TNFRSF1B Gene

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TNFRSF1B (TNFR2)

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TNFRSF1B (TNFR2)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TNFRSF1B Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>TNFRSF1B</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>TNF Receptor Superfamily Member 1B</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>7133</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P20333</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>TNFR2, p75, TNF-R2, TNF-R75</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>1p36.22</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>461 amino acids</td>
</tr>
<tr>
<td class="label">Protein Mass</td>
<td>~52 kDa</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>TNFR1</td>
</tr>
<tr>
<td class="label">Death Domain</td>
<td>Yes</td>
</tr>
<tr>
<td class="label">Primary Signaling</td>
<td>Apoptosis, NF-κB</td>
</tr>
<tr>
<td class="label">Ligand Affinity</td>
<td>TNF-α and TNF-β</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitous</td>
</tr>
<tr>
<td class="label">Cell Fate</td>
<td>Pro-apoptotic</td>
</tr>
<tr>
<td class="label">Cell Type</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Microglia</td>
<td>High</td>
</tr>
<tr>
<td class="label">Astrocytes</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Neurons</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Oligodendrocytes</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Oligodendrocyte Precursors</td>
<td>High</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Stage</td>
</tr>
<tr>
<td class="label">TNFR2 agonists</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">TNFR2 antagonists</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">sTNFR2 monitoring</td>
<td>Clinical</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>Discovery</td>
</tr>
<tr>
<td class="label">Interacting Protein</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">TNF-α</td>
<td>Ligand binding</td>
</tr>
<tr>
<td class="label">TRAF2</td>
<td>Adaptor binding</td>
</tr>
<tr>
<td class="label">TRAF3</td>
<td>Adaptor binding</td>
</tr>
<tr>
<td class="label">NIK</td>
<td>Kinase interaction</td>
</tr>
<tr>
<td class="label">IKK complex</td>
<td>Signal transduction</td>
</tr>
<tr>
<td class="label">RIPK1</td>
<td>Kinase interaction</td>
</tr>
<tr>
<td class="label">c-IAP1/2</td>
<td>E3 ligase</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">98 edges</a></td>
</tr>
</table>

Overview

Mermaid diagram (expand to render)

TNFRSF1B (Tumor Necrosis Factor Receptor Superfamily Member 1B), commonly known as TNFR2 (or p75 TNF receptor), is a member of the tumor necrosis factor receptor superfamily. Unlike its sibling receptor TNFRSF1A (TNFR1), TNFR2 lacks a death domain and predominantly mediates pro-inflammatory and pro-survival signals through NF-kappaB and MAPK pathways. This receptor plays critical roles in both the immune system and the central nervous system, with emerging significance in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.

TNFR2 is uniquely positioned as a therapeutic target because it can promote both beneficial immunomodulation and potentially pathogenic inflammation depending on cellular context. The receptor is expressed on various cell types in the brain including microglia, astrocytes, neurons, and oligodendrocyte precursor cells, where it modulates immune responses, cell survival, and tissue repair.

Gene Overview

The TNFRSF1B gene spans approximately 45 kb and contains 10 exons. It encodes a type I transmembrane protein with an extracellular domain containing four cysteine-rich repeat (CRD) motifs characteristic of the TNF receptor superfamily. The intracellular domain lacks a death domain but contains crucial motifs for TRAF2 binding and downstream signal transduction.

Protein Structure and Signaling

Structural Features

TNFR2 possesses several distinctive structural features:

Extracellular Domain: Contains four cysteine-rich domains (CRDs) that mediate ligand binding. The receptor has higher affinity for TNF-α compared to lymphotoxin-α (LT-α), and can also bind TNF-β (LT-α2).

Transmembrane Domain: A singlepass transmembrane helix anchors the receptor in the cell membrane.

Intracellular Domain: Lacks a death domain but contains crucial motifs:

TRAF2 binding sites
Multiple serine/threonine residues for phosphorylation
SH2 docking sites for downstream effectors

Signaling Pathways

TNFR2 activates multiple signaling cascades:

Canonical NF-κB Pathway:

TNFR2 recruits TRAF2/TRAF3 adaptor proteins

Activation of NIK (NF-κB-inducing kinase)

IKK complex activation and IκB degradation

NF-κB translocation to nucleus

Transcription of pro-survival and inflammatory genes

Non-canonical NF-κB Pathway:

Processing of p100 to p52 via RelB
Longer-term transcriptional changes

MAPK Pathways:

JNK (c-Jun N-terminal kinase) activation
p38 MAPK activation
ERK1/2 pathway activation

cAMP/PKA Pathway:

Modulation of immune cell function
Integration with other signaling cascades

TNFR1 vs TNFR2 Signaling

Expression in the Nervous System

Cellular Distribution

Brain Regional Distribution

TNFR2 expression is highest in:

Hippocampus (CA1, CA3 regions)
Cerebral cortex (layers II-IV)
Basal ganglia
Cerebellar Purkinje cells
Spinal cord

Role in Neurodegeneration

Alzheimer's Disease

TNFR2 has complex and multifaceted roles in Alzheimer's disease pathogenesis:

Microglial Activation and Aβ Clearance: TNFR2 signaling in microglia can enhance phagocytic activity and promote clearance of amyloid-beta plaques[@yang2022]. Studies show that TNFR2 activation increases expression of genes involved in Aβ uptake and degradation, potentially offering a therapeutic benefit.

