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HLA-DR

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HLA-DR1 with bound polypeptide from staphylcoccal enterotoxin I C-chain PDB: 2G9H​viewed through the cleft [1]
ligand (Staphylococcal enterotoxin 1-C peptide:pkyvkqntlklat) within the binding pocket of DR αβ101
DR1 binding pocket with ligand PDB: 2G9H​ [1]
major histocompatibility complex, class II, DR
Structure
Type Cell surface receptor
Subunit αβ-heterodimer
MMDB 40432
Identifiers
alpha
Symbol(s) HLA-DRA, HLA-DRA1
Entrez 3122
OMIM 142860
RefSeq NM_019111
UniProt P01903
Identifiers
beta 1
beta 3
Symbol(s) HLA-DRB1 HLA-DRB3
Entrez 3123 3125
OMIM 142857
RefSeq NM_002124 NM_022555
UniProt P01370 P01913
Identifiers
beta 4
beta 5
Symbol(s) HLA-DRB4 HLA-DRB5
Entrez 3126 3127
OMIM 604776
RefSeq NM_021483 NM_002125
UniProt Q30163 Q29703
Shared data
Locus chr.6 6p21.31

HLA-DR is a major histocompatibility complex, class II, cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. Receptor is frequently found with ligand, a peptide of 9 amino acids in length or longer, within the binding groove. The receptor/peptide complex is a ligand for T-cell receptor (TCR). HLA, human leukocyte antigens, were originally defined as cell surface antigens that mediate graft-versus-host disease, which resulted in the rejection of tissue transplants in HLA mismatched donors. Identification of these antigens has lead to greater success and longevity in organ transplant.

HLA-DR is also involved in several autoimmune conditions, disease susceptibility and disease resistence. It is also closely linked to HLA-DQ and this linkage often makes it difficult to resolve the more causative factor in disease.

Molecules particularly HLA-DR are upregulated in response to signalling. In the instance of an infection the peptide (such as the staphlococcal enterotoxin I peptide show in the two illustrations) is bound into a DR molecule and presented to a few of a great many T-cell receptors found on T-helper cells. These cells then bind to antigens on the surface of B-cells stimulating B-cell proliferation.

Function

Illustration of DR receptor presenting antigen to TCR on T-helper cell

The primary function of HLA-DR is to present peptide antigens, potentially foriegn in origin, to the immune system for the purpose of eliciting or suppressing T-(helper)-cell responses that eventually to the production of antibodies against the same peptide antigen. Antigen presenting cells (macropahges, B-cells and dendritic cells) are the cells in which DR are typically found. Increased abundance of DR 'antigen' on the cell surface is often in response to stimulation, and, therefore, DR is also a marker for immune stimulation.

Structure

HLA-DR is a αβ heterodimer, cell surface receptor, each subunit contains 2 extracellular domains, a membrane spanning domain and a cytoplasmic tail. Both α and β chains are anchored in the membrane. The N-terminal domain of the mature protein forms an alpha-helix that forms the exposed part of the binding groove, the C-terminal cytoplasmic region interact with the other chain forming a beta-sheet under the binding groove spanning to the cell membrane. The majority of the peptide contact positions are in the 1st 80 residues of each chain.

Genetics

Number of Variant Alleles HLA-DR Loci
HLA-DR
HLA -A1 -B1 -B3 to -B51 Potential
Locus # # # Combinations
Alleles[2] 3 394 72 1398
Mature subunit 1 336 48 384
1DRB3, DRB4, DRB5 have variable presence in humans

