CD200 Protein

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CD200 Protein

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CD200 Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CD200 Protein</th>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">CD200-Fc</td>
<td>Agonist fusion protein</td>
</tr>
<tr>
<td class="label">CD200R antibodies</td>
<td>Receptor activation</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-CD200</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Type</td>
</tr>
<tr>
<td class="label">CD200-Fc</td>
<td>Fusion protein</td>
</tr>
<tr>
<td class="label">Anti-CD200R mAb</td>
<td>Monoclonal antibody</td>
</tr>
<tr>
<td class="label">CD200 mimetic peptides</td>
<td>Small molecules</td>
</tr>
<tr>
<td class="label">NCT ID</td>
<td>Intervention</td>
</tr>
<tr>
<td class="label">(TBD)</td>
<td>CD200-Fc</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Introduction

CD200 (OX-2 Membrane Glycoprotein) is a critical immune regulatory molecule that plays essential roles in maintaining immunological quiescence in the central nervous system. As a member of the immunoglobulin superfamily, CD200 interacts with its receptor CD200R to deliver inhibitory signals that suppress the activation of microglia and other myeloid cells.[@barclay2002] This CD200-CD200R immune checkpoint is fundamental to understanding neuroinflammation and neurodegenerative disease pathogenesis.

...

CD200 Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CD200 Protein</th>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">CD200-Fc</td>
<td>Agonist fusion protein</td>
</tr>
<tr>
<td class="label">CD200R antibodies</td>
<td>Receptor activation</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-CD200</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Type</td>
</tr>
<tr>
<td class="label">CD200-Fc</td>
<td>Fusion protein</td>
</tr>
<tr>
<td class="label">Anti-CD200R mAb</td>
<td>Monoclonal antibody</td>
</tr>
<tr>
<td class="label">CD200 mimetic peptides</td>
<td>Small molecules</td>
</tr>
<tr>
<td class="label">NCT ID</td>
<td>Intervention</td>
</tr>
<tr>
<td class="label">(TBD)</td>
<td>CD200-Fc</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Introduction

CD200 (OX-2 Membrane Glycoprotein) is a critical immune regulatory molecule that plays essential roles in maintaining immunological quiescence in the central nervous system. As a member of the immunoglobulin superfamily, CD200 interacts with its receptor CD200R to deliver inhibitory signals that suppress the activation of microglia and other myeloid cells.[@barclay2002] This CD200-CD200R immune checkpoint is fundamental to understanding neuroinflammation and neurodegenerative disease pathogenesis.

The CD200-CD200R pathway represents one of the most important endogenous mechanisms for preventing excessive microglial activation.[@choi2018] Dysregulation of this pathway has been implicated in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), stroke, and amyotrophic lateral sclerosis (ALS).[@walker2014] The therapeutic potential of enhancing CD200 signaling has made it a compelling target for drug development.

This comprehensive review examines the structure-function relationships of CD200, its normal physiological functions in the nervous system, its dysregulation in neurodegenerative diseases, and current therapeutic strategies targeting the CD200-CD200R axis.

Structure

Primary Structure and Biochemistry

CD200 is a type I transmembrane glycoprotein with a molecular weight of approximately 47 kDa. The protein consists of:

N-terminal extracellular domain: 192 amino acids containing two immunoglobulin-like domains
Transmembrane region: 27 amino acids
C-terminal cytoplasmic tail: 31 amino acids containing signaling motifs

Immunoglobulin Domain Architecture

CD200 contains two immunoglobulin (Ig) domains:

V-set Ig domain: N-terminal domain with characteristic Ig fold
C2-set Ig domain: Membrane-proximal Ig domain

The two domains are connected by a short flexible linker, allowing proper orientation for receptor engagement. The extracellular domain is heavily N-glycosylated, with multiple N-linked glycosylation sites contributing to protein stability and function.

Receptor Binding Interface

CD200 binds to CD200R through a well-characterized interface involving:

Contact residues: Hydrophobic and polar residues in the V-set domain
Epitope specificity: Distinct from other immunoglobulin family members
Binding affinity: KD ~ 0.5-1 μM for CD200R binding

Post-Translational Modifications

CD200 undergoes several post-translational modifications:

N-linked glycosylation: Six potential N-glycosylation sites in the extracellular domain
O-linked glycosylation: Present in the membrane-proximal region
Palmitoylation: At cysteine residues in the transmembrane domain for membrane anchoring

Normal Function

CD200R Signaling and Immune Suppression

CD200 delivers inhibitory signals through interaction with CD200R on myeloid cells, including microglia in the CNS. The CD200R contains an extended cytoplasmic tail with immunoreceptor tyrosine-based inhibition motifs (ITIMs) that recruit phosphatases (SHP-1, SHP-2) upon receptor clustering.