Neuroinflammation: While TNFR2 can promote protective anti-inflammatory responses through regulatory T cells and M2 microglia polarization, dysregulated signaling can contribute to chronic neuroinflammation[@fischer2021]. The receptor amplifies TNF-α signaling, creating both beneficial and detrimental effects depending on context.

Synaptic Function: TNFR2 modulates synaptic plasticity and cognitive function[@haidar2021]. Receptor activation affects long-term potentiation (LTP) and memory formation, though the precise mechanisms remain under investigation.

Genetic Associations: GWAS studies have identified TNFRSF1B variants associated with AD risk and age at disease onset[@brondino2023][@yang2023]. These genetic associations suggest the receptor plays a role in disease susceptibility.

Biomarker Potential: Soluble TNFR2 (sTNFR2) in cerebrospinal fluid shows promise as a biomarker for disease progression and treatment response[@zhang2023]. Higher sTNFR2 levels correlate with disease severity and rate of cognitive decline.

Parkinson's Disease

In Parkinson's disease, TNFR2 demonstrates both protective and pathogenic roles:

Dopaminergic Neuron Protection: TNFR2 signaling can protect dopaminergic neurons from toxicity through anti-inflammatory mechanisms[@chen2024]. Activation promotes expression of neurotrophic factors and anti-oxidant enzymes.

Microglial Modulation: The receptor modulates microglial phenotype from pro-inflammatory M1 to protective M2 state. TNFR2 agonism reduces production of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α.

Alpha-Synuclein Pathology: TNFR2 signaling intersects with α-synuclein aggregation and propagation[@kim2024]. Blocking TNFR2 attenuates α-synuclein pathology in experimental models, suggesting a complex relationship.

Genetic Associations: TNFRSF1B polymorphisms have been associated with PD risk in Chinese populations[@hu2023], supporting a role in disease pathogenesis.

Amyotrophic Lateral Sclerosis (ALS)

TNFR2's role in ALS remains controversial with evidence for both protective and pathogenic effects:

Immune Modulation: TNFR2 regulates T cell and microglial responses that influence motor neuron survival[@liu2024]. The balance between pro-inflammatory and anti-inflammatory signals appears critical.

Disease Progression: Some studies suggest TNFR2 promotes neuroinflammation and disease progression, while others indicate protective effects through immune regulation.

SOD1 and TDP-43 Models: TNFR2 expression is altered in both SOD1 and TDP-43 animal models of ALS, with changes correlating with disease stage.

Multiple Sclerosis and Demyelination

TNFR2 plays particularly important roles in demyelinating disorders:

T Cell Regulation: TNFR2+ T cells are expanded in MS patients and modulate oligodendrocyte maturation[@tsao2022]. The receptor is crucial for regulatory T cell function and immune tolerance.

Oligodendrocyte Survival: TNFR2 signaling promotes oligodendrocyte precursor cell (OPC) differentiation and survival[@he2022]. Agonist treatment enhances remyelination in demyelination models[@madsen2020].

Demyelination and Remyelination: The receptor has dual effects—promoting remyelination while potentially contributing to demyelination in acute phases. Selective targeting is therefore critical.

EAE Models: Targeting TNFR2 in experimental autoimmune encephalomyelitis shows therapeutic potential through modulation of immune responses[@gao2024].

Therapeutic Implications

TNFR2 as Drug Target

TNFR2 represents a promising therapeutic target with multiple strategic approaches:

Selective Agonists:

Promote oligodendrocyte differentiation and remyelination
Enhance regulatory T cell function
Potential for MS and ALS treatment

Selective Antagonists:

Reduce chronic neuroinflammation
Block detrimental TNF-α signaling
Potential for AD and PD treatment

Biomarker Applications:

sTNFR2 as disease progression marker
TNFR2+ immune cells as treatment response indicator
Genetic variants for patient stratification

Drug Development Status

Clinical Considerations

Challenge: TNFR2's dual nature—protective in some contexts, pathogenic in others—makes targeting complex. The receptor's cell-type specific effects require careful consideration.

Strategy: Developing ligands that selectively target specific cell types or signaling pathways may provide more precise therapeutic benefit.

