HLA-DR

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Major histocompatibility complex, class II, DR alpha
PDB rendering based on 1a6a.
Identifiers
Symbols HLA-DRA ; HLA-DRA1
External IDs Template:OMIM5 Template:MGI HomoloGene: 7751
RNA expression pattern
More reference expression data
Orthologs
Template:GNF Ortholog box
Species Human Mouse
Entrez n/a n/a
Ensembl n/a n/a
UniProt n/a n/a
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a n/a
Location (UCSC) n/a n/a
PubMed search n/a n/a


Overview

HLA-DR is a major histocompatibility complex, MHC 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 led to greater success and longevity in organ transplant.

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

HLA-DR molecules 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 foreign in origin, to the immune system for the purpose of eliciting or suppressing T-(helper)-cell responses that eventually lead to the production of antibodies against the same peptide antigen. Antigen presenting cells (macrophages, 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 constitutes 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

The genetics of HLA-DR is complex because HLA-DR is encoded by several loci and several 'genes' of different function at each locus.

The DR α-chain is encoded by the HLA-DRA (DRA1) locus. Unlike the other DR loci functional variation in mature DRA gene products is absent. (Note: see table Number of Variant Alleles HLA-DR Loci- 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)).

28 (of 75) Most common DR-DQ haplotypes in Caucasian Americans
DR DR-DQ DR DQ Freq
Serotype haplotype B1 A1 B1 %[1]
DR1 DR1-DQ5 0101 0101 0501 9. 1
0102 0101 0501 1. 4
0103 0101 0501 0. 5
DR3 DR3-DQ2 0301 0501 0201 13. 1
DR4 DR4-DQ7 0401 0300 0301 5. 4
0407 0300 0301 0. 9
DR4-DQ8 0401 0300 0302 5. 0
0402 0300 0302 1. 0
0403 0300 0302 0. 4
0404 0300 0302 3. 9
0405 0300 0302 0. 3
DR7 DR7-DQ2 0701 0201 0202 11. 1
DR7-DQ9 0701 0201 0303 3. 7
DR8 DR8-DQ4 0801 0401 0402 2. 2
DR8-DQ7 0803 0601 0301 0. 1
DR9 DR9-DQ9 0901 0300 0303 0. 8
DR10 DR10-DQ5 1001 0104 0501 0. 7
DR11 DR11-DQ7 1101 0505 0301 5. 6
1103 0505 0301 0. 3
1104 0505 0301 2. 7
DR12 DR12-DQ7 1201 0505 0301 1. 1
DR13 DR13-DQ6 1301 0103 0603 5. 6
1302 0102 0604 3. 4
1302 0102 0609 0. 7
DR13-DQ7 1303 0505 0301 0. 7
DR14 DR14-DQ5 1401 0104 0503 2. 0
DR15 DR15-DQ6 1501 0102 0602 14. 2
1502 0103 0602 0. 7
DR16 DR16-DQ5 1601 0102 0502 1. 0

The DR β-chain[2] is encoded by 4 loci, however no more than 3 functional loci are present in a single individual, and no more than two on a single chromosome. Sometimes an individual may only possess 2 copies of the same locus, DRB1*. The HLA-DRB1 locus is ubiquitous and encodes a very large number of functionally variable gene products (HLA-DR1 to HLA-DR17). The HLA-DRB3 locus encodes the HLA-DR52 specificity, is moderately variable and is variably associated with certain HLA-DRB1 types. The HLA-DRB4 locus encodes the HLA-DR53 specificity, has some variation, and is associated with certain HLA-DRB1 types. The HLA-DRB5 locus encodes the HLA-DR51 specificity, which is typically invariable, and is linked to the HLA-DR2 types.

