n      \"pmids\": [\"34952004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD200R engagement activates STAT6 phosphorylation as a downstream effector; STAT6 activation modulates Foxp3 transcription in microglia. CD200R suppression prevents anti-inflammatory microglial phenotype, while Foxp3 overexpression enhances it. CD200R/Foxp3-mediated signaling enhances hippocampal neuronal viability and confers neuroprotection by counteracting iNOS.\",\n      \"method\": \"Excitotoxicity hippocampal neuroinflammation model, CD200R suppression, Foxp3 overexpression, STAT6 phosphorylation assay\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — STAT6 phosphorylation assay with genetic loss/gain of function; single lab\",\n      \"pmids\": [\"27731341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Anti-inflammatory stimulation of CD200R1 after germinal matrix hemorrhage (GMH) in rat pups activates Dok1 downstream: CD200Fc increases Dok1 expression and decreases IL-1β and TNF-α, whereas CD200R1 siRNA or Dok1 siRNA abolishes these effects. This places Dok1 as a downstream mediator of CD200R1 anti-inflammatory signaling in the neonatal brain.\",\n      \"method\": \"Neonatal rat GMH model, intracerebroventricular CD200Fc, siRNA knockdown of CD200R1 and Dok1, Western blot for Dok1/cytokines, neurobehavioral assessment\",\n      \"journal\": \"Journal of Cerebral Blood Flow and Metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA loss-of-function for both receptor and downstream effector with cytokine readouts; single lab\",\n      \"pmids\": [\"28792282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD200R expressed on ILC2s inhibits their activation, proliferation, and type 2 cytokine production upon engagement; mechanistically, CD200R engagement inhibits both canonical and non-canonical NF-κB signaling pathways in activated ILC2s. CD200R is also expressed on human ILC2s, and its engagement in humanized mouse models ameliorates airway hyperreactivity.\",\n      \"method\": \"Mouse and human ILC2 flow cytometry, CD200R engagement assays, NF-κB signaling pathway analysis, in vivo AHR models (preventative and therapeutic)\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined signaling pathway (NF-κB) with in vitro and in vivo validation across mouse and human\",\n      \"pmids\": [\"33953190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A humanized anti-CD200R1 antibody (23ME-00610) blocks CD200 binding to CD200R1 and inhibits recruitment of the downstream adaptor protein DOK2, inducing T-cell cytokine production and enhancing T cell-mediated tumor cell killing in vitro; it inhibits tumor growth in an S91 melanoma model in vivo. Genome-wide association data identified CD200, CD200R1, and DOK2 as a linked immune checkpoint pathway.\",\n      \"method\": \"High-affinity antibody binding assay (KD <0.1 nM), DOK2 recruitment inhibition assay, T cell cytokine/killing assays, syngeneic tumor model\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — DOK2 recruitment assay and T cell functional assays confirm mechanism; in vivo validation in single tumor model\",\n      \"pmids\": [\"37288324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD200Fc (CD200R1 agonist) in human renal proximal tubular epithelial cells inhibits LPS-induced TLR4 expression and its adapter interactions (MyD88 and phospho-TAK1), abolishes TLR4-MyD88 and TLR4-TAK1 co-immunoprecipitation, and attenuates downstream IκB phosphorylation, NF-κB-p65 nuclear translocation, and ERK1/2/p38/JNK phosphorylation, as well as pro-inflammatory mediator release.\",\n      \"method\": \"Co-immunoprecipitation, NF-κB nuclear translocation assay, Western blot for phosphorylated signaling intermediates, ELISA for cytokines\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling pathway readouts and co-IP; single lab, non-myeloid cell type\",\n      \"pmids\": [\"25791482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Novel CD200 homologues iSEC1 and iSEC2, expressed exclusively by secretory cells of the gastrointestinal epithelium, bind CD200R but not other CD200R family members. Binding of iSEC1 to CD200R on intraepithelial lymphocytes suppresses their cytokine production and cytolytic activity, identifying iSEC1 as a previously unrecognized CD200R ligand in gastrointestinal mucosal immunity.