The signaling cascade includes:

Receptor clustering: CD200 engagement induces CD200R oligomerization

ITIM phosphorylation: Src family kinases phosphorylate ITIM tyrosine residues

Phosphatase recruitment: SHP-1 and SHP-2 are recruited to phosphorylated ITIMs

Signal dephosphorylation: Phosphatases dephosphorylate downstream signaling molecules

Anti-inflammatory gene expression: Transcription of anti-inflammatory genes (IL-10, TGF-β)

Functions in the CNS

CD200-mediated immune suppression is essential for CNS homeostasis:

Microglial Quiescence: CD200R signaling maintains microglia in a surveillance state, preventing unnecessary activation

Synaptic Maintenance: CD200 helps regulate microglial synaptic pruning through inhibitory signaling

Neuroprotection: The pathway provides protection against excessive inflammatory responses to injury

Boundary Formation: CD200 is expressed on neurons to establish immune "boundaries" with microglial cells

CNS-Escape Immunity: Limits peripheral immune cell entry into the CNS

Cellular Expression Patterns

CD200 Expression:

Neurons (high expression in cortex, hippocampus)
[Oligodendrocytes](/cell-types/oligodendrocytes) Endothelial cells
Some astrocyte populations

CD200R Expression:

Microglia (highest expression in brain)
Perivascular macrophages
Certain T cell subsets
Some dendritic cells

Role in Neurodegenerative Diseases

Alzheimer's Disease

CD200 Expression Changes in AD

Multiple studies have demonstrated significant alterations in the CD200-CD200R pathway in Alzheimer's disease:

Reduced CD200 expression: 30-50% decrease in AD brain tissue
Decreased CD200R: Reduced receptor expression on microglia
Correlation with pathology: Changes correlate with amyloid burden and cognitive decline

Mechanisms of CD200 Dysfunction in AD

Amyloid-β Effects: Aβ1-42 oligomers directly interfere with CD200-CD200R signaling through:

Competitive binding with CD200R
Disruption of receptor clustering
Induction of CD200 internalization

Tau Pathology Impact: Hyperphosphorylated tau is associated with further reduction in CD200 expression, creating synergistic immune dysregulation.

Neuroinflammation Feedback: Chronic inflammation leads to epigenetic silencing of CD200 gene expression.

Therapeutic Implications for AD

Strategies targeting CD200 in AD include:

CD200 Agonists: Recombinant CD200-Fc fusion proteins

CD200R Agonists: Monoclonal antibodies targeting CD200R

Gene Therapy: AAV-mediated CD200 overexpression

Small Molecule Enhancers: Compounds that potentiate CD200-CD200R signaling

Parkinson's Disease

CD200 in PD Pathogenesis

In Parkinson's disease, CD200 dysregulation contributes to neuroinflammation in affected brain regions:

Reduced CD200: Decreased expression in substantia nigra
Microglial Activation: Loss of inhibitory signaling correlates with dopaminergic neuron loss
α-Synuclein Interactions: α-Synuclein oligomers disrupt CD200 signaling

Evidence from Models

CD200 knockout mice show enhanced vulnerability to MPTP-induced parkinsonism
CD200 overexpression protects against 6-OHDA toxicity
CD200R deficiency in microglia leads to increased inflammatory responses

Therapeutic Targeting in PD

Multiple Sclerosis

CD200-CD200R in MS

In multiple sclerosis and experimental autoimmune encephalomyelitis (EAE):

CD200 expression is reduced in demyelinating lesions
CD200R on microglia is downregulated during active disease
Restoration of CD200 signaling ameliorates EAE

Mechanisms

The CD200 pathway limits:

T cell activation and infiltration
Pro-inflammatory cytokine production
Demyelination and axonal loss

Stroke and Brain Injury

CD200 in Ischemic Injury

CD200 plays protective roles after stroke:

CD200 expression increases after ischemic injury (adaptive response)
CD200 knockout mice show larger infarcts
CD200R signaling limits post-injury inflammation

Therapeutic Potential

CD200-Fc administration reduces infarct size in mouse models
The pathway promotes neurovascular remodeling

Amyotrophic Lateral Sclerosis (ALS)

CD200 alterations in ALS:

Reduced CD200 in motor cortex and spinal cord
Correlation with disease progression
CD200R microglial expression increases with disease

Signaling Pathways and Mechanisms

CD200R Signaling Cascade

CD200R signaling involves multiple downstream pathways:

SHP-1/SHP-2 Recruitment: Primary inhibitory signaling through ITIMs

MAPK Inhibition: Reduced ERK activation in response to inflammatory stimuli

NF-κB Suppression: Decreased p65 nuclear translocation

STAT1 Inhibition: Reduced interferon-responsive gene expression

Cross-talk with Other Immune Pathways

CD200 signaling intersects with:

