Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1O2K47)

• DOT Name: Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2)
• Synonyms: CD85 antigen-like family member H; Immunoglobulin-like transcript 1; ILT-1; Leukocyte immunoglobulin-like receptor 7; LIR-7; CD antigen CD85h
• Gene Name: LILRA2
• Related Disease:
  HIV infectious disease
  Neoplasm
  Amyotrophic lateral sclerosis
  Microscopic polyangiitis
  Rheumatoid arthritis
  Systemic lupus erythematosus
• UniProt ID: LIRA2_HUMAN
• PDB ID: 2OTP
• Pfam ID: PF00047 ; PF13895
• Sequence:
  MTPILTVLICLGLSLGPRTHVQAGHLPKPTLWAEPGSVIIQGSPVTLRCQGSLQAEEYHL
  YRENKSASWVRRIQEPGKNGQFPIPSITWEHAGRYHCQYYSHNHSSEYSDPLELVVTGAY
  SKPTLSALPSPVVTSGGNVTLQCVSQVAFDGFILCKEGEDEHPQRLNSHSHARGWSWAIF
  SVGPVSPSRRWSYRCYAYDSNSPYVWSLPSDLLELLVPGVSKKPSLSVQPGPMVAPGESL
  TLQCVSDVGYDRFVLYKEGERDFLQRPGWQPQAGLSQANFTLGPVSPSHGGQYRCYSAHN
  LSSEWSAPSDPLDILITGQFYDRPSLSVQPVPTVAPGKNVTLLCQSRGQFHTFLLTKEGA
  GHPPLHLRSEHQAQQNQAEFRMGPVTSAHVGTYRCYSSLSSNPYLLSLPSDPLELVVSEA
  AETLSPSQNKTDSTTTSLGQHPQDYTVENLIRMGVAGLVLVVLGILLFEAQHSQRSLQDA
  AGR
• Function: Part of the innate immune responses against microbial infection. Specifically recognizes a set of N-terminally truncated immunoglobulins that are produced via cleavage by proteases from a range of pathogenic bacteria and fungi, including L.pneumophila, M.hyorhinis, S.pneumoniae, S.aureus and C.albicans. Recognizes epitopes that are in part in the variable region of the immunoglobulin light chains, but requires also the constant region for signaling. Binds to a subset of cleaved IgM, IgG3 and IgG4 molecules, but does not bind cleaved IgA1. Binding of N-terminally truncated immunoglobulins mediates activation of neutrophils. In monocytes, activation leads to the release of CSF2, CF3, IL6, CXCL8 and CCL3 and down-regulates responses to bacterial lipopolysaccharide (LPS), possibly via down-regulation of TLR4 expression and reduced signaling via TLR4. In eosinophils, activation by ligand binding leads to the release of RNASE2, IL4 and leukotriene C4. Does not bind class I MHC antigens.
• Tissue Specificity: Detected on the surface of all peripheral blood monocytes, neutrophils, basophils and eosinophils (at protein level) . Expression levels are very low or not detectable on monocytes, T-cells, B-cells, dendritic cells and natural killer (NK) cells .
• KEGG Pathway:
  Osteoclast differentiation (hsa04380)
  B cell receptor sig.ling pathway (hsa04662)
• Reactome Pathway: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
HIV infectious disease	DISO97HC	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[3]
Microscopic polyangiitis	DIS74KSO	Limited	Genetic Variation	[4]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[5]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[4]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2).	[14]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2).	[11]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2).	[12]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2).	[13]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2).	[15]

References

• [1] Mass Cytometry Analysis Reveals Complex Cell-State Modifications of Blood Myeloid Cells During HIV Infection.Front Immunol. 2019 Nov 22;10:2677. doi: 10.3389/fimmu.2019.02677. eCollection 2019.
• [2] Therapeutic predictors of neoadjuvant endocrine therapy response in estrogen receptor-positive breast cancer with reference to optimal gene expression profiling.Breast Cancer Res Treat. 2018 Nov;172(2):353-362. doi: 10.1007/s10549-018-4933-5. Epub 2018 Aug 27.
• [3] A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis.Acta Neuropathol Commun. 2017 Mar 16;5(1):23. doi: 10.1186/s40478-017-0424-x.
• [4] Association of LILRA2 (ILT1, LIR7) splice site polymorphism with systemic lupus erythematosus and microscopic polyangiitis.Genes Immun. 2008 Apr;9(3):214-23. doi: 10.1038/gene.2008.5. Epub 2008 Feb 14.
• [5] The co-expression of activating and inhibitory leukocyte immunoglobulin-like receptors in rheumatoid synovium.Am J Pathol. 2002 Feb;160(2):425-31. doi: 10.1016/S0002-9440(10)64861-4.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Vitamin D Counteracts an IL-23-Dependent IL-17A(+)IFN-(+) Response Driven by Urban Particulate Matter. Am J Respir Cell Mol Biol. 2017 Sep;57(3):355-366. doi: 10.1165/rcmb.2016-0409OC.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [13] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.