\",\n      \"method\": \"Binding assays across CD200R family members, IEL cytokine and cytolytic activity assays\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ligand-receptor binding specificity across receptor family and functional IEL suppression assays\",\n      \"pmids\": [\"27819346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD200R-deficient neutrophils display significantly reduced reactive oxygen species (ROS) production; in vivo, CD200R deficiency increases bacterial burden in neutrophils and enhances colonization by Francisella tularensis. Depletion of the neutrophil niche in CD200R-/- mice restores bacterial burden to wild-type levels. This establishes that CD200R promotes antimicrobial ROS production in neutrophils to limit intracellular bacterial proliferation.\",\n      \"method\": \"CD200R-/- mouse model, ROS production assay, in vitro and in vivo infection assays, neutrophil depletion\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with mechanistic ROS assay and rescue by neutrophil depletion in vivo\",\n      \"pmids\": [\"31073183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD200R1 knockout in CAR T cells is detrimental to their metabolic fitness and activity, while a CD200R-CD28 switch receptor (replacing CD200R cytoplasmic tail with CD28 signaling domain) potently enhances CAR T-cell polyfunctionality, cytotoxicity, proliferation, and metabolic fitness in response to CD200+ multiple myeloma cells in vitro and in xenograft models. CD200R dominant-negative provided modest benefit. This demonstrates that the CD200R cytoplasmic signaling domain determines functional outcome and can be rewired to deliver costimulation.\",\n      \"method\": \"CRISPR-Cas9 knockout, switch receptor engineering, in vitro co-culture killing assays, metabolic assays, murine xenograft models of plasmacytoma and disseminated disease\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic knockout vs. engineered switch receptor comparison with multiple orthogonal assays and in vivo validation\",\n      \"pmids\": [\"37616575\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD200R1 is a cell-surface inhibitory receptor on myeloid and lymphoid cells that, upon binding CD200 (or viral CD200 homologues) via its two Ig-like extracellular domains (interaction requiring N-glycosylation at Asn44), undergoes Src-family-kinase-mediated tyrosine phosphorylation at Y286 and Y297 in its cytoplasmic NPxY and juxtamembrane motifs, directly recruiting the adaptor Dok2 (with ~10-fold higher affinity than Dok1), which then recruits RasGAP to suppress Ras/MAPK activation and NF-κB signaling, thereby inhibiting myeloid cell activation, mast cell degranulation, ILC2 type-2 cytokine production, and microglial priming; Dok1/CrkL negatively modulates this pathway, while type I IFN-induced cleavage of p120-RasGAP can switch CD200R1 from inhibitory to pro-inflammatory, and CD200R1 expression is transcriptionally repressed by C/EBPβ/HDAC1 and post-transcriptionally by miR-129-5p under inflammatory conditions.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CD200R1 is an inhibitory immunoreceptor on myeloid cells, microglia, innate lymphoid cells, and T cells that transduces a tonic anti-inflammatory signal upon engagement by its ligands CD200, iSEC1, and iSEC2. Ligand binding, which requires N-glycosylation at Asn44, triggers Src-family-kinase-dependent phosphorylation of cytoplasmic tyrosines Y286 and Y297, recruitment of adaptors Dok1/Dok2, and activation of p120-RasGAP, thereby suppressing Ras/MAPK, NF-κB, and mTORC1 signaling and dampening pro-inflammatory cytokine production, ROS generation, and alloimmune responses [PMID:16330532, PMID:17667818, PMID:34637328, PMID:30574022]. Type I IFN-induced cleavage of p120-RasGAP rewires CD200R1 from inhibitory to proinflammatory output, potentiating IFN-γ production—a mechanism operative in systemic lupus erythematosus [PMID:34637328]. CD200R1 expression is transcriptionally repressed by a C/EBPβ–HDAC1 complex under inflammatory or stress conditions and post-transcriptionally silenced by miR-129-5p, and its engagement on tumor-infiltrating myeloid cells induces cathepsin K to promote metastasis, while on CAR T cells it suppresses polyfunctionality and metabolism [PMID:22776069, PMID:34952004, PMID:34183355, PMID:37616575].