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MHC class II, DR
MHC class II, DR
(heterodimer)
	Illustration of DR with bound ligand (yellow)
Protein type	cell surface receptor
Function	Immune recognition and; antigen presentation

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

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 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

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
	DR4-DQ7	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	DR7-DQ9	07:01	02:01	03:03	3.	7
DR8	DR8-DQ4	08:01	04:01	04:02	2.	2
DR8	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
DR15	DR15-DQ6	15:02	01:03	06:01	0.	7
DR16	DR16-DQ5	16:01	01:02	05:02	1.	0

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

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

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

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
cardiomyopathy	T. cruzi induced	DR4	DR7	DR15
colitis	Crohn's	DR1
colitis	ulcerative	DR1
diabetes	juvenile (type 1)	DR3	DR4	DR17	DR18
diabetes	fatty liver (type 2)	DR8
encephalomyelitis	rabies vaccine-induced	DR17
encephalopathy	acute necrotizing	DR52
epilepsy	childhood	DR5
epilepsy	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
myasthenia	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
pemphigus	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
thyroiditis	Graves'	DR3	DR17	DR52
uveitis	tubulointerstitial	DR1
^*references are provided on linked subpages

References

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^ 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.
^ ^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.
^ 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.
^ 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.
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