Definitions

HLA-DR antigens

HLA-DR

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. The complex of HLA-DR and its ligand, a peptide of 9 amino acids in length or longer, 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, 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

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. 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 Caucasian Americans
DR DR-DQ DR DQ Freq
Serotype haplotype B1 A1 B1 %
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 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.

Number of Variant Alleles HLA-DR Loci
HLA-DR
HLA -A1 -B1 -B3 to -B51 Potential
Locus # # # Combinations
Alleles 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

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. 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, 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

DRB1 is linked with other DRB loci in 4 ways

! width = "70px" | non-DRB1
! antigens
!  None
! DR51
! rowspan = "3"  | DR52
! DR53
DR1 to D17 genetic linkage to DR51, DR52, and DR53
linked DRB1 antigens
antigens
DR1 DR8 DR10
DR2 DR15 DR16
DR3 DR17 DR18
DR5 DR11 DR12
DR6 DR13 DR14
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

Further reading

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