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that CD200 is the shared ligand for the CD200R family resolved which receptor–ligand pair mediates immune suppression and showed that functional consequences differ between family members, with CD200R1 most potently suppressing CTL responses.\",\n      \"evidence\": \"FACS binding of FITC-CD200Fc to COS7 cells transfected with CD200R1–R4; cytokine and CTL assays\",\n      \"pmids\": [\"15187158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Affinities of CD200 for individual receptor family members not quantified\", \"Structural basis of ligand selectivity unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Systematic mutagenesis of the CD200R1 cytoplasmic tail identified Y286 and Y297 as the phosphorylation sites essential for inhibitory signaling and showed that Dok1/Dok2 recruitment links receptor engagement to Ras/MAPK suppression, defining the proximal signaling cascade.\",\n      \"evidence\": \"Site-directed mutagenesis in mouse mast cells; functional inhibition assays\",\n      \"pmids\": [\"16330532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the specific Src family kinase(s) phosphorylating Y286/Y297 not determined\", \"Crystal structure of the cytoplasmic domain–Dok complex lacking\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"CD200R1 knockout mice demonstrated that CD200R1 is the non-redundant receptor required for CD200-mediated suppression of myeloid activation and alloreactivity, and separately that CD200–CD200R1 signaling controls osteoclast differentiation through NF-κB and MAPK.\",\n      \"evidence\": \"CD200R1-null mice with LPS stimulation, MLCs, skin graft rejection; CD200-null mice with bone histomorphometry and shRNA\",\n      \"pmids\": [\"17667818\", \"17726108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD200R1 signals cell-autonomously in osteoclasts versus via macrophage-derived factors not resolved\", \"Contributions of CD200R2–R4 in vivo remain undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two parallel discoveries revealed that CD200R1 is not purely inhibitory: it is required for TLR2-mediated pro-inflammatory signaling and inflammasome assembly in macrophages during HSV-1 infection, and its expression in microglia is actively repressed by C/EBPβ–HDAC1 under inflammatory conditions, establishing a feedback loop.\",\n      \"evidence\": \"CD200R1-null peritoneal macrophages with TLR2 agonists and HSV-1; ChIP/co-IP of C/EBPβ–HDAC1 on CD200R1 promoter in microglia\",\n      \"pmids\": [\"23082204\", \"22776069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD200R1 enables TLR2 signaling mechanistically (direct interaction vs indirect) unclear\", \"Whether HDAC1 recruitment is the sole mechanism of transcriptional repression unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CD200R1 signaling was shown to inhibit the full TLR4–MyD88–TAK1–NF-κB/MAPK cascade, and agonist aptamers confirmed that receptor tail phosphorylation is sufficient to trigger inhibitory signaling and prolong allograft survival.\",\n      \"evidence\": \"CD200Fc treatment of hRPTECs with pathway western blots; aptamer SELEX with CD200R1-null controls and in vivo graft model\",\n      \"pmids\": [\"25791482\", \"25158092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TAK1 is a direct target of Dok/RasGAP or indirectly affected not determined\", \"Aptamer pharmacokinetics and off-target effects in vivo incompletely characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CD200R1 was found to have novel ligands (iSEC1/iSEC2) that selectively bind CD200R1 and suppress mucosal lymphocyte function, and a downstream STAT6–Foxp3 axis in microglia was identified, broadening both the ligand repertoire and downstream effector pathways.\",\n      \"evidence\": \"Recombinant iSEC1/iSEC2 binding and IEL functional assays; STAT6 phosphorylation and Foxp3 overexpression in microglia\",\n      \"pmids\": [\"27819346\", \"27731341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts where iSEC1/iSEC2 predominate over CD200 unknown\", \"Connection between Dok/RasGAP axis and STAT6 phosphorylation not clarified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Stress and C/EBPβ induction were shown to reduce CD200R1 in brain microglia, and pharmacologic CD200Fc delivery blocked stress-induced microglial priming, establishing the CD200–CD200R1 axis as a regulator of neuroimmune reactivity to psychological stress.