  • linkage (See Table)
    • DQA1 and DQB1
      • Linkage disequilibrium exists for many DR-DQ types.
    • Nomenclature issues. Some older studies may refer to DR15 or 16 as DR2 and DQ5 and DQ6 as DQ1 therefore a haplotype DR2-DQ1 is usually referring to DR15-DQ6 but could be referring to DR16-DQ5. DR5 is used to refer to DR11 and DR12, in which case DQ3 might be used. In these instances DQ3 almost always can be interpreted as DQ7, but DR5 is most often DR11 and less frequently DR12. Similar issues exist for DR6 versus DR13 and DR14. DR6-DQ1 can refer to either DR13-DQ6 or less frequently DR14-DQ5, but DR6-DQ3 or DR6-DQ7 generally refers to DR13-DQ7. Even older literature has more confusing designations. By looking at the change of disease association with improved testing we can see how science has evolved over time.

Evolution and Allele Frequencies

There is a high level of allelic diversity at HLA DRB1, it is second only to HLA-B locus in number of allelic variants. These two loci are highest sequence variation rate within human genome. This means HLA-DRB1 is rapidly evolving, much more rapidly than almost all other protein encoding loci. 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.

ligand (Staphylococcal enterotoxin 1-C peptide:pkyvkqntlklat) within the binding pocket of DR αβ101
ligand (Staphylococcal enterotoxin 1-C peptide:pkyvkqntlklat) within the binding pocket of DR αβ101

This means that most of the changes are functional in nature, and therefore are under selection. In the HLA region, genes are under heterozygous or balancing selection, although certain alleles appear to be under positive or negative selection, either in the past or present


HLA generally evolve through a process of gene conversion, which is a form of short distance or 'abortive' genetic recombination. Functional motifs in genes are exchanged to form new alleles, and frequently new, functionally different DR isoforms. HLA-DR represents an extreme example of this. A survey of X-linked loci 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.

Number of Variant Alleles HLA-DR Loci
HLA-DR
HLA -A1 -B1 -B3 to -B51 Potential
Locus # # # Combinations
Alleles[2][3] 3 463 74 1635
Unique Polypeptide 2 394 57 902
Contact Variant 1 ~300 ~30 ~330
1DRB3, DRB4, DRB5 have variable presence in humans

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 100,000 to 150,000 years ago. The HLA-DR locus represents a major exception to this observation[4]. Based on distribution of major groupings in the human population it is possible to assert that more than a dozen major variants survived the population bottleneck. 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 HLA alleles currently present in the human population can be explained by gene conversion between these ancient ancestral types[5], some that persist into the extant population.

Serogroups

Subpages for DR serotypes
Serotypes of HLA-DRB1 gene products
Split antigens
HLA-DR1
HLA-DR2 HLA-DR15 HLA-DR16
HLA-DR3 HLA-DR17 HLA-DR18
HLA-DR4
HLA-DR5 HLA-DR11 HLA-DR12
HLA-DR6 HLA-DR13 HLA-DR14
HLA-DR7
HLA-DR8
HLA-DR9
HLA-DR10

The table provide below links to subpages with information about distribution, genetic linkage and disease association for the HLA-DR serogroups.


Interlocus DRB Linkage

Subpages for DRB3, -B4, and -B5 serotypes
Locus Serotype
HLA-DRB3 HLA-DR52
HLA-DRB4 HLA-DR53
HLA-DRB5 HLA-DR51

DRB1 is linked with other DRB loci in 4 ways

DR1 to D17 genetic linkage to DR51, DR52, and DR53
non-DRB1 linked DRB1 antigens
antigens antigens
None DR1 DR8 DR10
DR51 DR2 DR15 DR16
DR52 DR3 DR17 DR18
DR5 DR11 DR12
DR6 DR13 DR14
DR53 DR4 DR7 DR8 DR9

