1. Gene Aliases

Leukocyte Immunoglobulin Like Receptor B4, LIR-5, ILT3, LIR5, Leukocyte Immunoglobulin-Like Receptor, Subfamily B (With TM And ITIM Domains), Member 4, Leukocyte Immunoglobulin-Like Receptor Subfamily B Member 4, Leukocyte Immunoglobulin-Like Receptor 5, CD85 Antigen-Like Family Member K, Monocyte Inhibitory Receptor HM18, Immunoglobulin-Like Transcript 3, Leucocyte Ig-Like Receptor B4, CD85, ILT-3, HM18, B4, CD85k Antigen, CD85k

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=LILRB4&keywords=Lilrb4]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

Interactions with text mining support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell: A number of receptors and cell adhesion molecules play a key role in modifying the response of cells of lymphoid origin (such as B-, T- and NK cells) to self and tumor antigens, as well as to pathogenic organisms.

Molecules such as KIRs and LILRs form part of a crucial surveillance system that looks out for any derangement, usually caused by cancer or viral infection, in MHC Class I presentation. Somatic cells are also able to report internal functional impairment by displaying surface stress markers such as MICA. The presence of these molecules on somatic cells is picked up by C-lectin NK immune receptors.

Lymphoid cells are able to regulate their location and movement in accordance to their state of activation, and home in on tissues expressing the appropriate complementary ligands. For example, lymphoid cells may fine tune the presence and concentration of adhesion molecules belonging to the IgSF, Selectin and Integrin class that interact with a number of vascular markers of inflammation.

Furthermore, there are a number of avenues through which lymphoid cells may interact with antigen. This may be presented directly to a specific T-cell receptor in the context of an MHC molecule. Antigen-antibody complexes may anchor to the cell via a small number of lymphoid-specific Fc receptors that may, in turn, influence cell function further. Activated complement factor C3d binds to both antigen and to cell surface receptor CD21. In such cases, the far-reaching influence of CD19 on B-lymphocyte function is tempered by its interaction with CD21.[https://reactome.org/PathwayBrowser/#/R-HSA-198933]

Regulation of NF-kappa B signaling: Nuclear factor kappa B (NF-kappa-B) is activated by a diverse range of stimuli including cytokines, ligands of pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs) in myeloid cells, antigen-activated TCR in T-cells and by DNA damage (reviewed in Yu H et al. 2020; Zhang T et al. 2021). NF-kappa-B regulates the transcription of genes that are involved in immune and inflammatory responses, cell cycle, cell proliferation and apoptosis (Bhatt D & Ghosh S 2014; Liu T et al. 2017; Yu H et al. 2020). In unstimulated cells, NF-kappa-B is sequestered in the cytosol through interactions with a class of inhibitor proteins, called NF-kappa-B inhibitors (IkBs, such as NFKBIA or NFKBIB) (Jacobs MD & Harrison SC 1998). IkBs mask the nuclear localization signal (NLS) of NF-kappa-B preventing its nuclear translocation (Cervantes CF et al. 2011). A key event in NF-kappa-B activation involves phosphorylation of IkBs by the IkappaB kinase (IKK) complex which consists of CHUK, IKBKB and IKBKG subunits (Israel A 2010). The activated NF-kappa-B signaling is tightly controlled at multiple levels (Dorrington MG & Fraser IDC 2019; Prescott JA et al. 2021). Dysregulated NF-kappa-B activity can cause tissue damage associated with inflammatory diseases and is also linked to tumorigenesis (Aggarwal BB & Sung B 2011; Liu T et al.2017; Barnabei L et al. 2021). The regulation of NF-kappa-B is cell-type-, context- , and stimulus-dependent and is crucial for orchestrating specific cellular responses (Mussbacher M et al. 2019). [PMID: 35957669, PMID: 30333625, PMID: 31138763], [https://reactome.org/PathwayBrowser/#/R-HSA-9758274&PATH=R-HSA-9020702].

GO terms:

Fc receptor mediated inhibitory signaling pathway [The series of molecular signals generated as a consequence of the binding of the Fc portion of an immunoglobulin by an Fc receptor capable of inhibiting an immune effector process contributing to an immune response. The Fc portion of an immunoglobulin is its C-terminal constant region. GO:0002774]

cytokine-mediated signaling pathway [The series of molecular signals initiated by the binding of a cytokine to a receptor on the surface of a cell, and ending with the regulation of a downstream cellular process, e.g. transcription. GO:0019221]

interleukin-10-mediated signaling pathway [The series of molecular signals initiated by interleukin-10 binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. GO:0140105]

mast cell activation [The change in morphology and behavior of a mast cell resulting from exposure to a cytokine, chemokine, soluble factor, or to (at least in mammals) an antigen which the mast cell has specifically bound via IgE bound to Fc-epsilonRI receptors. GO:0045576]