\",\n      \"evidence\": \"Rat acute stressor model; intracisterna magna CD200Fc/CD200R1Fc injection; hippocampal microglial isolation and priming assay\",\n      \"pmids\": [\"29104062\", \"28792282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether stress-induced CD200R1 downregulation is neuron- or microglia-autonomous not resolved\", \"Direct C/EBPβ ChIP at CD200R1 promoter in stressed brain not performed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"N-glycosylation at Asn44 was shown to be required for CD200 binding to CD200R1, providing the first post-translational determinant of ligand engagement and explaining why loss of this modification triggers microglial activation.\",\n      \"evidence\": \"Asn44 site-directed mutagenesis; neuronal–microglia co-culture with cytokine readouts\",\n      \"pmids\": [\"30574022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full glycosylation map of CD200R1 ectodomain not available\", \"Structural basis of Asn44 glycan contribution to binding interface not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies expanded CD200R1's functional scope: glucocorticoids were identified as upstream hormonal regulators that reduce CD200R1 in brain microglia, and CD200R1 was shown to promote antimicrobial ROS production in neutrophils, challenging its purely inhibitory classification.\",\n      \"evidence\": \"Adrenalectomy/RU486/exogenous CORT with CD200R1 expression in microglia; CD200R1-null neutrophils with F. tularensis infection and ROS quantification\",\n      \"pmids\": [\"31078691\", \"31073183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CD200R1 promotes ROS in neutrophils not identified\", \"Whether glucocorticoid effect on CD200R1 is direct (GRE) or via C/EBPβ not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The discovery that type I IFN–induced cleavage of p120-RasGAP switches CD200R1 from inhibitory to proinflammatory output (potentiating IFN-γ) revealed a rewiring mechanism operative in SLE, fundamentally altering the view of CD200R1 as a constitutively inhibitory receptor.\",\n      \"evidence\": \"IFN-α-treated PBMCs; western blot for cleaved p120-RasGAP; TLR7/8 stimulation; SLE patient cells\",\n      \"pmids\": [\"34637328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for p120-RasGAP cleavage not identified\", \"Whether rewiring occurs in tissue-resident macrophages beyond blood monocytes unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CD200R1 was shown to suppress ILC2 activation via both canonical and non-canonical NF-κB pathways, its expression was post-transcriptionally repressed by miR-129-5p, and tumor-expressed CD200 was found to induce cathepsin K in CD200R+ myeloid cells to promote metastasis, revealing context-dependent outputs.\",\n      \"evidence\": \"ILC2 functional/NF-κB assays; miR-129-5p 3′-UTR targeting with anti-miR rescue in microglia; RNAseq of tumor-infiltrating CD200R+ myeloid cells with Ctsk inhibition in vivo\",\n      \"pmids\": [\"33953190\", \"34952004\", \"34183355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ILC2 inhibition uses Dok/RasGAP pathway not tested\", \"miR-129-5p regulation of CD200R1 not confirmed outside CNS\", \"Whether cathepsin K induction requires Dok signaling unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Engineering studies showed that CD200R1 on CAR T cells suppresses polyfunctionality, proliferation, and metabolism upon CD200 engagement, but a CD200R–CD28 switch receptor converted inhibitory into co-stimulatory signaling, while simple CD200R knockout was detrimental—revealing that tonic CD200R signaling supports baseline T-cell fitness.\",\n      \"evidence\": \"CRISPR-Cas9 CD200R KO; CD200R–CD28 chimeric receptor; CAR T-cell functional/metabolic assays; xenograft models\",\n      \"pmids\": [\"37616575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CD200R supports baseline T-cell metabolism undefined\", \"Whether switch receptor approach applies to solid tumor CAR T cells not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the identity of the protease cleaving p120-RasGAP downstream of type I IFN; the structural basis of the CD200R1 ectodomain–CD200 interface and glycan contributions; how CD200R1 promotes ROS in neutrophils despite suppressing activation in myeloid cells; and whether the Dok-independent STAT6 pathway operates in parallel or is downstream of the canonical cascade.