Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5PM9N7)

• DOT Name: HLA class II histocompatibility antigen, DR beta 3 chain (HLA-DRB3)
• Synonyms: MHC class II antigen DRB3
• Gene Name: HLA-DRB3
• Related Disease:
  Ataxia-telangiectasia
  Acute graft versus host disease
  Autoimmune disease
  Autoimmune hepatitis
  Breast cancer
  Breast carcinoma
  Carpal tunnel syndrome
  Chronic obstructive pulmonary disease
  Coeliac disease
  Common variable immunodeficiency
  Crohn disease
  Epithelial ovarian cancer
  Essential hypertension
  Familial adenomatous polyposis 2
  Graft-versus-host disease
  Haematological malignancy
  Hepatitis C virus infection
  Hypercalcaemia
  Idiopathic thrombocytopenic purpura
  Juvenile idiopathic arthritis
  Liver cirrhosis
  Metastatic malignant neoplasm
  Neoplasm
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Primary biliary cholangitis
  Primary sclerosing cholangitis
  Pulmonary sarcoidosis
  Rheumatic heart disease
  Schizophrenia
  Sjogren syndrome
  Thrombocytopenia
  Tuberculosis
  Ulcerative colitis
  Vitiligo
  Inclusion body myositis
  Leukemia
  Stroke
  Thrombotic thrombocytopenic purpura
  Abdominal aortic aneurysm
  Arthritis
  Asthma
  Membranous glomerulonephritis
  Myasthenia gravis
• UniProt ID: DRB3_HUMAN
• PDB ID: 2Q6W; 3C5J; 4H1L
• Pfam ID: PF07654 ; PF00969
• Sequence:
  MVCLKLPGGSSLAALTVTLMVLSSRLAFAGDTRPRFLELRKSECHFFNGTERVRYLDRYF
  HNQEEFLRFDSDVGEYRAVTELGRPVAESWNSQKDLLEQKRGRVDNYCRHNYGVGESFTV
  QRRVHPQVTVYPAKTQPLQHHNLLVCSVSGFYPGSIEVRWFRNGQEEKAGVVSTGLIQNG
  DWTFQTLVMLETVPRSGEVYTCQVEHPSVTSALTVEWRARSESAQSKMLSGVGGFVLGLL
  FLGAGLFIYFRNQKGHSGLQPTGFLS
• Function: A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the alpha chain HLA-DRA, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DRB3-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells. Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes. In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins. Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance. The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides. The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules; ALLELE DRB3*01:01: Exclusively presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a significant role in immune recognition and long-term protection. Presents viral epitopes derived from HHV-6B U11, TRX2/U56 and U85 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection ; ALLELE DRB3*02:02 Exclusively presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a significant role in immune recognition and long-term protection. Upon EBV infection, presents to CD4-positive T cells latent antigen EBNA2 (PRSPTVFYNIPPMPLPPSQL) and lytic antigen BZLF1 (LTAYHVSTAPTGSWF) peptides, driving oligoclonal expansion and selection of virus-specific memory T cell subsets with cytotoxic potential to directly eliminate virus-infected B cells. Presents viral epitopes derived from HHV-6B U11, gB/U39 and gH/U48 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection. Plays a minor role in CD4-positive T cell immune response against Dengue virus by presenting conserved peptides from capsid and non-structural NS3 proteins. Displays peptides derived from IAV matrix protein M, implying a role in protection against IAV infection. In the context of tumor immunesurveillance, may present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies. Presents to Vbeta2-positive T-helper 1 cells specifically an immunodominant peptide derived from tumor antigen CTAG1A/NY-ESO-1(PGVLLKEFTVSGNILTIRLTAADHR) and confers protective memory response. In metastatic epithelial tumors, presents to intratumoral CD4-positive T cells a TP53 neoantigen (HYNYMCNSSCMGSMNRRPILTIITL) carrying G245S hotspot driver mutation and may mediate tumor regression ; ALLELE DRB3*03:01: Presents a series of conserved peptides derived from the M. tuberculosis PPE family of proteins, in particular PPE29 and PPE33, known to be highly immunogenic. Presents immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and long-term protection. Displays immunodominant viral peptides from HCV non-structural protein NS2, as part of a broad range T-helper response to resolve infection.
