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HLA-DR

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MHC class II, DR
(heterodimer)
Illustration of DR with bound ligand (yellow)
Protein typecell surface receptor
FunctionImmune recognition and
antigen presentation
Subunit name Gene Chromosomal locus
α HLA-DRA Chromosome 6p21.31
β1 HLA-DRB1 " "
β3 HLA-DRB3 " "
β4 HLA-DRB4 " "
β5 HLA-DRB5 " "

HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR (Human Leukocyte Antigen – DR isotype) and peptide, generally between 9 and 30 amino acids in length, constitutes a ligand for the T-cell receptor (TCR). HLA (human leukocyte antigens) were originally defined as cell surface antigens that mediate graft-versus-host disease. Identification of these antigens has led to greater success and longevity in organ transplant.

Antigens most responsible for graft loss are HLA-DR (first six months), HLA-B (first two years), and HLA-A (long-term survival).[1] Good matching of these antigens between host and donor is most critical for achieving graft survival.

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 staphylococcal enterotoxin I peptide) 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

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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

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HLA-DR is an αβ heterodimer, cell surface receptor, each subunit of which contains two 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 first 80 residues of each chain.

Genetics

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The genetics of HLA-DR is complex. 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 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 Americans of European descent
DR DR-DQ DR DQ Freq
Serotype haplotype B1 A1 B1 %[2]
DR1 DR1-DQ5 01:01 01:01 05:01 9. 1
01:02 01:01 05:01 1. 4
01:03 01:01 05:01 0. 5
DR3 DR3-DQ2 03:01 05:01 02:01 13. 1
DR4 DR4-DQ7 04:01 0300 03:01 5. 4
04:07 0300 03:01 0. 9
DR4-DQ8 04:01 0300 03:02 5. 0
04:02 0300 03:02 1. 0
04:03 0300 03:02 0. 4
04:04 0300 03:02 3. 9
04:05 0300 03:02 0. 3
DR7 DR7-DQ2 07:01 02:01 02:02 11. 1
DR7-DQ9 07:01 02:01 03:03 3. 7
DR8 DR8-DQ4 08:01 04:01 04:02 2. 2
DR8-DQ7 08:03 06:01 03:01 0. 1
DR9 DR9-DQ9 09:01 0300 03:03 0. 8
DR10 DR10-DQ5 10:01 01:04 05:01 0. 7
DR11 DR11-DQ7 11:01 05:05 03:01 5. 6
11:03 05:05 03:01 0. 3
11:04 05:05 03:01 2. 7
DR12 DR12-DQ7 12:01 05:05 03:01 1. 1
DR13 DR13-DQ6 13:01 01:03 06:03 5. 6
13:02 01:02 06:04 3. 4
13:02 01:02 06:09 0. 7
DR13-DQ7 13:03 05:05 03:01 0. 7
DR14 DR14-DQ5 14:01 01:04 05:03 2. 0
DR15 DR15-DQ6 15:01 01:02 06:02 14. 2
15:02 01:03 06:01 0. 7
DR16 DR16-DQ5 16:01 01:02 05:02 1. 0
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

The DR β-chain[3] 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 HLA nomenclature has evolved over time.
Number of Variant Alleles HLA-DR Loci
HLA-DR
HLA -A1 -B1 -B3 to -B51 Potential
Locus # # # Combinations
Alleles[3][4] 3 463 74 1635
Unique Polypeptide 2 394 57 902
Contact Variant 1 ~300 ~30 ~330
1DRB3, DRB4, DRB5 have variable presence in humans

Evolution and allele frequencies

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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. 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.

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.[5] 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,[6] some that persist into the extant population.

Serogroups

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

Interlocus DRB linkage

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DRB1 is linked with other DRB loci in four ways.

DR1 to DR18 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


Diseases associated with HLA-DR and links to DR subpages(V - T)
Class Disease Associated DR 2 3 4
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
seropositive DR1 DR4 DR10
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 syndrome DR15
lymphadenopathy generalized DR5
lymphoma, mycosis fungoides DR5
melioidosis DR16
myasthenia gravis DR3 DR6 DR13 DR14
penicillamine-induced DR1
myositis inflammatory 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, multiple 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 DR3 DR5
Graves' DR3 DR17 DR52
uveitis tubulointerstitial DR1
*references are provided on linked subpages

References

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  1. ^ Solomon S, Pitossi F, Rao MS (2015). "Banking on iPSC--is it doable and is it worthwhile". Stem Cell Reviews. 11 (1): 1–10. doi:10.1007/s12015-014-9574-4. PMC 4333229. PMID 25516409.
  2. ^ Klitz W, Maiers M, Spellman S, Baxter-Lowe LA, Schmeckpeper B, Williams TM, 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. doi:10.1034/j.1399-0039.2003.00103.x. PMID 12974796.
  3. ^ a b Marsh, S. G.; Albert, E. D.; Bodmer, W. F.; Bontrop, R. E.; Dupont, B.; Erlich, H. A.; Fernández-Viña, M.; Geraghty, D. E.; Holdsworth, R.; Hurley, C. K.; Lau, M.; Lee, K. W.; Mach, B.; Maiers, M.; Mayr, W. R.; Müller, C. R.; Parham, P.; Petersdorf, E. W.; Sasazuki, T.; Strominger, J. L.; Svejgaard, A.; Terasaki, P. I.; Tiercy, J. M.; Trowsdale, J. (2010). "Nomenclature for factors of the HLA system, 2010". Tissue Antigens. 75 (4): 291–455. doi:10.1111/j.1399-0039.2010.01466.x. PMC 2848993. PMID 20356336.
  4. ^ 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. doi:10.1093/nar/gkg070. PMC 165517. PMID 12520010.
  5. ^ Ayala F (1995). "The myth of Eve: molecular biology and human origins" (PDF). Science. 270 (5244): 1930–6. Bibcode:1995Sci...270.1930A. doi:10.1126/science.270.5244.1930. PMID 8533083.
  6. ^ Parham P, Ohta T (1996). "Population biology of antigen presentation by MHC class I molecules". Science. 272 (5258): 67–74. Bibcode:1996Sci...272...67P. doi:10.1126/science.272.5258.67. PMID 8600539. S2CID 22209086.

Further reading

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