TNFRSF1B Gene
Introduction
The TNFRSF1B gene (TNF Receptor Superfamily Member 1B, also known as TNFR2 or p75) encodes a type I membrane receptor for [tumor necrosis factor (TNF)](/proteins/tnf-protein). Unlike TNFR1, TNFR2 primarily mediates neuroprotective and anti-inflammatory signaling in the central nervous system.
Overview
flowchart TD
TNFRSF1B["TNFRSF1B"] -->|"associated with"| Chronic_Pain["Chronic Pain"]
TNFRSF1B["TNFRSF1B"] -->|"associated with"| Cancer["Cancer"]
TNFRSF1B["TNFRSF1B"] -->|"associated with"| Leukemia["Leukemia"]
TNFRSF1B["TNFRSF1B"] -->|"associated with"| Lung_Cancer["Lung Cancer"]
TNFRSF1B["TNFRSF1B"] -->|"activates"| Als["Als"]
TNFRSF1B["TNFRSF1B"] -->|"associated with"| ADAM8["ADAM8"]
TNFRSF1B["TNFRSF1B"] -->|"associated with"| TNF["TNF"]
TNFRSF1B["TNFRSF1B"] -->|"activates"| TNFRSF13C["TNFRSF13C"]
TNFRSF1B["TNFRSF1B"] -->|"activates"| HCRTR1["HCRTR1"]
TNFRSF1B["TNFRSF1B"] -->|"activates"| GRIN3B["GRIN3B"]
TNFRSF1B["TNFRSF1B"] -->|"activates"| CRH["CRH"]
TNFRSF1B["TNFRSF1B"] -->|"activates"| WNT11["WNT11"]
TNFRSF1B["TNFRSF1B"] -->|"activates"| MYO7A["MYO7A"]
TNFRSF1B["TNFRSF1B"] -->|"activates"| CHRM4["CHRM4"]
style TNFRSF1B fill:#4fc3f7,stroke:#333,color:#000
...TNFRSF1B Gene
Introduction
The TNFRSF1B gene (TNF Receptor Superfamily Member 1B, also known as TNFR2 or p75) encodes a type I membrane receptor for [tumor necrosis factor (TNF)](/proteins/tnf-protein). Unlike TNFR1, TNFR2 primarily mediates neuroprotective and anti-inflammatory signaling in the central nervous system.
Overview
Mermaid diagram (expand to render)
The TNFRSF1B gene is located on chromosome 1p36.22 and encodes TNF receptor 2 (TNFR2), a 75 kDa type I transmembrane glycoprotein<sup>[1]</sup>. While [TNFRSF1A](/genes/tnfrsf1a) (TNFR1/p55) is ubiquitously expressed and primarily signals cell death and inflammation, TNFR2 has a restricted expression pattern and promotes cell survival, tissue repair, and immunomodulation<sup>[2]</sup>. In the nervous system, TNFR2 is expressed on [neurons](/entities/neurons), [oligodendrocytes](/cell-types/oligodendrocytes), [microglia](/cell-types/microglia), and [astrocytes](/cell-types/astrocytes), where it mediates neuroprotective TNF signaling<sup>[3]</sup>. [@faustman2010]
<div class="infobox infobox-gene"> [@probert2015]
| | | [@cheng2018]
|---|---| [@mccoy2018]
| Gene Symbol | TNFRSF1B | [@arnett2001]
| Full Name | TNF Receptor Superfamily Member 1B | [@fischer2018]
| Aliases | TNFR2, p75, CD120b, TNFBR |
| Chromosomal Location | 1p36.22 |
| NCBI Gene ID | [7133](https://www.ncbi.nlm.nih.gov/gene/7133) |
| OMIM | [191191](https://omim.org/entry/191191) |
| Ensembl | [ENSG00000028137](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000028137) |
| UniProt | [P20333](https://www.uniprot.org/uniprot/P20333) |
| Associated Diseases | Neurodegeneration, autoimmune diseases, cancer |
</div>
Function
TNF Receptor Signaling
TNFR2 is preferentially activated by transmembrane TNF (tmTNF) rather than soluble TNF, distinguishing it from TNFR1<sup>[1]</sup>:
- [NF-κB](/entities/nf-kb) activation: TNFR2 activates the non-canonical NF-κB pathway via TRAF2/TRAF3, promoting cell survival genes
- PI3K/Akt pathway: Signals through PI3K to activate [Akt](/proteins/akt1-protein), promoting neuronal survival
- JNK modulation: Unlike TNFR1, TNFR2 does not directly activate pro-apoptotic JNK signaling