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Protease for p120-RasGAP cleavage unidentified\", \"No co-crystal structure of CD200R1–CD200\", \"Mechanism of neutrophil ROS promotion unknown\", \"Integration of STAT6 and Dok/RasGAP branches not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 9, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 13, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 4, 8, 9, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 9, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CD200\",\n      \"DOK1\",\n      \"DOK2\",\n      \"RASA1\",\n      \"CEBPB\",\n      \"HDAC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"CD200R1 is an inhibitory immunoreceptor on myeloid and lymphoid cells that restrains inflammatory activation upon engagement by CD200 or its homologues. Ligation triggers Src-family-kinase-dependent phosphorylation of cytoplasmic tyrosines Y286 and Y297 (the latter within an NPxY motif), directly recruiting the adaptor Dok2, which in turn recruits RasGAP to suppress Ras/MAPK and NF-κB signaling, thereby inhibiting macrophage TNF-α secretion, mast cell degranulation, ILC2 cytokine production, and microglial priming [PMID:19786546, PMID:16330532, PMID:33953190, PMID:15661892]. CD200R1 expression is transcriptionally repressed by a C/EBPβ/HDAC1 complex under inflammatory conditions and post-transcriptionally by miR-129-5p, while type I interferon-induced cleavage of p120-RasGAP can switch CD200R1 signaling from inhibitory to pro-inflammatory, as observed in systemic lupus erythematosus [PMID:22776069, PMID:34952004, PMID:34637328]. Beyond classical inhibition, CD200R1 is required for neutrophil ROS production limiting intracellular bacterial proliferation and for TLR2-dependent inflammasome assembly during herpesvirus infection, revealing context-dependent pro-host-defense functions [PMID:31073183, PMID:23082204].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of CD200R as the myeloid-restricted receptor for CD200 resolved how CD200 delivers its immunosuppressive signal, establishing binding affinity (~2.5 µM), tyrosine-phosphorylation potential, and in vivo inhibitory function in EAE.\",\n      \"evidence\": \"Surface plasmon resonance, pervanadate phosphorylation, and antibody blockade in murine EAE model\",\n      \"pmids\": [\"10981966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling intermediates unknown\", \"Cytoplasmic phosphorylation sites not mapped\", \"Expression on non-myeloid lineages not fully characterized\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Characterization of the CD200R gene family in human and mouse distinguished the inhibitory CD200R1 (which binds CD200) from activating CD200R-like receptors (which pair with DAP12 and do not bind CD200), clarifying receptor–ligand specificity within the family.\",\n      \"evidence\": \"DAP12 co-precipitation, quantitative RT-PCR, flow cytometry across human and mouse\",\n      \"pmids\": [\"12960329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway downstream of CD200R1 still unresolved\", \"Human CD200R family members less characterized than mouse\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that the viral CD200 homologue HHV-8 K14 engages CD200R with near-native affinity to suppress macrophage TNF-α established that pathogens exploit this checkpoint and confirmed the contact-dependent inhibitory mechanism.\",\n      \"evidence\": \"Surface plasmon resonance for K14–CD200R binding, TNF-α secretion assay with anti-CD200R blocking antibody\",\n      \"pmids\": [\"15220441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling events downstream of viral ligand engagement not compared to endogenous CD200\", \"Scope of viral mimicry across herpesviruses not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Systematic mutagenesis of the three cytoplasmic tyrosines identified Y286 and Y297 (NPxY motif) as the critical phosphorylation sites for CD200R-mediated mast cell inhibition, and showed Src-family kinases mediate this phosphorylation, defining the proximal signaling code.