Associated diseases

Diseases associated with HLA-DR and links to DR subpages*
Disease Associated DR
alopecia areata DR5
anemia pernicious DR15
antiphospholipid syndrome, primary DR5 DR12
aneurysm coronary artery DR16
arteritis Takayasu's DR16
arthritis, rheumatoid juvenile DR4 DR5 DR14 DR15
pauciarticular, juv. DR8
Still's disease DR12
iritis w/juv. arthritis DR12
seronegative DR1 DR4
w/systemic sclerosis DR1
lyme disease induced DR4
tiopronin intolerance DR5 DR11 DR12
cardiomyopathy hypertrophic DR4 DR17
T. cruzi induced DR4 DR7 DR15
colitis Crohn's DR1
ulcerative DR1
diabetes juvenile (type 1) DR3 DR4 DR17 DR18
fatty liver (type 2) DR8
encephalomyelitis rabies vaccine-induced DR17
encephalopathy acute necrotizing DR52
epilepsy childhood DR5
infantile/spasm DR17
heart disease rheumatic DR16
hepatitis autoimmune DR2 DR4 DR17
primary biliary cirrhosis DR2 DR8
chronic type C DR11
lichen planus DR1 DR10
lupus, systemic DR3 DR4 DR52
hydralazine-induced DR4
with Sjögren's syndrome DR15
lymphadenopathy generalized DR5
lymphoma, mycosis fungoides DR5
melioidosis DR16
myasthenia gravis DR3 DR6 DR13 DR14
penicillamine-induced DR1
myositis inflamatory inclusion body DR17 DR18 DR52
narcolepsy DR2 DR12
nephritis, tubulointerstitial DR1
nephropathy IgA-mediated DR4
polyglandular deficiency syndrome DR5
pemphigus foliaceous DR1
vulgaris DR4
psoriasis vulgaris DR1 DR7
papillomatosis, respiratory DR1
sarcoidosis non-chronic DR17 DR52
sclerosis, mulitple DR2 DR15 DR53
"bout onset" multiple DR3
systemic DR4 DR11 DR16 DR52
vulval lichen DR12
schizophrenia DR1
susceptibility leprosy DR2
tuberculosis DR2
ragweed Ra6 allergy DR5
asthma, mite sensitive DR11
2ndary infection, AIDS DR3
aspergillosis DR15
Kaposi's sarcoma DR5
thyroid carcinomas DR8 DR11
ovarian/cervical cancer DR10 DR11 DR15
grape induced anaphylaxis DR11
Chlamydia pneumoniae DR52
thyroiditis Hashimoto's DR2 DR5
Grave's DR3 DR17 DR52
uveitis tubulointerstitial DR1
*references are provided on linked subpages

External links

References

  1. ↑ Klitz W, Maiers M, Spellman S, Baxter-Lowe LA, Schmeckpeper B, Williams TM, and Fernandez-Vina M (2003). "New HLA haplotype frequency reference standards: high-resolution and large sample typing of HLA DR-DQ haplotypes in a sample of European Americans". Tissue Antigens. 62 (4): 296–307. PMID 12974796.
  2. ↑ 2.0 2.1 Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Geraghty DE, Hansen JA, Hurley CK, Mach B, Mayr WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GM, Strominger JL, Svejgaard A, Terasaki PI, and Trowsdale J. (2005). "Nomenclature for factors of the HLA System, 2004". Tissue antigens. 65: 301–369. PMID 15787720.
  3. ↑ Robinson J, Waller M, Parham P, de Groot N, Bontrop R, Kennedy L, Stoehr P, Marsh S (2003). "IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex". Nucleic Acids Res. 31 (1): 311–4. PMID 12520010.
  4. ↑ Ayala F (1995). "The myth of Eve: molecular biology and human origins". Science. 270 (5244): 1930–6. PMID 8533083.
  5. ↑ Parham P, Ohta T (1996). "Population biology of antigen presentation by MHC class I molecules". Science. 272 (5258): 67–74. PMID 8600539.

