Details of Drug Off-Target (DOT)

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

• DOT Name: HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4)
• Synonyms: MHC class II antigen DRB4
• Gene Name: HLA-DRB4
• Related Disease:
  Astrocytoma
  Acute monocytic leukemia
  Allergy
  Alzheimer disease
  Autoimmune disease
  Autoimmune hepatitis
  Autoimmune polyendocrinopathy
  Autoimmune thyroid disease
  Bipolar disorder
  Bladder cancer
  Bone osteosarcoma
  Carcinoma of liver and intrahepatic biliary tract
  Childhood acute lymphoblastic leukemia
  Colorectal carcinoma
  Cowden disease
  Eosinophilic granulomatosis with polyangiitis
  Graves disease
  Hashimoto thyroiditis
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Leprosy
  Liver cancer
  Lung cancer
  Lung carcinoma
  Melanoma
  Mixed connective tissue disease
  Multiple sclerosis
  Osteosarcoma
  Sarcoidosis
  Small lymphocytic lymphoma
  Type-1 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Vasculitis
  Vitiligo
  Encephalitis
  Immune system disorder
  Liver failure
  Narcolepsy
  Neoplasm
  Advanced cancer
  Arthritis
  Asthma
  Malignant tumor of nasopharynx
  Nasopharyngeal carcinoma
• UniProt ID: DRB4_HUMAN
• Pfam ID: PF07654 ; PF00969
• Sequence:
  MVCLKLPGGSCMAALTVTLTVLSSPLALAGDTQPRFLEQAKCECHFLNGTERVWNLIRYI
  YNQEEYARYNSDLGEYQAVTELGRPDAEYWNSQKDLLERRRAEVDTYCRYNYGVVESFTV
  QRRVQPKVTVYPSKTQPLQHHNLLVCSVNGFYPGSIEVRWFRNGQEEKAGVVSTGLIQNG
  DWTFQTLVMLETVPRSGEVYTCQVEHPSMMSPLTVQWSARSESAQSKMLSGVGGFVLGLL
  FLGTGLFIYFRNQKGHSGLQPTGLLS
• Function: Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.
• 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
Astrocytoma	DISL3V18	Definitive	Posttranslational Modification	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Genetic Variation	[2]
Allergy	DIS48ZAP	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[5]
Autoimmune hepatitis	DISOX03Q	Strong	Genetic Variation	[6]
Autoimmune polyendocrinopathy	DISOLDB2	Strong	Biomarker	[7]
Autoimmune thyroid disease	DISIHC6A	Strong	Biomarker	[7]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[8]
Bladder cancer	DISUHNM0	Strong	Biomarker	[9]
Bone osteosarcoma	DIST1004	Strong	Genetic Variation	[10]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Genetic Variation	[11]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[13]
Cowden disease	DISMYKCE	Strong	Biomarker	[14]
Eosinophilic granulomatosis with polyangiitis	DIS7ITOG	Strong	Biomarker	[15]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[16]
Hashimoto thyroiditis	DIS77CDF	Strong	Biomarker	[17]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[11]
Leprosy	DISAA4UI	Strong	Biomarker	[18]
Liver cancer	DISDE4BI	Strong	Genetic Variation	[11]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[19]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[19]
Melanoma	DIS1RRCY	Strong	Biomarker	[20]
Mixed connective tissue disease	DISXX0H8	Strong	Altered Expression	[21]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[22]
Osteosarcoma	DISLQ7E2	Strong	Genetic Variation	[10]
Sarcoidosis	DISE5B8Z	Strong	Genetic Variation	[23]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[24]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[25]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[9]
Vasculitis	DISQRKDX	Strong	Biomarker	[26]
Vitiligo	DISR05SL	Strong	Biomarker	[27]
Encephalitis	DISLD1RL	moderate	Biomarker	[28]
Immune system disorder	DISAEGPH	moderate	Biomarker	[29]
Liver failure	DISLGEL6	moderate	Genetic Variation	[29]
Narcolepsy	DISLCNLI	moderate	Genetic Variation	[30]
Neoplasm	DISZKGEW	moderate	Biomarker	[28]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[31]
Arthritis	DIST1YEL	Limited	Biomarker	[32]
Asthma	DISW9QNS	Limited	Altered Expression	[33]
Malignant tumor of nasopharynx	DISTGIGF	Limited	Genetic Variation	[31]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Genetic Variation	[31]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4) decreases the response to substance of Doxorubicin.	[44]
Arsenic	DMTL2Y1	Approved	HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4) decreases the response to substance of Arsenic.	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4).	[34]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4).	[35]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4).	[36]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4).	[37]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4).	[39]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4).	[40]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4).	[41]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4).	[42]
Manganese	DMKT129	Investigative	Manganese increases the expression of HLA class II histocompatibility antigen, DR beta 4 chain (HLA-DRB4).	[43]

References

• [1] Epigenetic silencing of death receptor 4 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in gliomas.Clin Cancer Res. 2009 Sep 1;15(17):5457-65. doi: 10.1158/1078-0432.CCR-09-1125. Epub 2009 Aug 25.
• [2] HLA class II allele and haplotype frequencies in Iranian patients with leukemia.Iran J Allergy Asthma Immunol. 2007 Sep;6(3):137-42.
• [3] [Analysis of a genetic factor of metal allergy--polymorphism of HLA-DR, -DQ gene].Kokubyo Gakkai Zasshi. 1996 Mar;63(1):53-69. doi: 10.5357/koubyou.63.53.
• [4] Association and interaction effects of Alzheimer's disease-associated genes and lifestyle on cognitive aging in older adults in a Taiwanese population.Oncotarget. 2017 Apr 11;8(15):24077-24087. doi: 10.18632/oncotarget.15269.
• [5] DRB4*01:01 Has a Distinct Motif and Presents a Proinsulin Epitope That Is Recognized in Subjects with Type 1 Diabetes.J Immunol. 2018 Dec 15;201(12):3524-3533. doi: 10.4049/jimmunol.1800723. Epub 2018 Nov 19.
• [6] Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis.J Hepatol. 2005 Apr;42(4):578-84. doi: 10.1016/j.jhep.2004.12.019. Epub 2005 Jan 21.
• [7] HLA antigen expression in autoimmune endocrinopathies.Physiol Res. 2004;53(2):191-7.
• [8] Human leukocyte antigen alleles in patients with bipolar disorder in the Korean population.Psychiatry Clin Neurosci. 2002 Aug;56(4):453-7. doi: 10.1046/j.1440-1819.2002.01035.x.
• [9] Genetic variants in the tumor necrosis factor-related apoptosis-inducing ligand and death receptor genes contribute to susceptibility to bladder cancer.Genet Test Mol Biomarkers. 2015 Jun;19(6):309-15. doi: 10.1089/gtmb.2015.0050. Epub 2015 May 8.
• [10] Mutation analysis of the apoptotic "death-receptors" and the adaptors TRADD and FADD/MORT-1 in osteosarcoma tumor samples and osteosarcoma cell lines.Int J Cancer. 2004 May 1;109(5):661-7. doi: 10.1002/ijc.20008.
• [11] TRAIL receptor I (DR4) polymorphisms C626G and A683C are associated with an increased risk for hepatocellular carcinoma (HCC) in HCV-infected patients.BMC Cancer. 2012 Mar 8;12:85. doi: 10.1186/1471-2407-12-85.
• [12] Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia.Blood. 1999 Jul 15;94(2):694-700.
• [13] Genetic variants in the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and death receptor (DR4) genes contribute to susceptibility to colorectal cancer in pakistani population.Cell Mol Biol (Noisy-le-grand). 2015 Oct 30;61(6):108-12.
• [14] The HLA-DRB4 gene is present in half of the Spanish HLA-DQ2-negative celiac patients.Immunogenetics. 2000 Oct;51(12):1045-6. doi: 10.1007/s002510000241.
• [15] Genetic aspects of anti-neutrophil cytoplasmic antibody-associated vasculitis.Nephrol Dial Transplant. 2015 Apr;30 Suppl 1:i37-45. doi: 10.1093/ndt/gfu386. Epub 2014 Dec 18.
• [16] HLA-DRB3*0101 is associated with Graves' disease in Jamaicans.Clin Endocrinol (Oxf). 2001 Dec;55(6):805-8. doi: 10.1046/j.1365-2265.2001.01414.x.
• [17] Identification of independent susceptible and protective HLA alleles in Japanese autoimmune thyroid disease and their epistasis.J Clin Endocrinol Metab. 2014 Feb;99(2):E379-83. doi: 10.1210/jc.2013-2841. Epub 2013 Nov 27.
• [18] [Role of HLA-DR and HLA-DQ alleles in multibacillary leprosy and paucibacillary leprosy in the province of Chaco (Argentina)].Enferm Infecc Microbiol Clin. 2007 Dec;25(10):627-31. doi: 10.1157/13112938.
• [19] Coding polymorphisms in Casp5, Casp8 and DR4 genes may play a role in predisposition to lung cancer.Cancer Lett. 2009 Jun 18;278(2):183-191. doi: 10.1016/j.canlet.2009.01.012. Epub 2009 Feb 8.
• [20] Identification of NY-ESO-1 epitopes presented by human histocompatibility antigen (HLA)-DRB4*0101-0103 and recognized by CD4(+) T lymphocytes of patients with NY-ESO-1-expressing melanoma.J Exp Med. 2000 Feb 21;191(4):625-30. doi: 10.1084/jem.191.4.625.
• [21] CD4+ T cells target epitopes residing within the RNA-binding domain of the U1-70-kDa small nuclear ribonucleoprotein autoantigen and have restricted TCR diversity in an HLA-DR4-transgenic murine model of mixed connective tissue disease.J Immunol. 2008 Jun 15;180(12):8444-54. doi: 10.4049/jimmunol.180.12.8444.
• [22] Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis.Mult Scler. 2019 May;25(6):772-782. doi: 10.1177/1352458518770019. Epub 2018 Apr 23.
• [23] HLA class II amino acid epitopes as susceptibility markers of sarcoidosis.Tissue Antigens. 2007 Jul;70(1):18-27. doi: 10.1111/j.1399-0039.2007.00842.x.
• [24] Fine-mapping of HLA associations with chronic lymphocytic leukemia in US populations.Blood. 2014 Oct 23;124(17):2657-65. doi: 10.1182/blood-2014-02-558767. Epub 2014 Sep 17.
• [25] Eleven Amino Acids of HLA-DRB1 and Fifteen Amino Acids of HLA-DRB3, 4, and 5 Include Potentially Causal Residues Responsible for the Risk of Childhood Type 1 Diabetes.Diabetes. 2019 Aug;68(8):1692-1704. doi: 10.2337/db19-0273. Epub 2019 May 24.
• [26] HLA-DRB4 as a genetic risk factor for Churg-Strauss syndrome.Arthritis Rheum. 2007 Sep;56(9):3159-66. doi: 10.1002/art.22834.
• [27] 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.
• [28] Anti-LGI1 encephalitis is strongly associated with HLA-DR7 and HLA-DRB4.Ann Neurol. 2017 Feb;81(2):193-198. doi: 10.1002/ana.24858. Epub 2017 Jan 27.
• [29] Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis.Hepatology. 1997 Feb;25(2):317-23. doi: 10.1002/hep.510250211.
• [30] HLA-DQA, -DQB and -DRB allele contribution to narcolepsy susceptibility.Eur J Immunogenet. 1997 Dec;24(6):409-21. doi: 10.1046/j.1365-2370.1997.d01-115.x.
• [31] Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance.Int J Oncol. 2000 May;16(5):917-25. doi: 10.3892/ijo.16.5.917.
• [32] Complementation between HLA-DR4 (DRB1*0401) and specific H2-A molecule in transgenic mice leads to collagen-induced arthritis.Hum Immunol. 1999 Sep;60(9):816-25. doi: 10.1016/s0198-8859(99)00070-1.
• [33] Bioinformatics analysis of gene expression in peripheral blood mononuclear cells from children with type 1 diabetes in 3 periods.Exp Clin Endocrinol Diabetes. 2014 Sep;122(8):477-83. doi: 10.1055/s-0034-1372599. Epub 2014 May 16.
• [34] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [35] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [36] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [37] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [38] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [39] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [40] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [41] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [42] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [43] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [44] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.
• [45] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.