\",\n      \"evidence\": \"Site-directed mutagenesis of Y286/Y289/Y297, phosphorylation and mast cell degranulation assays\",\n      \"pmids\": [\"16330532\", \"15661892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the adaptor recruited to phospho-NPxY not yet determined\", \"Relative contribution of each tyrosine in non-mast-cell lineages unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Generation of CD200R1-knockout mice proved CD200R1 is the essential receptor for CD200-mediated immunosuppression in vivo, as CD200Fc failed to suppress allograft rejection or modulate alloreactivity in CD200R1−/− animals, while a separate study revealed an unexpected positive role for CD200–CD200R in osteoclast fusion and RANK signaling.\",\n      \"evidence\": \"CD200R1−/− mouse model with skin graft rejection, MLR, LPS-TNF assay; CD200−/− mice with osteoclast differentiation/bone histology and recombinant protein rescue\",\n      \"pmids\": [\"17667818\", \"17726108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CD200R1 promotes RANK signaling in osteoclasts is unclear\", \"Possible CD200R1-independent effects of CD200 not fully excluded\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of Dok2 as the primary adaptor directly binding the phosphorylated NPxY motif, with ~10-fold higher affinity than Dok1, and its downstream recruitment of RasGAP, established the core inhibitory signaling cascade (CD200R1→Dok2→RasGAP) in human myeloid cells.\",\n      \"evidence\": \"Direct binding affinity measurements, RNAi knockdown of Dok2/RasGAP vs Dok1/SHIP, co-immunoprecipitation in U937 cells\",\n      \"pmids\": [\"19786546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Dok2 selectivity over Dok1 for the NPxY motif unknown\", \"Whether RasGAP enzymatic activity is the sole effector not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that Dok1/CrkL negatively regulates CD200R1 signaling by competing with Dok2 for receptor access revealed an internal rheostat that tunes the inhibitory output, explaining why Dok1 knockdown paradoxically enhances inhibition.\",\n      \"evidence\": \"RNAi knockdown of Dok1/CrkL, phosphorylation time-course, co-immunoprecipitation\",\n      \"pmids\": [\"21078907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometric model of Dok1 vs. Dok2 competition not quantified\", \"Role of Nck recruitment by Dok2 functionally undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two parallel discoveries reshaped understanding: (1) C/EBPβ and HDAC1 were shown to co-occupy the CD200R1 promoter upon LPS stimulation, defining the transcriptional repression mechanism that silences CD200R1 during inflammation; (2) CD200R1−/− macrophages failed to upregulate TLR2 or assemble inflammasomes upon HSV-1 infection, revealing an unexpected pro-inflammatory licensing role.\",\n      \"evidence\": \"Quantitative ChIP, co-IP of C/EBPβ/HDAC1, HDAC inhibitor rescue in microglia; CD200R1−/− macrophage cytokine/TLR2/inflammasome assays and in vivo HSV-1 infection\",\n      \"pmids\": [\"22776069\", \"23082204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin remodeling mechanism by HDAC1 at CD200R1 locus not resolved\", \"How CD200R1 licenses TLR2 expression mechanistically is unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of gastrointestinal epithelial CD200 homologues iSEC1/iSEC2 as additional CD200R ligands expanded the ligand repertoire beyond CD200, with functional suppression of intraepithelial lymphocytes demonstrating mucosal immune regulation.\",\n      \"evidence\": \"Binding assays across CD200R family, IEL cytokine and cytolytic activity assays\",\n      \"pmids\": [\"27819346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of iSEC1–CD200R interaction vs. CD200–CD200R not compared\", \"In vivo role of iSEC ligands in gut homeostasis not tested with genetic models\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Acute stress was shown to downregulate CD200R1 in brain regions via glucocorticoid-induced C/EBPβ, and soluble CD200Fc delivery blocked stress-induced microglial priming, linking neuroendocrine regulation to the CD200–CD200R1 checkpoint in the CNS.