Further reading

  • Bénichou S, Benmerah A (2003). "The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway". Med Sci (Paris). 19 (1): 100–6. PMID 12836198.
  • Tolstrup M, Ostergaard L, Laursen AL; et al. (2004). "HIV/SIV escape from immune surveillance: focus on Nef". Curr. HIV Res. 2 (2): 141–51. PMID 15078178.
  • Anderson JL, Hope TJ (2005). "HIV accessory proteins and surviving the host cell". Current HIV/AIDS reports. 1 (1): 47–53. PMID 16091223.
  • Li L, Li HS, Pauza CD; et al. (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Res. 15 (11–12): 923–34. doi:10.1038/sj.cr.7290370. PMID 16354571.
  • Stove V, Verhasselt B (2006). "Modelling thymic HIV-1 Nef effects". Curr. HIV Res. 4 (1): 57–64. PMID 16454711.
  • Matsushima GK, Itoh-Lindstrom Y, Ting JP (1992). "Activation of the HLA-DRA gene in primary human T lymphocytes: novel usage of TATA and the X and Y promoter elements". Mol. Cell. Biol. 12 (12): 5610–9. PMID 1448091.
  • Schaiff WT, Hruska KA, McCourt DW; et al. (1992). "HLA-DR associates with specific stress proteins and is retained in the endoplasmic reticulum in invariant chain negative cells". J. Exp. Med. 176 (3): 657–66. PMID 1512535.
  • Piatier-Tonneau D, Gastinel LN, Amblard F; et al. (1991). "Interaction of CD4 with HLA class II antigens and HIV gp120". Immunogenetics. 34 (2): 121–8. PMID 1869305.
  • Nong Y, Kandil O, Tobin EH; et al. (1991). "The HIV core protein p24 inhibits interferon-gamma-induced increase of HLA-DR and cytochrome b heavy chain mRNA levels in the human monocyte-like cell line THP1". Cell. Immunol. 132 (1): 10–6. PMID 1905983.
  • Rosenstein Y, Burakoff SJ, Herrmann SH (1990). "HIV-gp120 can block CD4-class II MHC-mediated adhesion". J. Immunol. 144 (2): 526–31. PMID 1967269.
  • Callahan KM, Fort MM, Obah EA; et al. (1990). "Genetic variability in HIV-1 gp120 affects interactions with HLA molecules and T cell receptor". J. Immunol. 144 (9): 3341–6. PMID 1970352.
  • Bowman MR, MacFerrin KD, Schreiber SL, Burakoff SJ (1991). "Identification and structural analysis of residues in the V1 region of CD4 involved in interaction with human immunodeficiency virus envelope glycoprotein gp120 and class II major histocompatibility complex molecules". Proc. Natl. Acad. Sci. U.S.A. 87 (22): 9052–6. PMID 1978941.
  • Koppelman B, Cresswell P (1990). "Rapid nonlysosomal degradation of assembled HLA class II glycoproteins incorporating a mutant DR alpha-chain". J. Immunol. 145 (8): 2730–6. PMID 2212658.
  • Clayton LK, Sieh M, Pious DA, Reinherz EL (1989). "Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding". Nature. 339 (6225): 548–51. doi:10.1038/339548a0. PMID 2543930.
  • Diamond DC, Sleckman BP, Gregory T; et al. (1988). "Inhibition of CD4+ T cell function by the HIV envelope protein, gp120". J. Immunol. 141 (11): 3715–7. PMID 2846691.
  • Tjernlund U, Scheynius A, Johansson C; et al. (1989). "T-cell response to purified protein derivative after removal of Langerhans' cells from epidermal cell suspensions containing keratinocytes expressing class II transplantation antigens". Scand. J. Immunol. 28 (6): 667–73. PMID 3266023.
  • Andrieu JM, Even P, Venet A (1986). "AIDS and related syndromes as a viral-induced autoimmune disease of the immune system: an anti-MHC II disorder. Therapeutic implications". AIDS research. 2 (3): 163–74. PMID 3489470.
  • Das HK, Lawrance SK, Weissman SM (1983). "Structure and nucleotide sequence of the heavy chain gene of HLA-DR". Proc. Natl. Acad. Sci. U.S.A. 80 (12): 3543–7. PMID 6304715.
  • Schamboeck A, Korman AJ, Kamb A, Strominger JL (1984). "Organization of the transcriptional unit of a human class II histocompatibility antigen: HLA-DR heavy chain". Nucleic Acids Res. 11 (24): 8663–75. PMID 6324094.
  • Das HK, Biro PA, Cohen SN; et al. (1983). "Use of synthetic oligonucleotide probes complementary to genes for human HLA-DR alpha and beta as extension primers for the isolation of 5'-specific genomic clones". Proc. Natl. Acad. Sci. U.S.A. 80 (6): 1531–5. PMID 6403940.


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