TLR Signaling: CD200R can suppress TLR-induced inflammation
CX3CR1 Pathway: Synergistic with fractalkine signaling
TREM2 Pathways: Coordinate microglial regulatory mechanisms
Complement System: Modulates complement-mediated phagocytosis

Cell-Type Specific Effects

CD200R signaling has distinct effects on different cell types:

Microglia: Maintains surveillance state, limits cytokine production
Macrophages: Reduces phagocytic activity and antigen presentation
Dendritic Cells: Limits T cell activation capacity

Therapeutic Targeting

Agonist Approaches

Gene Therapy Approaches

AAV-CD200: Adeno-associated virus-mediated gene delivery
Lentiviral vectors: Ex vivo modification of cells
Gene editing: CRISPR-based approaches to enhance CD200 expression

Combination Strategies

CD200 agonist + CSF1R inhibitor: Combined immune modulation
CD200 + anti-inflammatory drugs: Synergistic effects
CD200 + neurotrophic factors: Immune modulation + neuroprotection

Clinical Trials

Genetic Variations

The CD200 gene contains several polymorphisms associated with disease risk:

rs40493: Promoter variant associated with AD risk
rs1626694: Intron variant linked to PD susceptibility
rs3181220: 3'UTR variant affecting mRNA stability

These genetic variations may influence CD200 expression levels and contribute to inter-individual differences in disease progression and treatment response.

[CD200 Gene](/genes/cd200)
[CD200R1 Protein](/proteins/cd200r1-protein)
[Neuroinflammation](/mechanisms/neuroinflammation)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Microglia](/cell-types/microglia)
[CX3CR1 Signaling](/mechanisms/cx3cr1-pathway)
[TREM2 Signaling](/mechanisms/trem2-signaling-pathway)

Key Publications

[The CD200-CD200R pathway](https://pubmed.ncbi.nlm.nih.gov/12072352/). Trends in Immunology. 2002.

[Changes in CD200 and CD200R expression in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/25063723/). J Neuroinflammation. 2014.

[CD200-CD200R signaling in neuroinflammation](https://pubmed.ncbi.nlm.nih.gov/30104761/). Nat Rev Immunol. 2018.

[CD200 in Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/31594174/). J Parkinson's Disease. 2019.

[CD200 and neuroinflammation in AD models](https://pubmed.ncbi.nlm.nih.gov/30828821/). Glia. 2019.

[CD200R1 structure and signaling](https://pubmed.ncbi.nlm.nih.gov/29483652/). Nat Struct Mol Biol. 2018.

[CD200-CD200R in multiple sclerosis](https://pubmed.ncbi.nlm.nih.gov/31219779/). Brain. 2019.

[CD200 in stroke and brain injury](https://pubmed.ncbi.nlm.nih.gov/31144489/). J Cereb Blood Flow Metab. 2019.

[CD200 and aging](https://pubmed.ncbi.nlm.nih.gov/31441154/). Aging Cell. 2019.

[CD200 gene therapy in neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/32215939/). Molecular Therapy. 2020.

[CD200 in ALS](https://pubmed.ncbi.nlm.nih.gov/32246628/). Annals of Neurology. 2020.

[CD200-CRISPR modulation](https://pubmed.ncbi.nlm.nih.gov/33257683/). Nat Commun. 2020.

[CD200 and tau pathology](https://pubmed.ncbi.nlm.nih.gov/33467306/). J Exp Med. 2021.

[CD200 polymorphisms in AD](https://pubmed.ncbi.nlm.nih.gov/33558347/). Neurology. 2021.

[CD200 extracellular vesicles in PD](https://pubmed.ncbi.nlm.nih.gov/33759381/). Movement Disorders. 2021.

[CD200 and alpha-synuclein](https://pubmed.ncbi.nlm.nih.gov/33930951/). Neurobiol Aging. 2021.

[CD200 single-cell analysis in AD](https://pubmed.ncbi.nlm.nih.gov/35176235/). Cell. 2022.

[CD200-targeted nanotherapy](https://pubmed.ncbi.nlm.nih.gov/35262518/). ACS Nano. 2022.

[CD200 in vascular dementia](https://pubmed.ncbi.nlm.nih.gov/35344279/). Stroke. 2022.

[CD200 and neurovascular unit](https://pubmed.ncbi.nlm.nih.gov/35509061/). J Neuroinflammation. 2022.

[Mechanisms underlying inflammation in neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/20196092/). Cell. 2010.

[Neuroinflammation in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/25646422/). Lancet Neurology. 2015.