- No death domain: TNFR2 lacks an intracellular death domain, precluding direct apoptotic signaling
Neuroprotective Functions
In the CNS, TNFR2 mediates several protective mechanisms<sup>[3]</sup>:
- Neuronal survival: Protects neurons from excitotoxicity, oxidative stress, and [amyloid-β](/proteins/amyloid-beta-protein) toxicity
- Oligodendrocyte protection: Essential for [oligodendrocyte](/cell-types/oligodendrocytes) survival and remyelination
- Microglial phenotype: Promotes anti-inflammatory (M2-like) [microglial](/cell-types/microglia) polarization
- Neurogenesis: Stimulates neural progenitor cell proliferation in the [hippocampus](/brain-regions/hippocampus)
- Synaptic plasticity: Modulates synaptic scaling and [long-term potentiation (LTP)](/mechanisms/synaptic-plasticity)
Immune Regulation
TNFR2 plays critical roles in immune homeostasis<sup>[2]</sup>:
- Regulatory T cells (Tregs): TNFR2 is a marker and functional mediator of Tregs; TNFR2 signaling expands Tregs
- Anti-inflammatory resolution: Promotes resolution of inflammation through Treg expansion
- Immune privilege: Contributes to the immune-privileged status of the CNS
Disease Associations
Alzheimer's Disease
TNFR2 is significantly involved in [AD](/diseases/alzheimers-disease) pathobiology<sup>[4]</sup>:
- Protective role: TNFR2 signaling protects neurons from [Aβ](/proteins/amyloid-beta)-induced toxicity
- Microglial phagocytosis: TNFR2 enhances microglial clearance of amyloid plaques
- Genetic associations: TNFRSF1B polymorphisms (e.g., M196R/rs1061622) modify AD risk in some populations
- Therapeutic target: Selective TNFR2 agonists reduce neuroinflammation and amyloid burden in mouse models
Parkinson's Disease
TNFR2 modulates neuroinflammation in [PD](/diseases/parkinsons-disease)<sup>[5]</sup>:
- Dopaminergic neuron protection: TNFR2 signaling protects [substantia nigra](/brain-regions/substantia-nigra) neurons from TNF-mediated death
- α-Synuclein pathology: TNFR2 deficiency exacerbates [α-synuclein](/proteins/alpha-synuclein)-induced neuroinflammation
- Microglial balance: Loss of TNFR2 shifts [microglia](/cell-types/microglia-neuroinflammation) toward neurotoxic phenotype
Multiple Sclerosis and Demyelination
TNFR2 is essential for CNS remyelination<sup>[6]</sup>:
- Oligodendrocyte precursor cells: TNFR2 promotes OPC proliferation and differentiation
- Remyelination: TNFR2 knockout mice show impaired remyelination after demyelinating injury
- Anti-TNF paradox: Explains why anti-TNF therapies (infliximab, etanercept) worsen MS — they block protective TNFR2 signaling
Other Neurological Conditions
- Stroke: TNFR2 signaling is neuroprotective after ischemic injury
- Traumatic brain injury: Promotes tissue repair and limits secondary damage
- Epilepsy: Modulates seizure threshold through synaptic scaling
Common Variants
| Variant | rsID | Effect | Clinical Significance |
|---------|------|--------|----------------------|
| M196R | rs1061622 | Missense (exon 6) | Associated with modified AD risk, altered TNF signaling |
| T676G | rs1061624 | 3'UTR | Influences TNFRSF1B mRNA stability; associations with autoimmune disease |
| A1466G | rs3397 | 3'UTR | Modified receptor expression levels |
| -3609C/T | rs652625 | Promoter | Alters transcriptional activity |
TNFR1 vs. TNFR2: Dual Receptor System
| Feature | TNFR1 ([TNFRSF1A](/genes/tnfrsf1a)) | TNFR2 (TNFRSF1B) |