\",\n      \"evidence\": \"In vivo stressor model, microglia isolation, RU486 blockade, adrenalectomy with corticosterone replacement, intracisterna magna CD200Fc injection\",\n      \"pmids\": [\"29104062\", \"31078691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether glucocorticoid receptor acts directly on CD200R1 promoter or indirectly through C/EBPβ not distinguished\", \"Translational relevance to human stress responses not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"N-glycosylation at Asn44 was shown to be required for CD200 binding; its mutation abolished the interaction and de-repressed microglial pro-inflammatory markers, pinpointing a post-translational determinant of receptor competence.\",\n      \"evidence\": \"Site-directed mutagenesis of N44 glycosylation site, neuronal-microglia co-culture functional assay\",\n      \"pmids\": [\"30574022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other glycosylation sites not systematically tested\", \"Crystal structure of glycosylated CD200R–CD200 complex unavailable\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"CD200R-deficient neutrophils displayed reduced ROS production and increased intracellular bacterial burden in Francisella infection, and neutrophil depletion rescued the phenotype, establishing a non-classical pro-defense role for CD200R in innate antimicrobial killing.\",\n      \"evidence\": \"CD200R−/− mouse model, ROS assay, in vivo Francisella tularensis infection, neutrophil depletion rescue\",\n      \"pmids\": [\"31073183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking CD200R signaling to NADPH oxidase activation unknown\", \"Whether this extends to other intracellular pathogens not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Three key advances emerged: (a) type I IFN-induced cleavage of p120-RasGAP switches CD200R from inhibitory to pro-inflammatory, explaining the paradoxical IFN-γ potentiation seen in SLE patients; (b) miR-129-5p was identified as a post-transcriptional repressor targeting CD200R1 3′-UTR, silenceable by anti-miR in vivo; (c) CD200R engagement inhibits both canonical and non-canonical NF-κB in ILC2s, expanding the receptor's scope to innate lymphoid regulation of type-2 immunity.\",\n      \"evidence\": \"Human PBMC signaling assays with p120-RasGAP cleavage analysis and SLE patient samples; primary microglia miR-129-5p/anti-miR experiments with methylation analysis; mouse and human ILC2 NF-κB pathway analysis with in vivo AHR models\",\n      \"pmids\": [\"34637328\", \"34952004\", \"33953190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for p120-RasGAP cleavage during IFN signaling not identified\", \"Whether miR-129-5p regulation operates in non-CNS tissues not determined\", \"Structural basis of CD200R non-canonical NF-κB inhibition unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A therapeutic anti-CD200R1 blocking antibody confirmed the CD200–CD200R1–DOK2 axis as an immune checkpoint in cancer: antibody blockade prevented DOK2 recruitment, enhanced T cell cytotoxicity, and suppressed tumor growth, linking GWAS-identified pathway genes to a druggable target.\",\n      \"evidence\": \"Humanized antibody binding/DOK2 recruitment assays, T cell killing assays, S91 melanoma syngeneic model, GWAS data\",\n      \"pmids\": [\"37288324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Efficacy across diverse tumor types not shown\", \"Biomarkers for patient selection not defined\", \"Whether combination with other checkpoint inhibitors is synergistic not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of Dok2 selectivity for the CD200R1 NPxY motif, the protease mediating IFN-induced p120-RasGAP cleavage that switches CD200R1 output, the mechanism linking CD200R1 to neutrophil NADPH oxidase activation, and whether the inhibitory-to-activating switch operates in tissue-resident macrophage subsets beyond PBMCs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of CD200R1 cytoplasmic domain with Dok2\", \"Protease identity for p120-RasGAP cleavage unknown\", \"CD200R1 signaling in tissue-specific macrophage subsets incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3, 4, 5, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 14, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 5, 8, 19, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 6, 14, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD200\", \"DOK2\", \"DOK1\", \"RASA1\", \"CRKL\", \"NCK1\"],\n    \"other_free_text\": []\n  }\n}\n```"}