negative regulation of IP-10 production [Any process that stops, prevents, or reduces the frequency, rate, or extent of production of IP-10. GO:0071659]

negative regulation of MAPK cascade [Any process that stops, prevents, or reduces the frequency, rate or extent of signal transduction mediated by the MAPKKK cascade. GO:0043409]

negative regulation of T cell costimulation [Any process that stops, prevents or reduces the frequency, rate or extent of T cell costimulation. GO:2000524]

negative regulation of T cell cytokine production [Any process that stops, prevents, or reduces the frequency, rate, or extent of T cell cytokine production. GO:0002725]

negative regulation of T cell proliferation [Any process that stops, prevents or reduces the rate or extent of T cell proliferation. GO:0042130]

negative regulation of T cell receptor signaling pathway [Any process that stops, prevents, or reduces the frequency, rate or extent of signaling pathways initiated by the cross-linking of an antigen receptor on a T cell. GO:0050860]

negative regulation of activated T cell proliferation [Any process that stops, prevents or reduces the rate or extent of activated T cell proliferation. GO:0046007]

negative regulation of canonical NF-kappaB signal transduction [Any process that stops, prevents, or reduces the frequency, rate or extent of a canonical NF-kappaB signaling cascade. GO:0043124]

negative regulation of chemokine production [Any process that stops, prevents, or reduces the frequency, rate, or extent of chemokine production. GO:0032682]

negative regulation of cytokine production involved in inflammatory response [Any process that stops, prevents or reduces the frequency, rate or extent of cytokine production involved in inflammatory response. GO:1900016]

negative regulation of cytotoxic T cell differentiation [Any process that stops, prevents, or reduces the frequency, rate or extent of cytotoxic T cell differentiation.|Note that immunologists typically use the word 'development' to refer to cells of B or T cell lineages undergoing the process that GO describes as 'cell differentiation'. GO:0045584]

negative regulation of interleukin-1 beta production [Any process that stops, prevents, or reduces the frequency, rate, or extent of interleukin-1 beta production. GO:0032691]

negative regulation of interleukin-10 production [Any process that stops, prevents, or reduces the frequency, rate, or extent of interleukin-10 production. GO:0032693]

negative regulation of interleukin-2 production [Any process that stops, prevents, or reduces the frequency, rate, or extent of interleukin-2 production. GO:0032703]

negative regulation of interleukin-5 production [Any process that stops, prevents, or reduces the frequency, rate, or extent of interleukin-5 production. GO:0032714]

negative regulation of interleukin-6 production [Any process that stops, prevents, or reduces the frequency, rate, or extent of interleukin-6 production. GO:0032715]

negative regulation of miRNA transcription [Any process that stops, prevents or reduces the frequency, rate or extent of microRNA (miRNA) gene transcription. GO:1902894]

negative regulation of monocyte activation [Any process that stops, prevents or reduces the frequency, rate or extent of monocyte activation. GO:0150102]

negative regulation of osteoclast differentiation [Any process that stops, prevents, or reduces the frequency, rate or extent of osteoclast differentiation. GO:0045671]

negative regulation of protein localization to nucleus [Any process that stops, prevents or reduces the frequency, rate or extent of protein localization to nucleus. GO:1900181]

negative regulation of tumor necrosis factor production [Any process that stops, prevents, or reduces the frequency, rate, or extent of tumor necrosis factor production.|Note that this term refers only to the specific, original 'tumor necrosis factor' protein (TNF) and not other members of the tumor necrosis factor superfamily (those with the gene symbol root 'TNFSF'). GO:0032720]

negative regulation of type II interferon production [Any process that stops, prevents, or reduces the frequency, rate, or extent of interferon-gamma production. Interferon-gamma is also known as type II interferon. GO:0032689]

positive regulation of CD8-positive, alpha-beta T cell differentiation [Any process that activates or increases the frequency, rate or extent of CD8-positive, alpha-beta T cell differentiation.|Note that immunologists typically use the word 'development' to refer to cells of B or T cell lineages undergoing the process that GO describes as 'cell differentiation'. GO:0043378]

positive regulation of T cell anergy [Any process that activates or increases the frequency, rate, or extent of T cell anergy. GO:0002669]

positive regulation of regulatory T cell differentiation [Any process that activates or increases the frequency, rate or extent of differentiation of regulatory T cells.|Note that immunologists typically use the word 'development' to refer to cells of B or T cell lineages undergoing the process that GO describes as 'cell differentiation'. GO:0045591]

receptor internalization [A receptor-mediated endocytosis process that results in the movement of receptors from the plasma membrane to the inside of the cell. The process begins when cell surface receptors are monoubiquitinated following ligand-induced activation. Receptors are subsequently taken up into endocytic vesicles from where they are either targeted to the lysosome or vacuole for degradation or recycled back to the plasma membrane. GO:0031623]

tolerance induction [A process that directly activates any of the steps required for tolerance, a physiologic state in which the immune system does not react destructively against the components of an organism that harbors it or against antigens that are introduced to it. GO:0002507]