• Tissue Specificity: Expressed in professional APCs: monocyte/macrophages, dendritic cells and B cells (at protein level).
• KEGG Pathway:
  Phagosome (hsa04145)
  Cell adhesion molecules (hsa04514)
  Antigen processing and presentation (hsa04612)
  Hematopoietic cell lineage (hsa04640)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  Intesti.l immune network for IgA production (hsa04672)
  Type I diabetes mellitus (hsa04940)
  Leishmaniasis (hsa05140)
  Toxoplasmosis (hsa05145)
  Staphylococcus aureus infection (hsa05150)
  Tuberculosis (hsa05152)
  Influenza A (hsa05164)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Asthma (hsa05310)
  Autoimmune thyroid disease (hsa05320)
  Inflammatory bowel disease (hsa05321)
  Systemic lupus erythematosus (hsa05322)
  Rheumatoid arthritis (hsa05323)
  Allograft rejection (hsa05330)
  Graft-versus-host disease (hsa05332)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  Phosphorylation of CD3 and TCR zeta chains (R-HSA-202427)
  Translocation of ZAP-70 to Immunological synapse (R-HSA-202430)
  Generation of second messenger molecules (R-HSA-202433)
  MHC class II antigen presentation (R-HSA-2132295)
  PD-1 signaling (R-HSA-389948)
  Interferon gamma signaling (R-HSA-877300)
  Downstream TCR signaling (R-HSA-202424)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ataxia-telangiectasia	DISP3EVR	Definitive	Genetic Variation	[1]
Acute graft versus host disease	DIS8KLVM	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Biomarker	[3]
Autoimmune hepatitis	DISOX03Q	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Carpal tunnel syndrome	DISHQ3BE	Strong	Genetic Variation	[6]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[7]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[8]
Common variable immunodeficiency	DISHE7JQ	Strong	Biomarker	[9]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[11]
Essential hypertension	DIS7WI98	Strong	Biomarker	[12]
Familial adenomatous polyposis 2	DIS62W3Y	Strong	Biomarker	[13]
Graft-versus-host disease	DIS0QADF	Strong	Biomarker	[14]
Haematological malignancy	DISCDP7W	Strong	Genetic Variation	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[15]
Hypercalcaemia	DISKQ2K7	Strong	Biomarker	[16]
Idiopathic thrombocytopenic purpura	DISFKGJU	Strong	Genetic Variation	[17]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[18]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[19]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[11]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[20]
Obesity	DIS47Y1K	Strong	Altered Expression	[12]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[11]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[11]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[21]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Genetic Variation	[22]
Pulmonary sarcoidosis	DIS1XQCN	Strong	Biomarker	[23]
Rheumatic heart disease	DISCI8JQ	Strong	Genetic Variation	[24]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[25]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[26]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[27]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[28]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[29]
Vitiligo	DISR05SL	Strong	Biomarker	[30]
Inclusion body myositis	DISZXXG5	moderate	Genetic Variation	[31]
Leukemia	DISNAKFL	moderate	Genetic Variation	[32]
Stroke	DISX6UHX	moderate	Biomarker	[33]
Thrombotic thrombocytopenic purpura	DIS3LDOU	Disputed	Altered Expression	[34]
Abdominal aortic aneurysm	DISD06OF	Limited	Genetic Variation	[35]
Arthritis	DIST1YEL	Limited	Biomarker	[36]
Asthma	DISW9QNS	Limited	Genetic Variation	[37]
Membranous glomerulonephritis	DISFSUKQ	Limited	Biomarker	[38]
Myasthenia gravis	DISELRCI	Limited	Genetic Variation	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Selenium	DM25CGV	Approved	Selenium increases the expression of HLA class II histocompatibility antigen, DR beta 3 chain (HLA-DRB3).	[40]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of HLA class II histocompatibility antigen, DR beta 3 chain (HLA-DRB3).	[41]
Lovastatin	DM9OZWQ	Approved	Lovastatin affects the expression of HLA class II histocompatibility antigen, DR beta 3 chain (HLA-DRB3).	[42]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of HLA class II histocompatibility antigen, DR beta 3 chain (HLA-DRB3).	[40]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of HLA class II histocompatibility antigen, DR beta 3 chain (HLA-DRB3).	[43]

References

• [1] Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid-intolerant asthma.Clin Exp Allergy. 2005 May;35(5):585-90. doi: 10.1111/j.1365-2222.2005.02220.x.
• [2] HLA-DRB3/4/5 mismatches are associated with increased risk of acute GVHD in 10/10 matched unrelated donor hematopoietic cell transplantation.Am J Hematol. 2018 May 4. doi: 10.1002/ajh.25133. Online ahead of print.
• [3] Genetic control of immune response in carriers of the 8.1 ancestral haplotype: correlation with levels of IgG subclasses: its relevance in the pathogenesis of autoimmune diseases.Ann N Y Acad Sci. 2007 Sep;1110:151-8. doi: 10.1196/annals.1423.017.
• [4] Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2.Am J Gastroenterol. 1999 Jul;94(7):1906-13. doi: 10.1111/j.1572-0241.1999.01229.x.
• [5] Genetic susceptibility to breast cancer: HLA DQB*03032 and HLA DRB1*11 may represent protective alleles.Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11451-4. doi: 10.1073/pnas.97.21.11451.
• [6] Some implications of genetic biomarkers in occupational epidemiology and practice.Scand J Work Environ Health. 2004 Feb;30(1):71-9. doi: 10.5271/sjweh.767.
• [7] Genetic susceptibility to beryllium: a case-referent study of men and women of working age with sarcoidosis or other chronic lung disease.Occup Environ Med. 2015 Jan;72(1):21-7. doi: 10.1136/oemed-2014-102359. Epub 2014 Oct 10.
• [8] Different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease.HLA. 2017 Aug;90(2):95-101. doi: 10.1111/tan.13065. Epub 2017 Jun 5.
• [9] HLA class II homozygosity confers susceptibility to common variable immunodeficiency (CVID).Clin Exp Immunol. 1999 Jun;116(3):516-20. doi: 10.1046/j.1365-2249.1999.00926.x.
• [10] Analysis of MHC class II DP, DQ and DR alleles in Crohn's disease.Gut. 1998 Aug;43(2):210-5. doi: 10.1136/gut.43.2.210.
• [11] T-cell Responses to TP53 "Hotspot" Mutations and Unique Neoantigens Expressed by Human Ovarian Cancers.Clin Cancer Res. 2018 Nov 15;24(22):5562-5573. doi: 10.1158/1078-0432.CCR-18-0573. Epub 2018 May 31.
• [12] Association of HLA-DRB3*0202 and serum IgG antibodies to Chlamydia pneumoniae with essential hypertension in a highly homogeneous population from Majorca (Balearic Islands, Spain).J Hum Hypertens. 2005 Aug;19(8):615-22. doi: 10.1038/sj.jhh.1001872.
• [13] Characterization of the bovine salivary gland transcriptome associated with Mycobacterium avium subsp. paratuberculosis experimental challenge.BMC Genomics. 2019 Jun 13;20(1):491. doi: 10.1186/s12864-019-5845-4.
• [14] Mismatched HLA-DRB3 Can Induce a Potent Immune Response After HLA 10/10 Matched Stem Cell Transplantation.Transplantation. 2017 Dec;101(12):2850-2854. doi: 10.1097/TP.0000000000001713.
• [15] Relation of HLA class I and II supertypes with spontaneous clearance of hepatitis C virus.Genes Immun. 2013 Jul-Aug;14(5):330-5. doi: 10.1038/gene.2013.25. Epub 2013 May 2.
• [16] HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites.Am J Hum Genet. 2003 Oct;73(4):720-35. doi: 10.1086/378097. Epub 2003 Aug 20.
• [17] Pregnancy-associated autoimmune neonatal thrombocytopenia: role of maternal HLA genotype.Br J Haematol. 1999 Mar;104(4):878-85. doi: 10.1046/j.1365-2141.1999.01270.x.
• [18] Immunogenetics of juvenile idiopathic arthritis: A comprehensive review.J Autoimmun. 2015 Nov;64:113-24. doi: 10.1016/j.jaut.2015.08.002. Epub 2015 Aug 21.
• [19] Long-term follow-up of hepatitis C virus infection: HLA class II loci influences the natural history of the disease.Tissue Antigens. 2003 Feb;61(2):159-65. doi: 10.1034/j.1399-0039.2003.00015.x.
• [20] HLA and KIR Associations of Cervical Neoplasia.J Infect Dis. 2018 Nov 5;218(12):2006-2015. doi: 10.1093/infdis/jiy483.
• [21] Association of primary biliary cirrhosis with the allele HLA-DPB1*0301 in a German population.Hepatology. 1995 Feb;21(2):398-402. doi: 10.1002/hep.1840210221.
• [22] Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population.PLoS One. 2014 Dec 18;9(12):e114486. doi: 10.1371/journal.pone.0114486. eCollection 2014.
• [23] Lung T-helper cells expressing T-cell receptor AV2S3 associate with clinical features of pulmonary sarcoidosis.Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):814-8. doi: 10.1164/ajrccm.161.3.9906001.
• [24] The role of HLA molecules in susceptibility to chronic rheumatic heart disease.Int J Immunogenet. 2006 Feb;33(1):41-4. doi: 10.1111/j.1744-313X.2006.00562.x.
• [25] Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
• [26] Associations of MHC class II alleles in Norwegian primary Sjgren's syndrome patients: implications for development of autoantibodies to the Ro52 autoantigen.Scand J Immunol. 2001 Oct;54(4):428-33. doi: 10.1046/j.1365-3083.2001.00993.x.
• [27] The natural history of fetomaternal alloimmunization to the platelet-specific antigen HPA-1a (PlA1, Zwa) as determined by antenatal screening.Blood. 1998 Oct 1;92(7):2280-7.
• [28] Discovery of susceptibility loci associated with tuberculosis in Han Chinese.Hum Mol Genet. 2017 Dec 1;26(23):4752-4763. doi: 10.1093/hmg/ddx365.
• [29] Strong protective effect of DR3 against ulcerative colitis in the Spanish population.Am J Gastroenterol. 2007 Dec;102(12):2762-6. doi: 10.1111/j.1572-0241.2007.01487.x. Epub 2007 Aug 21.
• [30] Association of HLA loci alleles and antigens in Saudi patients with vitiligo.Arch Dermatol Res. 2006 Dec;298(7):347-52. doi: 10.1007/s00403-006-0699-4. Epub 2006 Sep 22.
• [31] Sporadic inclusion body myositis: phenotypic variability and influence of HLA-DR3 in a cohort of 57 Australian cases.J Neurol Neurosurg Psychiatry. 2008 Sep;79(9):1056-60. doi: 10.1136/jnnp.2007.138891. Epub 2008 Feb 7.
• [32] BOLA-DRB3 gene polymorphisms influence bovine leukaemia virus infection levels in Holstein and HolsteinJersey crossbreed dairy cattle.Anim Genet. 2017 Aug;48(4):420-430. doi: 10.1111/age.12566. Epub 2017 May 31.
• [33] Distinct HLA associations by stroke subtype in children with sickle cell anemia.Blood. 2003 Apr 1;101(7):2865-9. doi: 10.1182/blood-2002-09-2791. Epub 2002 Nov 27.
• [34] Human leukocyte antigen association in idiopathic thrombotic thrombocytopenic purpura: evidence for an immunogenetic link.J Thromb Haemost. 2010 Feb;8(2):257-62. doi: 10.1111/j.1538-7836.2009.03692.x. Epub 2009 Nov 17.
• [35] HLA-DQA is associated with abdominal aortic aneurysms in the Belgian population.Ann N Y Acad Sci. 2006 Nov;1085:392-5. doi: 10.1196/annals.1383.045.
• [36] DPP-4 inhibitor (sitagliptin)-induced seronegative rheumatoid arthritis.BMJ Case Rep. 2019 Aug 22;12(8):e228981. doi: 10.1136/bcr-2018-228981.
• [37] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [38] HLA-DRB1*15:01 and HLA-DRB3*02:02 in PLA2R-Related Membranous Nephropathy.J Am Soc Nephrol. 2017 May;28(5):1642-1650. doi: 10.1681/ASN.2016060644. Epub 2016 Dec 27.
• [39] HLA and Singaporean Chinese myasthenia gravis.Int Arch Allergy Immunol. 1993;101(2):119-25. doi: 10.1159/000236508.
• [40] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [41] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [42] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [43] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.