The genetics of HLA-DR is complex. HLA-DR is encoded by several loci

  • α-chain
    • DRA (DRA1) locus
      • functional variation in mature DRA gene products is absent
      • (see table) reduces the potential functional combinations from ~1400 to ~400 (table is not exact because new alleles are continually being added not all new alleles are functional variants of the mature subunits.
  • β-chain [2]
    • DRB1 locus (ubiquitous)
      • very large number of functionally variable gene products.
    • DRB3 locus (variable-assocated with certain DR types)
      • modest number of functionally variable gene products.
    • DRB4 locus (variable-assocated with certain DR types)
      • modest number of functionally variable gene products.
    • DRB5 locus (variable-assocated with certain DR types)
      • modest number of functionally variable gene products.
25 (of 75) Most common DR-DQ haplotypes in Caucasian Americans
DQ DR-DQ DR DQ Freq
Serotype haplotype B1 A1 B1 %[3] rank
DQ2 DR17-DQ2 0301 0501 0201 13. 1 2
DR7-DQ2 0701 0201 0202 11. 1 3
DQ4 DR8-DQ4 0801 0401 0402 2. 2 12
DQ5 DR1-DQ5 0101 0101 0501 9. 1 4
0102 0101 0501 1. 4 14
0103 0101 0501 0. 5 25
DR10-DQ5 1001 0104 0501 0. 7 21
DR16-DQ5 1601 0102 0502 1. 0 17
DR14-DQ5 1401 0104 0503 2. 0 13
DQ6 DR15-DQ6 1502 0103 0601 0. 7 23
1501 0102 0602 14. 2 1
DR13-DQ6 1301 0103 0603 5. 6 6
1302 0102 0604 0. 7 10
1302 0102 0609 3. 4 22
DQ7 DR11-DQ7 1101 0505 0301 5. 6 5
1104 0505 0301 2. 7 11
DR12-DQ7 1201 0505 0301 1. 1 15
DR13-DQ7 1303 0505 0301 0. 7 20
DR4-DQ7 0401 0303 0301 5. 3 7
0407 0303 0301 0. 9 18
DQ8 DR4-DQ8 0402 0301 0302 1. 0 16
0404 0301 0302 4. 2 8
0401 0302 0302 0. 7 24
DQ9 DR7-DQ9 0701 0201 0303 3. 7 9
DR9-DQ9 0901 0302 0303 0. 8 19

Evolution and Allele Frequencies

There is an relatively extreme level of allelic diversity at HLA DRB1, it is second only to HLA B in number of allelic variants. Much of the variation at HLA DRB1 occurs at peptide contact positions in the binding groove, as a result many of the alleles alter the way the DR binds peptide ligands and changes the repertoire each receptor can bind.
HLA generally evolve through a process of gene conversion a form of short distance or 'abortive' recombination. Functional motifs in other HLA are transferred to form new alleles, and frequently new DR isoforms. HLA-DR represents an extreme example of this. A survey of X-linked chromosome reveals that most human loci have undergone fixation within the last 600,000 years, and diploid loci have undergone significant proportion of fixation in that period of time. The level of deep branching at X-linked loci indicates loci were close to fixation or fixed at the end of the human population bottleneck ~150 kya. The HLA-DR locus represents a major exception to this observation. Based on distribution of Major groupings in the Human population it is possible to assert that more than a dozen major variants survived the constriction. This observation is supported by the concept of a heterozygous selection coefficient operating on the HLA-DR, and at the HLA-DRB1 locus to a greater degree relative to HLA-DQB1 and HLA-DPB1. Most of the alleles currently present in the human population can be explained by gene conversion between these ancient ancestral types.


Disease associations

Because DR alleles are in disequilibrium with HLA-DQ loci, early studies often cannot resolve exact disease association. In such cases the DR-DQ haplotype will be referred to. See table above on DR-DQ linkage in caucasians. (*#### = DRB1*####)

DR1

Diseases associated with DR1 serotypes or cognate alleles are: seronegative[4]-rheumatoid arthritis[5][6], penicillamine-induced myasthenia[7], and schizophrenia[8]


DR2

DR2 is a broad antigen serotype made up of split antigens DR15 and DR16 serotypes. Diseases associated with DR2 serotypes or cognate alleles are: Goodpasture syndrome, multiple sclerosis[17], and narcolepsy, tuberculoid leprosy[18], Hashimoto's thyroiditis[19], ulcerative colitis(Japanese)[20], biliary cirrhosis and autoimmune hepatitis[21]