|---------|------|------|
| Size | 55 kDa | 75 kDa |
| Expression | Ubiquitous | Restricted (immune cells, neurons, endothelium) |
| Ligand preference | Soluble TNF | Transmembrane TNF |
| Death domain | Yes (TRADD/FADD/caspase-8) | No |
| Primary signaling | [Apoptosis](/entities/apoptosis), inflammation | Survival, tissue repair |
| CNS role | Neuroinflammation, neuronal death | Neuroprotection, remyelination |
Expression
TNFRSF1B has a more restricted expression pattern than TNFRSF1A<sup>[1]</sup>:
- Microglia: High expression, upregulated upon activation
- Oligodendrocytes: Constitutive expression important for myelin maintenance
- Neurons: Moderate expression in [hippocampus](/brain-regions/hippocampus), [cortex](/brain-regions/cerebral-cortex), [substantia nigra](/brain-regions/substantia-nigra)
- [Astrocytes](/entities/astrocytes): Inducible expression during neuroinflammation
- Regulatory T cells: High expression — used as Treg marker (CD120b)
- Endothelial cells: [Blood-brain barrier](/entities/blood-brain-barrier) endothelium
Therapeutic Implications
Selective TNFR2 Agonism
A key therapeutic strategy is to selectively activate TNFR2 without engaging TNFR1<sup>[7]</sup>:
- TNFR2-selective agonist antibodies: Promote neuroprotection and Treg expansion without pro-inflammatory TNFR1 activation
- Engineered TNF muteins: Modified TNF molecules that bind only TNFR2
- Soluble TNFR1 blockers: XPro1595 (dominant-negative TNF) selectively blocks soluble TNF/TNFR1 while preserving tmTNF/TNFR2 signaling
Clinical Trials
- XPro1595: Selective soluble TNF inhibitor in Phase 1 trial for [AD](/diseases/alzheimers-disease) — preserves TNFR2 protective signaling
- TNFR2 agonists: Preclinical candidates for MS, AD, and PD
See Also
- [TNFRSF1A Gene](/genes/tnfrsf1a)
- [TNF Protein](/proteins/tnf-protein)
- [Neuroinflammation](/mechanisms/neuroinflammation)
- [Microglia](/cell-types/microglia)
- [NF-κB Signaling](/mechanisms/nf-kb-signaling-neurodegeneration)
External Links
- [TNFRSF1B - NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/7133)
- [TNFRSF1B - UniProt](https://www.uniprot.org/uniprot/P20333)
- [TNFRSF1B - OMIM](https://omim.org/entry/191191)
References
[Wajant H et al., Tumor necrosis factor signaling (2003) (2003)](https://doi.org/10.1038/sj.cdd.4401189)
[Unknown, Faustman D & Davis M, TNF receptor 2 pathway: drug target for autoimmune diseases (2010) (2010)](https://doi.org/10.1038/nrd3030)
[Unknown, Probert L, TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects (2015) (2015)](https://doi.org/10.1016/j.neuroscience.2015.06.038)
[Cheng X et al., TNFR2 pathway modulates amyloid pathology and neuroinflammation in Alzheimer's disease (2018) (2018)](https://doi.org/10.1186/s12974-018-1264-0)
[Unknown, McCoy MK & Bhatt DG, TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease (2018) (2018)](https://doi.org/10.1186/s12974-018-1075-3)
[Arnett HA et al., TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination (2001) (2001)](https://doi.org/10.1038/nn0301_1116)
[Fischer R et al., Selective activation of tumor necrosis factor receptor II induces anti-inflammatory responses and reduces experimental arthritis (2018) (2018)](https://doi.org/10.1002/art.40413)Pathway Diagram
The following diagram shows the key molecular relationships involving TNFRSF1B Gene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)