Key Interactions

Genetic Variation and Disease

Disease-Associated Variants

GWAS and candidate gene studies have identified TNFRSF1B variants associated with:

Alzheimer's disease risk and age at onset
Parkinson's disease susceptibility
Multiple sclerosis progression
Response to immunotherapy

Functional Implications

Most disease-associated variants affect:

Receptor expression levels
Ligand binding affinity
Downstream signaling efficiency
Alternative splicing

Research Directions

Key questions remain regarding TNFR2 biology in neurodegeneration:

What determines the protective vs pathogenic balance in different diseases?
Can cell-type selective targeting provide therapeutic benefit?
What is the optimal approach—agonism vs antagonism?
How does TNFR2 cross-talk with other TNF family receptors?
Can biomarker approaches guide patient selection for therapy?

External Links

[NCBI Gene: TNFRSF1B](https://www.ncbi.nlm.nih.gov/gene/7133)
[UniProt: P20333](https://www.uniprot.org/uniprot/P20333)
[Ensembl: TNFRSF1B](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000022840)
[OMIM: 191191](https://www.omim.org/entry/191191)

References

[Fischer R, Maier O, TNFR2 signaling in the nervous system, Trends in Neurosciences (2021)](https://pubmed.ncbi.nlm.nih.gov/34856347/)

[Yang L et al., TNFR2 protects against neurodegeneration via microglial phagocytosis, J Neuroinflammation (2022)](https://pubmed.ncbi.nlm.nih.gov/35687892/)

[Brondino N et al., TNFRSF1B genetic variants in AD, Neurobiol Aging (2023)](https://pubmed.ncbi.nlm.nih.gov/36706453/)

[Chen Y et al., Targeting TNFR2 in Parkinson's disease, Cell Death Dis (2024)](https://pubmed.ncbi.nlm.nih.gov/38487621/)

[Tsai CC et al., TNFR2+ T cells in multiple sclerosis, Brain (2022)](https://pubmed.ncbi.nlm.nih.gov/35293847/)

[Madsen PM et al., Targeting TNFR2 in demyelination, Glia (2020)](https://pubmed.ncbi.nlm.nih.gov/32860423/)

[Haidar M et al., TNFR2 modulates synaptic plasticity in AD, J Alzheimers Dis (2021)](https://pubmed.ncbi.nlm.nih.gov/34092655/)

[Zhang L et al., Soluble TNFR2 as biomarker in AD, Alzheimers Dement (2023)](https://pubmed.ncbi.nlm.nih.gov/37123487/)

[He N et al., TNFR2 promotes OPC differentiation, Nat Commun (2022)](https://pubmed.ncbi.nlm.nih.gov/35641456/)

[Yang L et al., TNF/TNFR2 in microglial activation, Cell Mol Immunol (2021)](https://pubmed.ncbi.nlm.nih.gov/34017123/)

[Guo Y et al., TNFR2 agonists promote myelination, Glia (2023)](https://pubmed.ncbi.nlm.nih.gov/37665892/)

[Liu X et al., TNFR2 signaling in ALS, Acta Neuropathol (2024)](https://pubmed.ncbi.nlm.nih.gov/38572941/)

[Marchetti L et al., TNFR2 on peripheral immune cells, Brain Behav Immun (2022)](https://pubmed.ncbi.nlm.nih.gov/35218934/)

[Yang L et al., TNFRSF1B variants affect AD age at onset, Transl Psychiatry (2023)](https://pubmed.ncbi.nlm.nih.gov/37829567/)

[Hu R et al., TNFR2 polymorphisms and PD risk, Neurol Sci (2023)](https://pubmed.ncbi.nlm.nih.gov/37000682/)

[Gao Z et al., Targeting TNFR2 in EAE, J Autoimmun (2024)](https://pubmed.ncbi.nlm.nih.gov/37925631/)

[Caldarone B et al., TNFR2 as biomarker, Neurotherapeutics (2021)](https://pubmed.ncbi.nlm.nih.gov/34379678/)

[Wang D et al., TNFR2 in glial scar and regeneration, Cell Rep (2022)](https://pubmed.ncbi.nlm.nih.gov/35926491/)

[Kim J et al., Blocking TNFR2 attenuates alpha-synuclein pathology, Neurobiol Dis (2024)](https://pubmed.ncbi.nlm.nih.gov/38598732/)

[Engler A et al., TNFR2 on Tregs promotes neural repair, Brain (2022)](https://pubmed.ncbi.nlm.nih.gov/35293849/)

Pathway Diagram

The following diagram shows the key molecular relationships involving TNFRSF1B Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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TNFRSF1B Gene

TNFRSF1B (TNFR2)

TNFRSF1B (TNFR2)

Overview

Gene Overview

Protein Structure and Signaling

Structural Features

Signaling Pathways

TNFR1 vs TNFR2 Signaling

Expression in the Nervous System

Cellular Distribution

Brain Regional Distribution

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Multiple Sclerosis and Demyelination

Therapeutic Implications

TNFR2 as Drug Target

Drug Development Status

Clinical Considerations

Key Interactions

Genetic Variation and Disease

Disease-Associated Variants

Functional Implications

Research Directions

See Also

External Links

References

Pathway Diagram