DR15

Goodpasture syndrome[22], early age onset multiple schlerosis[23], pernicious anaemia[24]

  • 15:DQA1*0102:DQB1*0602 haplotype: cervical cancer (human papillomavirus infection)[25]
  • *1501: Goodpasture syndrome[26][27], juvenile rheumatoid arthritis [28], allergic bronchopulmonary aspergillosis[29], multiple schlerosis[30], systemic lupus erythematosus[31], cervical cancer (human papillomavirus infection)[32], and Sjogren's syndrome associated with systemic lupus erythematosus[33]
    • *1501:DQA1*0102:DQB1*0602 haplotype: cervical cancer (human papillomavirus infection)[32]
  • *1502: Systemic lupus erythematosus[34], systemic sclerosis (SSc) & anti-DNA topoisomerase I (anti-topo I) antibody[35]
    • *1502:DQA1*????:DQB1*0501 haplotype: Systemic lupus erythematosus[34]
  • *1503: Trypannosome cruzi infection with cardiomyopathy[36], allergic bronchopulmonary aspergillosis[37], multiple sclerosis[30], cervical cancer (human papillomavirus infection)[25]

DR16

Chaga's cardiomyopathy[38], rheumatic heart disease[39], coronary artery ectasia[40], and

  • *1601: Tubeculousis risk[41]
    • *1601:DQA1*0102:DQB1*0502 haplotype: Tubeculousis risk [41]
  • *1602: Juvenile rheumatoid arthritis[28], rheumatic heart disease[39], Takayasu arteritis[42], systemic sclerosis (SSc) & anti-DNA topoisomerase I (anti-topo I) antibody [35][43], melioidosis (Burkholderia pseudomallei infection)[44]
    • *1602:DQA1*0102:DQB1*0502 haplotype: graves disease[45][46], cervical caner (human papilloma virus infection)[47], schleroderma[48]
    • *1602:DQA1*05:DQB1*0301 haplotype: rheumatic heart disease[39], systemic schlerosis[49]


DR3

DR3 is composed to the DR17 and DR18 split 'antigens' serotypes. Diseases associated with DR2 serotypes or cognate alleles are: early-age onset myasthenia gravis, and opportunistic infections in AIDS

  • *0305
  • *0306

DR17

non-chronic sarcoidosis[50][51], infantile spasm/epilepsy[52], rabies vaccine-induced autoimmune encephalomyelitis[53] and cardiovascular hypertrophy in subjects with arterial hypertension[54]

DR18

rheumatoid polyarthritis[68]


DR4

DR4 serotype is a diverse subgroup of antigens composed of several alleles. Diseases associated with DR4 serotype or cognate alleles are: extraarticular[69]rheumatoid arthritis[70], hydralazine-induced female systemic lupus erythematosus[71],pemphigoid gestationis[72], phemphigus foliaceus[73], hypertrophic obstructive cardiomyopathy[74], IgA nephropathy[75]

  • *0401: multiple sclerosis[76], rheumatoid arthritis[77], type 1 diabetes[78][79], lyme disease induced arthritis[80]
  • *0402: drug-triggered[81]/idiopathic pemphigus vulgaris[82], type 1 diabetes[83], SLE associated anti-cardiolipin and anti-beta2GPI[84]
  • *0403: polycystic ovary syndrome[85], SLE associated anti-cardiolipin and anti-beta2GPI[86]
  • *0404: anti-citrullinated fibrinogen[87] in rheumatoid arthritis[88], autoimmune hepatitis[89]
  • *0405: rheumatoid arthritis[90], Autoimmune hepatitis[91], type 1 diabetes[92][93]
    • as part of :DQA1*0303-DQB1*0401 haplotype: type III autoimmune polyglandular syndrome[94], autoimmune hepatitis [95], autoimmune pancreatitis[96]
    • as part of :DQA1*03-DQB1*0302 haplotype: Type 1 diabetes[97][98]
  • *0406: caspase-8 autoantibodies silicosis-systemic sclerosis (SSc)-systemic lupus erythematosus (SLE)[99]
  • DR4-DQ8 juvenile diabetes,coeliac disease, rheumatoid arthritis[100]
  • *0409: T. cruzi infection with cardiomyopathy[36]



