LILRB2 — Leukocyte Immunoglobulin-Like Receptor B2

LILRB2 — Leukocyte Immunoglobulin-Like Receptor B2

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">LILRB2 — Leukocyte Immunoglobulin-Like Receptor B2</th>
</tr>
<tr> [@kim2013a]
<td class="label">Symbol</td> [@bhatt2022]
<td><strong>LILRB2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Leukocyte Immunoglobulin-Like Receptor Subfamily B Member 2 (ILT4 / CD85d / LIR-2)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>19q13.42</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/10288" target="_blank">10288</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000131042" target="_blank">ENSG00000131042</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/604815" target="_blank">604815</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q8N423" target="_blank">Q8N423</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Microglia, Macrophages, Monocytes, Dendritic cells, Osteoclasts</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</t

LILRB2 — Leukocyte Immunoglobulin-Like Receptor B2

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">LILRB2 — Leukocyte Immunoglobulin-Like Receptor B2</th>
</tr>
<tr> [@kim2013a]
<td class="label">Symbol</td> [@bhatt2022]
<td><strong>LILRB2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Leukocyte Immunoglobulin-Like Receptor Subfamily B Member 2 (ILT4 / CD85d / LIR-2)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>19q13.42</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/10288" target="_blank">10288</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000131042" target="_blank">ENSG00000131042</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/604815" target="_blank">604815</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q8N423" target="_blank">Q8N423</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Microglia, Macrophages, Monocytes, Dendritic cells, Osteoclasts</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">69 edges</a></td>
</tr>
</table>

LILRB2 — Leukocyte Immunoglobulin-Like Receptor B2

Overview

LILRB2 (Leukocyte Immunoglobulin-Like Receptor Subfamily B Member 2), also known as ILT4, CD85d, or LIR-2, encodes an inhibitory immunoreceptor on chromosome 19q13.42 that has emerged as a critical receptor for [amyloid-beta](/proteins/amyloid-beta) (Abeta) oligomers on [microglia](/cell-types/microglia-neuroinflammation). LILRB2 is the human ortholog of murine PirB (Paired Immunoglobulin-like Receptor B), which was identified as a high-affinity receptor for Abeta oligomers — the most neurotoxic species in [Alzheimer's disease](/diseases/alzheimers-disease)[@kim2013].

LILRB2 is a type I transmembrane glycoprotein containing four immunoglobulin-like domains in its extracellular region and immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic tail. Through its interaction with amyloid-beta, LILRB2 modulates microglial phagocytosis, synaptic plasticity, and neuroinflammatory signaling, making it a high-priority therapeutic target for Alzheimer's disease["@bhatt2021"].

Gene Structure and Protein Products

Genomic Organization

The LILRB2 gene is located within the leukocyte receptor complex (LRC) on chromosome 19q13.42, a genomic region that encodes multiple immunoglobulin-like receptors. The gene spans approximately 13 kb and contains 16 exons. The LRC region shows significant copy number variation and polymorphism across human populations[@borges2003].

Protein Structure

The LILRB2 protein (598 amino acids) has a modular architecture:

• Four Ig-like domains (D1–D4): Extracellular ligand-binding region. D1 and D2 mediate binding to MHC class I molecules and amyloid-beta oligomers
• Transmembrane domain: Single-pass type I transmembrane segment
• Cytoplasmic tail: Contains three ITIMs that recruit SHP-1 and SHP-2 phosphatases upon receptor engagement, transducing inhibitory signals

Ligand Interactions

LILRB2 binds multiple ligands with distinct functional consequences:

Function

Immune Inhibitory Signaling

In its canonical role, LILRB2 functions as an inhibitory receptor on myeloid cells:

• Immune tolerance: LILRB2 engagement by HLA-G on fetal trophoblasts promotes maternal-fetal immune tolerance
• Dendritic cell regulation: Suppresses dendritic cell maturation and antigen presentation
• Monocyte/macrophage modulation: Inhibits pro-inflammatory cytokine production through ITIM-mediated SHP-1/SHP-2 recruitment

Microglial Function in the CNS

LILRB2 plays specialized roles on [microglia](/cell-types/microglia-neuroinflammation):

• Phagocytic regulation: LILRB2 engagement by Aβ oligomers inhibits microglial phagocytic activity, impairing amyloid clearance[@bhatt2021a]
• Inflammatory polarization: Aβ-LILRB2 interaction shifts microglia toward a [disease-associated microglia](/mechanisms/disease-associated-microglia) (DAM) phenotype
• Complement regulation: Modulates complement-mediated [synaptic pruning](/mechanisms/microglial-synaptic-pruning-dysregulation)
• Cytokine production: LILRB2 signaling influences production of TNF-α, IL-1β, and IL-6

Synaptic Plasticity

The murine ortholog PirB directly regulates synaptic plasticity:

• PirB limits ocular dominance plasticity in the visual [cortex](/brain-regions/cortex)
• Aβ oligomers bind PirB to suppress [long-term potentiation](/mechanisms/long-term-potentiation) (LTP) and enhance long-term depression (LTD)
• PirB/LILRB2 interacts with cofilin signaling to regulate actin dynamics at synapses[@kim2013a]

Disease Associations

Alzheimer's Disease

LILRB2 has emerged as a major receptor mediating Aβ neurotoxicity in [Alzheimer's disease](/diseases/alzheimers-disease):

• Aβ oligomer receptor: LILRB2/PirB was identified as a high-affinity receptor for amyloid-beta oligomers, the most synaptotoxic Aβ species. Binding occurs at nanomolar concentrations to the D1-D2 domains[@kim2013]
• Synaptic loss: Aβ-LILRB2 interaction drives synapse loss through cofilin-mediated actin depolymerization, contributing to the cognitive decline characteristic of AD
• Impaired phagocytosis: Aβ engagement of LILRB2 paradoxically inhibits microglial phagocytosis of amyloid plaques, reducing clearance and promoting accumulation[@bhatt2021a]
• PirB knockout protection: PirB-deficient mice crossed with AD transgenic models show preserved synaptic density, enhanced LTP, and improved cognitive performance despite amyloid deposition
• Upregulation in AD brain: LILRB2 expression is increased on microglia surrounding amyloid plaques in human AD brain tissue
• Genetic association: Variants in the LILRB2 locus have been associated with AD risk in some genome-wide analyses, though not yet reaching genome-wide significance

Parkinson's Disease

Emerging evidence links LILRB2 to [Parkinson's disease](/diseases/parkinsons-disease):

• [Alpha-synuclein](/proteins/alpha-synuclein) oligomers may interact with LILRB2, though with lower affinity than Aβ
• LILRB2 modulates microglial responses to α-synuclein aggregates in the [substantia nigra](/brain-regions/substantia-nigra)
• LILRB2 expression patterns on microglia shift during PD progression

Cancer and Immune Evasion

LILRB2 is also implicated in tumor immune evasion:

• Tumor cells upregulate HLA-G to engage LILRB2 on tumor-associated macrophages, suppressing anti-tumor immunity
• Anti-LILRB2 antibodies are in clinical development for cancer immunotherapy, providing potential drug repurposing opportunities for neurodegeneration

Expression

Brain Expression

LILRB2 expression in the human brain is restricted to myeloid lineage cells:

• Microglia: Primary CNS cell type expressing LILRB2, with upregulation in disease states
• Perivascular macrophages: Express LILRB2 at the [blood-brain barrier](/entities/blood-brain-barrier)
• Border-associated macrophages: Present in meninges and choroid plexus

• Vicinity of amyloid plaques in AD brain
• Regions of active neuroinflammation
• Aging brain (correlating with increased microglial activation)

Peripheral Expression

Outside the CNS, LILRB2 is expressed on:

• Monocytes and macrophages
• Dendritic cells
• Osteoclasts
• Some myeloid leukemia cells

Therapeutic Implications

Anti-LILRB2 Antibodies

LILRB2 is a high-priority therapeutic target for AD:

Small Molecule Approaches

• Structure-based drug design targeting the D1-D2 Aβ-binding pocket
• Allosteric modulators that enhance LILRB2 internalization
• ITIM signaling modulators downstream of LILRB2

Challenges

• LILRB2 has no direct mouse ortholog (PirB has broader expression); human-relevant models are needed
• Blocking LILRB2 systemically could impair immune tolerance mechanisms
• CNS delivery of antibody therapeutics requires specialized approaches
• The complex ligand repertoire of LILRB2 demands selective targeting of the Aβ interaction

Key Publications

See Also

• [TREM2](/genes/trem2) — Triggering receptor expressed on myeloid cells 2
• [CD33](/genes/cd33) — Siglec-3, myeloid cell surface antigen
• [Disease-Associated Microglia](/mechanisms/disease-associated-microglia) — DAM phenotype
• [Microglial Phagocytosis](/mechanisms/microglial-phagocytosis) — Phagocytic clearance mechanisms
• [TREM2–Microglial Pathway in Alzheimer's](/mechanisms/trem2-microglia-pathway-alzheimers) — [TREM2](/proteins/trem2) signaling axis
• [Amyloid Cascade Pathway](/mechanisms/amyloid-cascade-pathway) — Amyloid-beta pathology

External Links

• [NCBI Gene: LILRB2](https://www.ncbi.nlm.nih.gov/gene/10288)
• [UniProt: Q8N423](https://www.uniprot.org/uniprot/Q8N423)
• [OMIM: 604815](https://omim.org/entry/604815)
• [GeneCards: LILRB2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=LILRB2)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving LILRB2 — Leukocyte Immunoglobulin-Like Receptor B2 discovered through SciDEX knowledge graph analysis: