HLA-DRB4

Summary

HLA-DRB4 (major histocompatibility complex, class II, DR beta 4, HGNC:4952) is a protein-coding gene on chromosome 6p21.3 alternate reference locus, encoding HLA class II histocompatibility antigen, DR beta 4 chain (P13762). 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.

HLA-DRB4 belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DRA) and a beta (DRB) chain, both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells. The beta chain is approximately 26-28 kDa and its gene contains 6 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DR molecule the beta chain contains all the polymorphisms specifying the peptide binding specificities. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. There are multiple pseudogenes of this gene.

Source: NCBI Gene 3126 — RefSeq curated summary.

At a glance

• Druggable target: yes
• MANE Select transcript: NM_021983

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4952
Approved symbol	HLA-DRB4
Name	major histocompatibility complex, class II, DR beta 4
Location	6p21.3 alternate reference locus
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000227357
Entrez	3126

Gene structure

Transcript identifiers

Ensembl transcripts: 0

RefSeq mRNA: 1 — MANE Select: NM_021983 NM_021983

Canonical transcript exons

ENST00000411565 — 0 exons

Expression profiles

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2769 / max 38.8763, expressed in 120 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72978	6.8048	524
72979	2.9042	547
72976	0.2769	120
72975	0.1851	92
72974	0.0377	14
72973	0.0194	6

Top tissues by expression

0 total, by Bgee expression score (0-100, higher = more expressed):

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-10137	yes	656.60
E-GEOD-84465	yes	593.21
E-CURD-11	yes	38.49
E-MTAB-6678	yes	22.85
E-MTAB-9801	yes	10.19
E-GEOD-76312	no	306.65

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CIITA, RFX5, RFXANK, RFXAP

Literature-anchored findings (GeneRIF, showing 40)

• Complete coding sequence of the HLA alleles DRB4*0103101 and DRB4*01033 (PMID:11972878)
• DRB4 was increased in males with childhood ALL compared to age- and sex-matched controls) and female patients. HLA-DRB4 is over-represented in high-risk patients. The HLA system may be a component of genetic leukemia susceptibility in male children only. (PMID:12008082)
• Comparison of HLA-DR4-associated peptides in neuroendocrine cells with those identified in lymphoblastoid B cells (LCLs) suggests that intracellular pathways allowing HLA-DR endogenous peptide processing are more efficient in endocrine cells than in LCLs. (PMID:12391221)
• A novel allele of HLA-DRB4 was found. (PMID:12859598)
• differential expression of genes encoded within the RA-associated HLA-DR4 superhaplotype and within the neutral DR7 and DR9 superhaplotypes. (PMID:14558083)
• In patients with autoimmune thyroiditis the HLA-DR11 frequency was higher than control values, while in patients with autoimmune polyglandular syndrome type II, the HLA-DR3 frequency was found to be higher. (PMID:15046556)
• Interaction between the HLA-DRB4 and CTLA-4 genes determines the thyroid function of TPO-positive goitrous Japanese Hashimoto’s thyroiditis patients. (PMID:15055474)
• DR1 and DR4 not only bind and present the same CII immunodominant peptide, but also stimulate a highly restricted subset of T cells. (PMID:15188377)
• No definite association was found between HLA-DR alleles and the risk of psoriasis or psoriatic arthritis. (PMID:15513680)
• HIP is an islet protein naturally processed and presented by HLA-DR4 molecules (PMID:15721314)
• analysis of coding sequences and haplotypic associations of HLA-B and HLA-DRB1 and association to HLA-DRB3 and HLA-DRB4 loci (PMID:15896200)
• Genetic variation associated with type 1 diabetes in a Czech Republic population with childhood onset. (PMID:16629714)
• The HLA-DR locus seems to be associated with the genetic susceptibility to develop SNP in Mexicans. (PMID:16815190)
• results for antigens and allele frequency of various HLA Loci in vitiligo patients and control subjects suggested that HLA-B7, Bw6, Cw6, Cw7, and DRB4*010101 could be susceptible to vitiligo (PMID:17021767)
• HLA-DR and INS VNTR alleles mark both type 1 diabetes disease susceptibility and separate Caucasian parental subpopulations (PMID:17052889)
• a diabetic intrauterine environment interacts with gene(s) marked by the type 1 diabetes susceptibility HLA DR4 alleles to increase fetal growth (PMID:17310371)
• The shared epitope assessed on all HLA-DRB1 serotypic backgrounds except DR1 was associated with RA susceptibility. The presence of the shared epitope on DR4 is associated with greater RA susceptibility and certain disease-activity measures. (PMID:17491100)
• findings indicate that HLA-DRB4 is a genetic risk factor for the development of Churg-Strauss syndrome and increases the likelihood of development of vasculitic manifestations of the disease. (PMID:17763415)
• DRB1*04 may be a protective factor in paucibacillary leprosy. (PMID:18053473)
• No predisposition to CAID was associated to HLA-DRB1*04 or DDB4*01 alleles. (PMID:18223493)
• A model of mixed connective tissue disease has been developed in mice that express the transgene HLA-DRA*0101/DRB1*0401 in a fusion protein with U1-70-kDa ribonucleoprotein autoantigen. (PMID:18523312)
• Thirty-eight percent of the B burgdorferi-infected DR4+/+CD28(-/-)MHCII(-/-) mice, but none of the B burgdorferi-infected CD28(-/-)MHCII(-/-) mice, remained arthritic post-antibiotic treatment (PMID:19035513)
• associated with antiphospholipid syndrome (PMID:19052923)
• Significant transmission disequilibrium for HLA-DR4 was seen (odds ratio, 4.67; 95% confidence interval, 1.34-16.24; P = .008) for transmissions from maternal grandparents to mothers of probands. (PMID:19487610)
• primary biliary cirrhosis patients had a higher gene frequency of HLA-DR4 and DR1 compared to healthy controls and patients with overlap syndromes (PMID:19811438)
• Our results revealed HLA-DRB1*04 as predisposing factor in papillary thyroid carcinoma in Iranian population. (PMID:20164547)
• IA2 positivity was associated with HLA-DR4/X and HLA-DR3/4 positivity, and hypothyroidism was linked to HLA-DR4/4. More females carried the HLA-DR4/4 genotype or were thyroid antibody positive. (PMID:20371654)
• HLA-DR14/DR7/DQ5 alleles significantly increase the risk for toxic shock syndrome, regardless of individual variations in T cell receptor variable region repertoires. (PMID:21282506)
• DRB4*01:08 is a novel HLA-DRB4 allele (PMID:21410658)
• Elevated frequencies of HLA-DR4 and HLA-DR5 alleles were found in patients with idiopathic dilated cardiomyopathy compared with controls. (PMID:21556773)
• Data indicate that invariant NKT (iNKT) cell-mediated cytokine secretion in staphylococcal enterotoxin B (SEB)-challenged HLA-DR4-transgenic mice was CD1d-independent. (PMID:22041925)
• There are no significant differences in the HLA-DRB3/B4/B5 homozygosity and heterozygosity rates between Korean males and females in both newborns and adults. (PMID:22531795)
• Heterozygosity of HLA-DRB3*01:01 and HLA-DRB4*01:01 as a potential predictor of fetal neonatal alloimmune thrombocytopenia. (PMID:22671039)
• There was a strong association of aspirin resistant thrombophilia with expression of HLA-DRB4 and HLA-DQA1. (PMID:23454623)
• The HLA- DR4 gene was clearly associated with susceptibility to rheumatoid arthritis. (PMID:23537298)
• HLA-DR4 codes for susceptibility to RF+ polyarticular JIA with a six-fold risk. (PMID:24618287)
• The study identifies a region of focus for B and T cell responses to IA-2 in HLA-DR4 diabetic patients that may explain HLA associations of IA-2 autoantibodies. (PMID:25225671)
• HLA-DRB4 affects type 1 diabetes risk and islet autoantibodies. (PMID:26740600)
• HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of Tregs and reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen-presenting cells and CD8(+) T effectors, facilitating the induction of AIH and persistent liver damage. (PMID:27414259)
• Strong association of nontumor anti-LGI1 encephalitis with HLA-DRB4. (PMID:28026046)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

HLA class II histocompatibility antigen, DR beta 4 chain — P13762 (reviewed: P13762)

Alternative names: MHC class II antigen DRB4

All UniProt accessions (1): P13762

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane. Golgi apparatus. trans-Golgi network membrane. Endosome membrane. Lysosome membrane. Late endosome membrane.

Post-translational modifications. Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II. When associated with ubiquitination of the alpha subunit of HLA-DR: HLA-DRA ‘Lys-244’, the down-regulation of MHC class II may be highly effective.

Polymorphism. The following alleles of DRB4 are known: DRB401:01, DRB401:02, DRB401:03, DRB401:04, DRB401:05, DRB401:06 and DRB401:07. The sequence shown is that of DRB401:03.

Similarity. Belongs to the MHC class II family.

RefSeq proteins (1): NP_068818* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000353	MHC_II_b_N	Domain
IPR003006	Ig/MHC_CS	Conserved_site
IPR003597	Ig_C1-set	Domain
IPR007110	Ig-like_dom	Domain
IPR011162	MHC_I/II-like_Ag-recog	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014745	MHC_II_a/b_N	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050160	MHC/Immunoglobulin	Family

Pfam: PF00969, PF07654

UniProt features (21 total): sequence variant 6, mutagenesis site 3, disulfide bond 2, topological domain 2, region of interest 2, signal peptide 1, chain 1, cross-link 1, transmembrane region 1, domain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13762-F1	88.09	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 254

Disulfide bonds (2): 146–202, 44–108

Glycosylation sites (1): 48

Mutagenesis-validated functional residues (3):

Position	Phenotype
254	almost no change in down-regulation of mhc class ii. no ubiquitination and complete loss of down-regulation of mhc class
264	almost no change in down-regulation of mhc class ii; when associated with a-265.
265	almost no change in down-regulation of mhc class ii; when associated with a-264.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-202424	Downstream TCR signaling
R-HSA-202427	Phosphorylation of CD3 and TCR zeta chains
R-HSA-202430	Translocation of ZAP-70 to Immunological synapse
R-HSA-202433	Generation of second messenger molecules
R-HSA-2132295	MHC class II antigen presentation
R-HSA-389948	Co-inhibition by PD-1
R-HSA-877300	Interferon gamma signaling

MSigDB gene sets: 178 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, MCLACHLAN_DENTAL_CARIES_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, BIOCARTA_TCRA_PATHWAY, GCANCTGNY_MYOD_Q6, MODULE_45, GAURNIER_PSMD4_TARGETS, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_ANTIGEN, GRAHAM_CML_QUIESCENT_VS_NORMAL_QUIESCENT_DN, MODULE_143, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_CELL_CELL_ADHESION

GO Biological Process (9): adaptive immune response (GO:0002250), peptide antigen assembly with MHC class II protein complex (GO:0002503), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), positive regulation of immune response (GO:0050778), positive regulation of T cell activation (GO:0050870), immune system process (GO:0002376), antigen processing and presentation of peptide or polysaccharide antigen via MHC class II (GO:0002504), immune response (GO:0006955), antigen processing and presentation (GO:0019882)

GO Molecular Function (2): MHC class II protein complex binding (GO:0023026), peptide antigen binding (GO:0042605)

GO Cellular Component (18): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), ER to Golgi transport vesicle membrane (GO:0012507), transport vesicle membrane (GO:0030658), endocytic vesicle membrane (GO:0030666), clathrin-coated endocytic vesicle membrane (GO:0030669), late endosome membrane (GO:0031902), trans-Golgi network membrane (GO:0032588), MHC class II protein complex (GO:0042613), lumenal side of endoplasmic reticulum membrane (GO:0098553), lysosome (GO:0005764), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), endosome membrane (GO:0010008), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
TCR signaling	4
Adaptive Immune System	1
Regulation of T cell activation by CD28 family	1
Interferon Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
bounding membrane of organelle	4
cytoplasmic vesicle membrane	3
endomembrane system	3
immune response	2
antigen processing and presentation of peptide antigen via MHC class II	2
immune system process	2
organelle membrane	2
cytoplasm	2
intracellular membrane-bounded organelle	2
MHC class II protein complex assembly	1
peptide antigen assembly with MHC protein complex	1
antigen processing and presentation of exogenous peptide antigen	1
positive regulation of immune system process	1
positive regulation of response to stimulus	1
regulation of immune response	1
T cell activation	1
regulation of T cell activation	1
positive regulation of lymphocyte activation	1
positive regulation of leukocyte cell-cell adhesion	1
biological_process	1
antigen processing and presentation	1
response to stimulus	1
MHC protein complex binding	1
antigen binding	1
peptide binding	1
Golgi apparatus	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
COPII-coated ER to Golgi transport vesicle	1
transport vesicle membrane	1
coated vesicle membrane	1
transport vesicle	1
endocytic vesicle	1
clathrin-coated vesicle membrane	1
endocytic vesicle membrane	1
clathrin-coated endocytic vesicle	1
late endosome	1
endosome membrane	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

2 interactions, top by confidence:

A	B	Type	Score
HLA-DRB4	ASMTL	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (10): PKM (Affinity Capture-MS), HSP90AA1 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), ANXA11 (Affinity Capture-MS), HSP90AB1 (Affinity Capture-MS), ATP1B1 (Affinity Capture-MS), YWHAE (Affinity Capture-MS), MS4A1 (Affinity Capture-MS), MAGEA6 (Protein-peptide), HLA-DRB4 (Two-hybrid)

ESM2 similar proteins: C1ITJ8, O19477, P01901, P01902, P01911, P01915, P01920, P01921, P03991, P04230, P04231, P04440, P05538, P06341, P06342, P06343, P06344, P06345, P06346, P13599, P13762, P13765, P14428, P14483, P15464, P15979, P15982, P15983, P16391, P18211, P18467, P18468, P18469, P18470, P20040, P20756, P23068, P25311, P29826, P35737

Diamond homologs: A0A0G2K7V7, C1ITJ8, O19477, O35799, P01889, P01893, P01894, P01895, P01896, P01897, P01898, P01899, P01900, P01901, P01902, P01911, P01920, P03991, P04223, P04227, P04439, P04440, P05538, P06140, P06339, P10321, P13747, P13748, P13749, P13750, P13751, P13752, P13753, P13762, P14426, P14427, P14428, P14429, P14430, P14431

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CIITA	“up-regulates quantity by expression”	HLA-DRB4	“transcriptional regulation”
MARCHF8	“down-regulates quantity by destabilization”	HLA-DRB4	polyubiquitination
MARCHF1	“down-regulates quantity by destabilization”	HLA-DRB4	polyubiquitination
“RFX complex”	“up-regulates quantity by expression”	HLA-DRB4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

0 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1004310020 (6:32554642 T>A,G), RS1006902570 (6:32553277 C>T), RS1007018334 (6:32552755 T>C), RS1008572887 (6:32555574 T>C), RS1010738230 (6:32552409 G>T), RS1011417918 (6:32552533 A>G), RS1012929735 (6:32555490 C>T), RS1014737473 (6:32552322 G>A,C,T), RS1016841350 (6:32554650 T>A,C), RS1018233512 (6:32552895 C>T), RS1021424874 (6:32553681 C>T), RS1023930146 (6:32554507 C>T), RS1024363664 (6:32554636 G>C), RS1024758504 (6:32553369 G>A), RS1025489471 (6:32553006 T>C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3988561 (PROTEIN FAMILY)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	decreases expression, increases expression	2
quercitrin	affects expression	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
manganese chloride	increases expression	1
Irinotecan	increases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	increases expression	1
Arsenic	decreases response to substance	1
Benzo(a)pyrene	increases expression	1
Carcinogens	decreases expression	1
Demecolcine	decreases expression	1
Doxorubicin	decreases response to substance	1
Ethyl Methanesulfonate	decreases expression	1
Manganese	increases expression	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Mutagens	decreases expression	1
Nickel	affects response to substance	1
Palladium	affects response to substance	1
Tobacco Smoke Pollution	decreases expression	1
Vincristine	decreases expression	1
Antirheumatic Agents	decreases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.