DR5

- Kaposi sarcoma in AIDS & juvenile rheumatoid arthritis

DR11

Diseases associated with DR11 serotype or cognate alleles are: Grape anaphylaxis[101], well-differentiated thyroid cancer[102], low antibody production in Hepatitis C[103]

  • *11: systemic sclerosis (SSc) & anti-DNA topoisomerase I (anti-topo I) antibody [35]
  • *1104: pauciarticular juvenil rheumatoid arthritisJuvenile rheumatoid arthritis[28]

DR12

vulval lichen schlerosis [104]

DR6

DR6 is a broad-antigen serotype that is further split into DR13 and DR14 antigen serotypes.

DR13

  • *1302: Early childhood myastenia gravis[105]
    • *1032:DQA1*0102:DQB1*0604: Early childhood myastenia gravis[105]

DR14

  • *1402: Juvenile rheumatoid arthritis[28]



DR7

psoriasis vulgaris

  • *07: T. cruzi infection with cardiomyopathy[36]

DR8

papillary thyroid carcinomas [106]

DR9

  • *0901: Early childhood myastenia gravis[105]
    • *0901:DQA1*0301:DQB1*0303 haplotype: Early childhood myastenia gravis[105]

DR10

Nomenclature

Since DRA is invariable is not neccesary to define in the nomenclature DR1 to DR18 serogroups and cognate allele groups. For details about serotypable alleles in each group see Marsh et al[2]

DR1 - DR18 Serogroups

  • DR1
    • DRB1*01
  • DR2
    • broad antigen
    • compontet split antigens
      • DR15
      • DR16
  • DR3
    • DRB1*0305, *0306 and *0307
    • DR17
    • DR18
  • DR4
    • DRB1*04
  • DR5
    • broad antigen
    • component split antigens
      • DR11
      • DR12
  • DR6
    • broad antigen
    • component split antigens
      • DR13
      • DR14
  • DR7
    • DRB1*07
  • DR8
    • DRB1*08
  • DR9
    • DRB1*09
  • DR10
    • DRB1*10
  • DR11 (see also DR5)
    • DRB1*11
  • DR12 (see also DR5)
    • DRB1*12
  • DR13 (see also DR6)
    • DRB1*13
  • DR14 (see also DR6)
    • DRB1*14
  • DR15 (see also DR2)
    • DRB1*15
  • DR16 (see also DR2)
    • DRB1*16
  • DR17 (see also DR3)
    • DRB1 *0301, *0304
  • DR18 (see also DR3)
    • DRB1*0302, *0303

DR51 - DR53 Serogroups

  • DR51
    • DRB5
      • *0101, *0102, *0107, *0202
  • DR52
    • DRB3
      • *0101,*0106,*0107,*0110,*0201-*0203, *0207-*0211, *0301
  • DR53
    • DRB4
      • *0101, *0103, *0104, *0105


  • HLA-DR+antigens at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  • Antoniades CG, Berry PA, Davies ET, Hussain M, Bernal W, Vergani D, Wendon J. (2006). "Reduced monocyte HLA-DR expression: A novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure". Hepatology. 44 (1): 34–43. PMID 16799971.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Lekkou A, Karakantza M, Mouzaki A, Kalfarentzos F, Gogos C (2004). "Cytokine production and monocyte HLA-DR expression as predictors of outcome for patients with community-acquired severe infections". Clin Diagn Lab Immunol. 11 (1): 161–7. PMID 14715564.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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