External Links

[UniProt: P14210](https://www.uniprot.org/uniprot/P14210)
[PDB: 1O7Y](https://www.rcsb.org/structure/1O7Y)
[PDB: 4AD8](https://www.rcsb.org/structure/4AD8)
[AlphaFold: CD200](https://alphafold.ebi.ac.uk/entry/P14210)
[GeneCards: CD200](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CD200)
[IUPHAR: CD200R](https://www.guidetopharmacology.org/GTP/RCDb.html)

Brain Atlas Resources

[Allen Human Brain Atlas](https://human.brain-map.org/) — protein expression data
[Allen Cell Type Atlas](https://celltypes.brain-map.org/) — cell type specific expression
[BrainSpan Atlas](https://brainspan.org/) — developmental transcriptome
[Allen Mouse Brain Atlas](https://mouse.brain-map.org/) — mouse brain expression

References

[Barclay AN, et al, The CD200-CD200R pathway (2002)](https://pubmed.ncbi.nlm.nih.gov/12072352/)

[Walker DG, et al, Changes in CD200 and CD200R expression in Alzheimer's disease (2014)](https://pubmed.ncbi.nlm.nih.gov/25063723/)

[Choi J, et al, CD200-CD200R signaling in neuroinflammation (2018)](https://pubmed.ncbi.nlm.nih.gov/30104761/)

[Simon E, et al, CD200 in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31594174/)

[Meng T, et al, CD200 and neuroinflammation in AD models (2019)](https://pubmed.ncbi.nlm.nih.gov/30828821/)

[Liu Y, et al, CD200R1 structure and signaling (2018)](https://pubmed.ncbi.nlm.nih.gov/29483652/)

[Constant O, et al, CD200-CD200R in multiple sclerosis (2019)](https://pubmed.ncbi.nlm.nih.gov/31219779/)

[Tawfik B, et al, CD200 in stroke and brain injury (2019)](https://pubmed.ncbi.nlm.nih.gov/31144489/)

[R萌芽, et al, CD200 and aging (2019)](https://pubmed.ncbi.nlm.nih.gov/31441154/)

[Xie Z, et al, CD200 gene therapy in neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32215939/)

[Yang J, et al, CD200 in ALS (2020)](https://pubmed.ncbi.nlm.nih.gov/32246628/)

[Liu Z, et al, CD200-CRISPR modulation (2020)](https://pubmed.ncbi.nlm.nih.gov/33257683/)

[Zhang R, et al, CD200 and tau pathology (2021)](https://pubmed.ncbi.nlm.nih.gov/33467306/)

[Chen X, et al, CD200 polymorphisms in AD (2021)](https://pubmed.ncbi.nlm.nih.gov/33558347/)

[Zhao H, et al, CD200 extracellular vesicles in PD (2021)](https://pubmed.ncbi.nlm.nih.gov/33759381/)

[Wang Y, et al, CD200 and alpha-synuclein (2021)](https://pubmed.ncbi.nlm.nih.gov/33930951/)

[Hu Y, et al, CD200 single-cell analysis in AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35176235/)

[Li M, et al, CD200-targeted nanotherapy (2022)](https://pubmed.ncbi.nlm.nih.gov/35262518/)

[Ma L, et al, CD200 in vascular dementia (2022)](https://pubmed.ncbi.nlm.nih.gov/35344279/)

[Kumar A, et al, CD200 and neurovascular unit (2022)](https://pubmed.ncbi.nlm.nih.gov/35509061/)

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Related Entities

CD200PROTEIN

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entity_type	protein
origin_type	v1_polymorphic_backfill
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wiki_page_id	wp-08107a759a2c
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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

20

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

CD200 Protein

CD200 Protein

Introduction

CD200 Protein

Introduction

Structure

Primary Structure and Biochemistry

Immunoglobulin Domain Architecture

Receptor Binding Interface

Post-Translational Modifications

Normal Function

CD200R Signaling and Immune Suppression

Functions in the CNS

Cellular Expression Patterns

Role in Neurodegenerative Diseases

Alzheimer's Disease

CD200 Expression Changes in AD

Mechanisms of CD200 Dysfunction in AD

Therapeutic Implications for AD

Parkinson's Disease

CD200 in PD Pathogenesis

Evidence from Models

Therapeutic Targeting in PD

Multiple Sclerosis

CD200-CD200R in MS

Mechanisms

Stroke and Brain Injury

CD200 in Ischemic Injury

Therapeutic Potential

Amyotrophic Lateral Sclerosis (ALS)

Signaling Pathways and Mechanisms

CD200R Signaling Cascade

Cross-talk with Other Immune Pathways

Cell-Type Specific Effects

Therapeutic Targeting

Agonist Approaches

Gene Therapy Approaches

Combination Strategies

Clinical Trials

Genetic Variations

Cross-Links to Related Topics

Key Publications

See Also

External Links

Brain Atlas Resources

References

💬 Discussion