MSigDB Signatures:

REACTOME_ADAPTIVE_IMMUNE_SYSTEM: Adaptive Immune System [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_ADAPTIVE_IMMUNE_SYSTEM.html]

7. Gene Descriptions

NCBI Gene Summary: This gene is a member of the leukocyte immunoglobulin-like receptor (LIR) family, which is found in a gene cluster at chromosomal region 19q13.4. The encoded protein belongs to the subfamily B class of LIR receptors which contain two or four extracellular immunoglobulin domains, a transmembrane domain, and two to four cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The receptor is expressed on immune cells where it binds to MHC class I molecules on antigen-presenting cells and transduces a negative signal that inhibits stimulation of an immune response. The receptor can also function in antigen capture and presentation. It is thought to control inflammatory responses and cytotoxicity to help focus the immune response and limit autoreactivity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GeneCards Summary: LILRB4 (Leukocyte Immunoglobulin Like Receptor B4) is a Protein Coding gene. Among its related pathways are Innate Immune System and Class I MHC mediated antigen processing and presentation. Gene Ontology (GO) annotations related to this gene include signaling receptor activity and antigen binding. An important paralog of this gene is LILRB1.

UniProtKB/Swiss-Prot Summary: Inhibitory receptor involved in the down-regulation of the immune response and the development of immune tolerance [PMID: 11875462]. Receptor for FN1 [PMID: 34089617]. Receptor for apolipoprotein APOE [PMID: 30333625]. Receptor for ALCAM/CD166 [PMID: 29263213]. Inhibits receptor-mediated phosphorylation of cellular proteins and mobilization of intracellular calcium ions [PMID: 9151699]. Inhibits FCGR1A/CD64-mediated monocyte activation by inducing phosphatase-mediated down-regulation of the phosphorylation of multiple proteins including LCK, SYK, LAT and ERK, leading to a reduction in TNF production [PMID: 19833736]. This inhibition of monocyte activation occurs at least in part via binding to FN1 [PMID: 34089617]. Inhibits T cell proliferation, inducing anergy, suppressing the differentiation of IFNG-producing CD8+ cytoxic T cells and enhancing the generation of CD8+ T suppressor cells [PMID: 16493035, PMID: 19833736, PMID: 29263213]. Induces up-regulation of CD86 on dendritic cells [PMID: 19860908]. Interferes with TNFRSF5-signaling and NF-kappa-B up-regulation [PMID: 11875462].

8. Cellular Location of Gene Product

Expression in immune cells in several tissues. Predicted location: Membrane, Intracellular (different isoforms) [https://www.proteinatlas.org/ENSG00000186818/subcellular]

9. Mechanistic Information

Summary

The leukocyte immunoglobulin-like receptor 4 (LILRB4), encoded by the Lilrb4 gene, functions as an inhibitory receptor involved in the down-regulation of the immune response and the development of immune tolerance [CS: 9]. It inhibits monocyte activation, T cell proliferation, induces anergy, and suppresses differentiation of IFNgamma-producing CD8+ cytotoxic T cells [CS: 8]. Additionally, LILRB4 modulates immune responses by inducing the generation of CD8+ T suppressor cells and up-regulating CD86 on dendritic cells [CS: 7].

In the brain, during conditions of disease or toxicity, LILRB4 expression is upregulated [CS: 6]. For instance, in Alzheimer's disease, its increased expression in microglia around plaques suggests a response to inflammatory conditions [CS: 6]. This upregulation is likely a mechanism to control excessive immune responses and limit neuroinflammation [CS: 7]. By dampening the activation of microglia and other immune cells in the brain, LILRB4 helps to prevent further damage that could be caused by an overactive immune response, thus potentially protecting neural tissues [CS: 6]. In the context of aging and diseases like amyotrophic lateral sclerosis, the increased expression of Lilrb4 in microglia may serve a similar function, acting to mitigate chronic inflammatory responses and maintain a balance in the brain's immune environment [CS: 5]. This response can be seen as a protective measure against the detrimental effects of prolonged inflammation and immune activation in the brain, which are characteristic of various neurodegenerative conditions [CS: 6].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: brain, lung, lymphoid tissue (tissue enhanced) [https://www.proteinatlas.org/ENSG00000186818/tissue]

Cell type enchanced: dendritic cells, hofbauer cells, kupffer cells, macrophages, plasma cells (cell type enhanced) [https://www.proteinatlas.org/ENSG00000186818/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: