HLA-DQ
Encyclopedia
HLA-DQ is a cell surface receptor type protein
found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II
type. The α and β chains are encoded by HLA-DQA1
and HLA-DQB1
, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain vary greatly. A person often produces two α-chain and two β-chain variants and thus 4 DQ isoforms. The DQ loci are in close genetic linkage
to HLA-DR but less closely linked to HLA-DP
, HLA-A
, HLA-B
and HLA-C
.
DQ functions on antigen presenting cells, and is an antigen
presenting molecule
. Different DQ isoforms can bind to and present different antigens to T-cells. In this process T-cells are stimulated to grow and can signal B-cells to produce antibodies. DQ functions in recognizing and presenting foreign antigens (proteins derived from potential pathogens). But DQ is also involved in recognizing common self-antigens and presenting those antigens to the immune system in order to develop tolerance
from a very young age.
When tolerance to self proteins is lost, DQ may become involved in autoimmune disease
. Two autoimmune diseases in which HLA-DQ is involved are coeliac disease
and diabetes mellitus type 1
. DQ is one of several antigens involved in rejection of organ transplants
. As a variable cell surface receptor on immune cells, these D antigens, originally HL-A4 antigens, are involved in graft versus host disease when lymphoid tissues are transplanted between people. Serological studies
of DQ recognized that antibodies to DQ bind primarily to the β-chain. The currently used serotypes are HLA-DQ2
, -DQ3
, -DQ4
, -DQ5
, -DQ6
, -DQ7
, -DQ8
, -DQ9
. HLA-DQ1
is a weak reaction to the α-chain and was replaced by DQ5 and DQ6 serology. Serotyping is capable of identifying most aspects of DQ isoform structure and function, however sequence specific PCR is now the preferred method of determining HLA-DQA1 and HLA-DQB1 alleles, as serotyping cannot resolve, often, the critical contribution of the DQ α-chain. This can be compensated for by examining DR serotypes as well as DQ serotypes.
of humans; however, this status is an artifact of the early era of organ transplantation.
HLA DQ functions as a cell surface receptor for foreign or self antigens. The immune system surveys antigens for foreign pathogens when presented by MHC receptors (like HLA DQ). The MHC Class II antigens are found on antigen presenting cells (APC) (macrophages, dendritic cells, and B-lymphocytes). Normally, these APC 'present' class II receptor/antigens to a great many T-cells, each with unique T-cell receptor (TCR) variants. A few TCR variants that recognize these DQ/antigen complexes are on CD4 positive (CD4+) T-cells. These T-cells, called T-helper cells, can promote the amplification of B-cells which, in turn recognize a different portion of the same antigen. Alternatively, macrophages and other megalocytes consume cells by apoptotic signaling and present self-antigens. Self antigens, in the right context, form a suppressor T-cell population that protects self tissues from immune attack or autoimmunity.
HLA-DQ (DQ) is encoded on the HLA
region of chromosome 6p21.3, in what was classically known as the "D" antigen region. This region encoded the subunits for DP,-Q and -R which are the major MHC class II
antigens in humans. Each of these proteins have slightly different functions and are regulated in slightly different ways.
DQ is made up of two different subunits to form an αβ-heterodimer. Each subunit is encoded by its own "gene" (a coding locus). The
DQ α subunit is encoded by the HLA-DQA1
gene and the DQ β subunit is encoded by the HLA-DQB1
gene. Both loci are variable in the human population (see regional evolution).
and are the result of single nucleotide polymorphism
s (SNP). Some
SNP result in no change in amino-acid sequence. Others result in changes in regions that are removed when the proteins is processed to the cell surface, still others result in change in the non-functional regions of the protein, and some changes result in a change of function of the DQ isoform that is produced. The isoforms generally
change in the peptides they bind and present to T-cells. Much of
the isoform variation in DQ is within these 'functional' regions.
Serotyping. Antibodies raised against DQ tend to recognize these functional regions, in most cases the β-subunit. As a result these antibodies can discriminate different classes of DQ based on the recognition similar DQβ proteins known as serotype
s.
An example of a serotype is DQ2.
Sometimes DQ2 antibodies recognize other gene products, such as DQB1*0303, resulting
serotyping errors. Because of this mistyping serotyping is not as reliable as gene sequencing
or SSP-PCR.
While the DQ2 isoforms are recognized by the same antibodies, and all
DQB1*02 are functionally similar, they can bind different α subunit and these αβ isoform variants can bind different sets of peptides. This difference in binding is an important feature that helps to understand autoimmune disease.
The first identified DQ were DQw1 to DQw3. DQw1 (DQ1) recognized the alpha chain of DQA1*01 alleles. This group was later split by beta chain recognition to DQ5 and DQ6. DQ3 is known as broad antigen serotypes, because they recognize a broad group of antigens. However, because of this broad antigen recognition their specificity and usefulness is somewhat less than desirable.
For most modern typing the DQ2, DQ4 - DQ9 set is used.
Genetic Typing. With the exception of DQ2 (*0201) which
has a 98% detection capability, serotyping has drawbacks in relative accuracy. In addition, for many HLA studies genetic typing
does not offer that much greater advantage over serotyping, but in the case of DQ there is a need for precise identification
of HLA-DQB1 and HLA-DQA1 which cannot be provided by serotyping.
Isoform functionality is dependent on αβ composition. Most studies indicate a chromosomal linkage between disease causing
DQA1 and DQB1 genes. Therefore the DQA1, α, component is as important as DQB1. An example of this is DQ2, DQ2 mediates Coeliac disease
and Type 1 diabetes but only if the α5 subunit is present. This subunit can be encoded by either DQA1*0501 or DQA1*0505. When the DQ2 encoding β-chain gene is on the same chromosome as the α5 subunit isoform, then individuals
who have this chromosome have a much higher risk of these two disease. When DQA1 and DQB1 alleles are linked in this way
they form a haplotype. The DQA1*0501-DQB1*0201 haplotype is called the DQ2.5 haplotype, and the DQ that results α5β² is the "cis-haplotype" or "cis-chromosomal" isoform of DQ2.5
To detect these potential combinations one uses a technique called SSP-PCR (Sequence specific primer polymerase chain reaction). This techniques works because, outside of a few areas of Africa, we know the overwhelming majority of all DQ alleles in the world. The primers are specific for known DQ and thus, if a product is seen it means that gene motif is present. This results in nearly 100% accurate typing of DQA1 and DQB1 alleles.
'How does one know which isoforms are functionally unique and which isoforms are functionally synonymous with other isoforms'?. The IMGT/HLA database also provides alignments for various alleles, these alignments show the variable regions and conserved regions. By examining the structure of these variable regions with different ligands bound
(such as the MMDB) one can see which residues come into close contact with peptides and those the have side chains that are distal. Those changes more than 10 Angstoms away generally do not affect binding of peptides. The structure of HLA-DQ8/insulin peptide at NCBI can be view with Cn3D
or Rasmol
. In Cn3D one can highlight the peptide and then select for amino acids within 3 or more Angstroms of the peptide. Side chains that come close to the peptide can be identified and then examined on the sequence alignments at IMGT/HLA database. Anyone can download software and sequence. Have fun!
containing two protein subunits, alpha (DQA1 gene product) and beta (DQB1 gene product), a DQ heterodimer. These receptors can be made from alpha+beta sets of two different DQ haplotype
s, one set from the maternal and paternal chromosome
. If one carries haplotype -A-B- from one parent and -a-b- from the other, that person makes 2 alpha isoforms (A and a) and 2 beta isoforms (B and b). This can produce 4 slightly different receptor heterodimers (or more simply, DQ isoforms). Two isoforms are in the cis
-haplotype pairing (AB and ab) and 2 are in the trans
-haplotype pairing (Ab and aB). Such a person is a double heterozygote for these genes, for DQ the most popular situation. If a person carries haplotypes -A-B- and -A-b- then they can only make 2 DQ (AB and Ab), but if a person carries haplotypes -A-B- and -A-B- then they can only make DQ isoform AB, called a double homozygote. In coeliac disease, certain homozygotes and are at higher risk for disease and some specific complications of coeliac disease such as Gluten-sensitive enteropathy associated T-cell lymphoma
homozygotes and double homozygotes. Homozygotes at DQ loci can change risk for disease. In mice for instance, mice with 2 copies of the DQ-like Iab haplotype are more likely to progress toward fatal disease compared to mice that are heterozygotes only for the beta allele (MHC IAαb / IAαb, IAβb / IAβbm12). In humans, celiac disease DQ2.5/DQ2 homozygotes are several times more likely to have celiac disease versus DQ2.5/DQX individuals. DQ2/DQ2 homozygotes are at elevated risk for severe complications of disease. For an explanation of the risk association see:Talk:HLA-DQ#Effects of heterogeneity of isoform pairing-Expanded
Involvement of transhaplotypes in disease
There is some controversy in the literature whether trans-isoforms are relevant. Recent genetic studies into coeliac disease
have revealed that the DQA1*0505:X/Y:DQB1*0202 gene products explain disease not linked to the haplotype that produces DQ8 and DQ2.5, strongly suggesting the trans-isoforms can be involved in disease. But, in this example, it is known that the transproduct is almost identical to a know cis-'isoform' produced by DQ2.5. There is other evidence that some haplotypes are linked to disease but show neutral linkage with other particular haplotypes are present. At present, the bias of relative isoform frequency toward cis pairing is unknown, it is known that some trans-isoforms occur.
see:Talk:HLA-DQ#Effects of heterogeneity of isoform pairing-Expanded
(MHC) gene family and have analogs in other mammalian species. In mice the MHC locus known as IA is homologous to human HLA DQ. Several autoimmune diseases that occur in humans that are mediated by DQ also can be induced in mice and are mediated through IA. Myasthenia gravis
is an example of one such disease. Linking specific sites on autoantigens is more difficult in humans due to the complex variation of heterologous humans, but subtle differences in T-cell stimulation associated with DQ-types has been observed. These studies indicate that potentially a small change or increase in the presentation of a potential self-antigen can result in autoimmunity. This may explain
why there is often linkage to DR or DQ, but the linkage is often weak.
Regional Evolution
Many HLA DQ were under positive selection of 10,000s potentially 100,000s of years in some regions. As people moved they have tended to lose haplotypes and in the process lose
allelic diversity. On the other hand, on arrival at new distal locations, selection
would offer unknown selective forces that would have initially favored diversity in arrivals. By an unknown process, rapid evolution occurs, as has been seen in South Americas
indigeonous population (Parham and Ohta, 1996, Watkins 1995), and new alleles rapidly
appear. This process may be of immediate benefit of being positively selective in that new environment, but these new alleles might also be 'sloppy' in a selective perspective, having side effects if selection changed. The table to the left demonstrates how absolute diversity
at the global level translates into relative diversity at the regional level.
-
frequencies, by random mating, are expected in Sweden, but pockets of high levels also occur in Mexico, and a larger range risk exists in Central Asia.
Diseases that appear to be increased in Heterozygotes are Type 1 Diabetes. New evidence is showing an increased risk for late onset Type 1 diabetes in Heterozygotes (which includes ambiguous Type I/Type II diabetes). There is no evidence that celiac disease may have a slightly increased risk with
a more severe course of disease.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
type. The α and β chains are encoded by HLA-DQA1
HLA-DQA1
Major histocompatibility complex, class II, DQ alpha 1, also known as HLA-DQA1, is a human gene present on short arm of chromosome 6 and also denotes the genetic locus which contains this gene...
and HLA-DQB1
HLA-DQB1
Major histocompatibility complex, class II, DQ beta 1, also known as HLA-DQB1, is a human gene and also denotes the genetic locus that contains this gene...
, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain vary greatly. A person often produces two α-chain and two β-chain variants and thus 4 DQ isoforms. The DQ loci are in close genetic linkage
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
to HLA-DR but less closely linked to HLA-DP
HLA-DP
HLA-DP is a protein/peptide-antigen receptor and graft-versus-host disease antigen that is composed of 2 subunits, DPα and DPβ. DPα and DPβ are encoded by two loci, HLA-DPA1 and HLA-DPB1, that are found in the MHC Class II region in the Human Leukocyte Antigen complex on human chromosome 6 .Less...
, HLA-A
HLA-A
HLA-A are a group of human leukocyte antigens that are encoded by the HLA-A locus on human chromosome 6p. The HLA genes constitute a large subset of the Major histocompatibility complex of humans. HLA-A is a component of certain MHC class I cell surface receptor isoforms that resides on the...
, HLA-B
HLA-B
HLA-B is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen complex...
and HLA-C
HLA-C
HLA-C belongs to the MHC class I heavy chain receptors. The C receptor is a heterodimer consisting of a HLA-C mature gene product and β2-microglobulin. The mature C chain is anchored in the membrane...
.
DQ functions on antigen presenting cells, and is an antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
presenting molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
. Different DQ isoforms can bind to and present different antigens to T-cells. In this process T-cells are stimulated to grow and can signal B-cells to produce antibodies. DQ functions in recognizing and presenting foreign antigens (proteins derived from potential pathogens). But DQ is also involved in recognizing common self-antigens and presenting those antigens to the immune system in order to develop tolerance
Immune tolerance
Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either 'natural' or 'self tolerance', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which tolerance to external antigens can...
from a very young age.
When tolerance to self proteins is lost, DQ may become involved in autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
. Two autoimmune diseases in which HLA-DQ is involved are coeliac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
and diabetes mellitus type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
. DQ is one of several antigens involved in rejection of organ transplants
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
. As a variable cell surface receptor on immune cells, these D antigens, originally HL-A4 antigens, are involved in graft versus host disease when lymphoid tissues are transplanted between people. Serological studies
Serology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
of DQ recognized that antibodies to DQ bind primarily to the β-chain. The currently used serotypes are HLA-DQ2
HLA-DQ2
HLA-DQ2 is a serotype group within HLA-DQ serotyping system. The serotype is determined by the antibody recognition of β2 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ2 are encoded by the HLA-DQB1*02 allele group. This group currently contains two common alleles,...
, -DQ3
HLA-DQ3
HLA-DQ3 is a broad serotype category with split antigens HLA-DQ7, DQ8, and DQ9. Historically, originally recognized as MB3 a DC4 serotype, DQw3 was one of three early determined antigens recognized as HLA-DQ along with HLA-DQ1 and HLA-DQ2...
, -DQ4
HLA-DQ4
HLA-DQ4 is a serotype subgroup within HLA-DQ serotypes. The serotype is determined by the antibody recognition of β4 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ4 are encoded by the HLA-DQB1*04 allele group. This group currently contains 2 common alleles, DQB1*0401...
, -DQ5
HLA-DQ5
HLA-DQ4 is a human leukocyte antigen serotype subgroup within HLA-DQ serotypes. The serotype is determined by the antibody recognition of β5.x subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ5 are encoded by the HLA-DQB1*05 allele group. This group currently contains 4...
, -DQ6
HLA-DQ6
HLA-DQ6 is a human leukocyte antigen serotype within HLA-DQ serotype group. The serotype is determined by the antibody recognition of β6 subset of DQ β-chains. The β-chain of DQ isoforms are encoded by HLA-DQB1 locus and DQ6 are encoded by the HLA-DQB1*06 allele group. This group currently...
, -DQ7
HLA-DQ7
HLA-DQ7 is an HLA-DQ serotype that recognizes the common HLA DRB1*0301 and the less common HLA DRB1*0304 gene products. DQ7 is a form of 'split antigen' of the broad antigen group DQ3 which also contains DQ8 and DQ9....
, -DQ8
HLA-DQ8
HLA-DQ8 is a human leukocyte antigen serotype within the HLA-DQ serotype group. DQ8 is a split antigen of the DQ3 broad antigen. DQ8 is determined by the antibody recognition of β8 and this generally detects the gene product of DQB1*0302....
, -DQ9
HLA-DQ9
HLA-DQ9 is a human leukocyte antigen serotype within the HLA-DQ serotype group. DQ8 is a split antigen of the DQ3 broad antigen. DQ8 is determined by the antibody recognition of β9 and this generally detects the gene product of DQB1*0303.-Serology:...
. HLA-DQ1
HLA-DQ1
HLA-DQ1 is a serotype that covers a broad range of HLA-DQ haplotypes. Historically it was identified as a DR-like alpha chain called DC1, later, it was among 3 types DQw1 , DQw2 and DQw3. Of these three serotyping specificities only DQw1 recognized DQ alpha chain. The serotype is positive in...
is a weak reaction to the α-chain and was replaced by DQ5 and DQ6 serology. Serotyping is capable of identifying most aspects of DQ isoform structure and function, however sequence specific PCR is now the preferred method of determining HLA-DQA1 and HLA-DQB1 alleles, as serotyping cannot resolve, often, the critical contribution of the DQ α-chain. This can be compensated for by examining DR serotypes as well as DQ serotypes.
Structure, Functions, Genetics
Function
The name 'HLA DQ' originally describes a transplantation antigen of MHC class II category of the major histocompatibility complexMajor histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
of humans; however, this status is an artifact of the early era of organ transplantation.
HLA DQ functions as a cell surface receptor for foreign or self antigens. The immune system surveys antigens for foreign pathogens when presented by MHC receptors (like HLA DQ). The MHC Class II antigens are found on antigen presenting cells (APC) (macrophages, dendritic cells, and B-lymphocytes). Normally, these APC 'present' class II receptor/antigens to a great many T-cells, each with unique T-cell receptor (TCR) variants. A few TCR variants that recognize these DQ/antigen complexes are on CD4 positive (CD4+) T-cells. These T-cells, called T-helper cells, can promote the amplification of B-cells which, in turn recognize a different portion of the same antigen. Alternatively, macrophages and other megalocytes consume cells by apoptotic signaling and present self-antigens. Self antigens, in the right context, form a suppressor T-cell population that protects self tissues from immune attack or autoimmunity.
Genetics
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
region of chromosome 6p21.3, in what was classically known as the "D" antigen region. This region encoded the subunits for DP,-Q and -R which are the major MHC class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
antigens in humans. Each of these proteins have slightly different functions and are regulated in slightly different ways.
DQ is made up of two different subunits to form an αβ-heterodimer. Each subunit is encoded by its own "gene" (a coding locus). The
DQ α subunit is encoded by the HLA-DQA1
HLA-DQA1
Major histocompatibility complex, class II, DQ alpha 1, also known as HLA-DQA1, is a human gene present on short arm of chromosome 6 and also denotes the genetic locus which contains this gene...
gene and the DQ β subunit is encoded by the HLA-DQB1
HLA-DQB1
Major histocompatibility complex, class II, DQ beta 1, also known as HLA-DQB1, is a human gene and also denotes the genetic locus that contains this gene...
gene. Both loci are variable in the human population (see regional evolution).
Detecting DQ isoforms
In the human population DQ is highly variable, the β subunit more so than the alpha chain. The variants are encoded by the HLA DQ genesand are the result of single nucleotide polymorphism
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
s (SNP). Some
SNP result in no change in amino-acid sequence. Others result in changes in regions that are removed when the proteins is processed to the cell surface, still others result in change in the non-functional regions of the protein, and some changes result in a change of function of the DQ isoform that is produced. The isoforms generally
change in the peptides they bind and present to T-cells. Much of
the isoform variation in DQ is within these 'functional' regions.
Serotyping. Antibodies raised against DQ tend to recognize these functional regions, in most cases the β-subunit. As a result these antibodies can discriminate different classes of DQ based on the recognition similar DQβ proteins known as serotype
Serotype
Serotype or serovar refers to distinct variations within a subspecies of bacteria or viruses. These microorganisms, viruses, or cells are classified together based on their cell surface antigens...
s.
An example of a serotype is DQ2.
- Recognize HLA-DQB1*02 gene products which include gene products of the following alleles:
- HLA-DQB1*0201
- HLA-DQB1*0202
- HLA-DQB1*0203
Sometimes DQ2 antibodies recognize other gene products, such as DQB1*0303, resulting
serotyping errors. Because of this mistyping serotyping is not as reliable as gene sequencing
or SSP-PCR.
While the DQ2 isoforms are recognized by the same antibodies, and all
DQB1*02 are functionally similar, they can bind different α subunit and these αβ isoform variants can bind different sets of peptides. This difference in binding is an important feature that helps to understand autoimmune disease.
The first identified DQ were DQw1 to DQw3. DQw1 (DQ1) recognized the alpha chain of DQA1*01 alleles. This group was later split by beta chain recognition to DQ5 and DQ6. DQ3 is known as broad antigen serotypes, because they recognize a broad group of antigens. However, because of this broad antigen recognition their specificity and usefulness is somewhat less than desirable.
For most modern typing the DQ2, DQ4 - DQ9 set is used.
| DQ | DQ | DQ | Freq | |||||
|---|---|---|---|---|---|---|---|---|
| Serotype | cis-isoform | Subtype | A1 | B1 | % | rank | ||
| DQ2 HLA-DQ2 HLA-DQ2 is a serotype group within HLA-DQ serotyping system. The serotype is determined by the antibody recognition of β2 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ2 are encoded by the HLA-DQB1*02 allele group. This group currently contains two common alleles,... |
α5-β2 | 2.5 | 0501♣ | 0201 | 13. | 16 | 2nd | |
| α2-β2 | 2.2 | 0201 | 0202 | 11. | 08 | 3rd | ||
| α3-β2 | 2.3 | 0302♠ | 0202 | 0. | 08 | |||
| DQ4 HLA-DQ4 HLA-DQ4 is a serotype subgroup within HLA-DQ serotypes. The serotype is determined by the antibody recognition of β4 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ4 are encoded by the HLA-DQB1*04 allele group. This group currently contains 2 common alleles, DQB1*0401... |
α3-β4 | 4.3 | 0301 | 0402 | 0. | 03 | ||
| 0302♠ | 0402 | 0. | 11 | |||||
| α4-β4 | 4.4 | 0401 | 0402 | 2. | 26 | |||
| DQ5 HLA-DQ5 HLA-DQ4 is a human leukocyte antigen serotype subgroup within HLA-DQ serotypes. The serotype is determined by the antibody recognition of β5.x subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ5 are encoded by the HLA-DQB1*05 allele group. This group currently contains 4... |
α1-β5.1 | 5.1 | 0101 | 0501 | 10. | 85 | 5th | |
| 0102 | 0501 | 0. | 03 | |||||
| 0103 | 0501 | 0. | 03 | |||||
| 0104 | 0501 | 0. | 71 | |||||
| α1-β5.2 | 5.2 | 0102 | 0502 | 1. | 20 | |||
| 0103 | 0502 | 0. | 05 | |||||
| α1-β5.3 | 5.3 | 0104 | 0503 | 2. | 03 | |||
| α1-β5.4 | 5.4 | 0102 | 0504 | 0. | 08 | |||
| DQ6 HLA-DQ6 HLA-DQ6 is a human leukocyte antigen serotype within HLA-DQ serotype group. The serotype is determined by the antibody recognition of β6 subset of DQ β-chains. The β-chain of DQ isoforms are encoded by HLA-DQB1 locus and DQ6 are encoded by the HLA-DQB1*06 allele group. This group currently... |
α1-β6.1 | 6.1 | 0103 | 0601 | 0. | 66 | ||
| α1-β6.2 | 6.2 | 0102 | 0602 | 14. | 27 | 1st | ||
| 0103 | 0602 | 0. | 03 | |||||
| 0104 | 0602 | 0. | 03 | |||||
| α1-β6.3 | 6.3 | 0102 | 0603 | 0. | 27 | |||
| 0103 | 0603 | 5. | 66 | 8th | ||||
| α1-β6.4 | 6.4 | 0102 | 0604 | 3. | 40 | 10th | ||
| α1-β6.9 | 6.9 | 0102 | 0609 | 0. | 71 | |||
| DQ7 HLA-DQ7 HLA-DQ7 is an HLA-DQ serotype that recognizes the common HLA DRB1*0301 and the less common HLA DRB1*0304 gene products. DQ7 is a form of 'split antigen' of the broad antigen group DQ3 which also contains DQ8 and DQ9.... |
α2-β7 | 7.2 | 0201 | 0301 | 0. | 05 | ||
| α3-β7 | 7.3 | 0301 | 0301 | 0. | 16 | |||
| 0303♠ | 0301 | 6. | 45 | 7th | ||||
| 0301 | 0304 | 0. | 09 | |||||
| 0302♠ | 0304 | 0. | 09 | |||||
| α4-β7 | 7.4 | 0401 | 0301 | 0. | 03 | |||
| α5-β7 | 7.5 | 0505♣ | 0301 | 11. | 06 | 4th | ||
| α6-β7 | 7.6 | 0601 | 0301 | 0. | 11 | |||
| DQ8 HLA-DQ8 HLA-DQ8 is a human leukocyte antigen serotype within the HLA-DQ serotype group. DQ8 is a split antigen of the DQ3 broad antigen. DQ8 is determined by the antibody recognition of β8 and this generally detects the gene product of DQB1*0302.... |
α3-β8 | 8.1 | 0301 | 0302 | 9. | 62 | 6th | |
| 0302♠ | 0302 | 0. | 93 | |||||
| DQ9 HLA-DQ9 HLA-DQ9 is a human leukocyte antigen serotype within the HLA-DQ serotype group. DQ8 is a split antigen of the DQ3 broad antigen. DQ8 is determined by the antibody recognition of β9 and this generally detects the gene product of DQB1*0303.-Serology:... |
α2-β9 | 9.2 | 0201 | 0303 | 3. | 66 | 9th | |
| α3-β9 | 9.3 | 0302 | 0303 | 0. | 79 | |||
| ♠DQA1*0302 & *0303 not resolved; ♣DQB1*0501 & *0505, and some *0303 are resolvable by haplotype | ||||||||
Genetic Typing. With the exception of DQ2 (*0201) which
has a 98% detection capability, serotyping has drawbacks in relative accuracy. In addition, for many HLA studies genetic typing
does not offer that much greater advantage over serotyping, but in the case of DQ there is a need for precise identification
of HLA-DQB1 and HLA-DQA1 which cannot be provided by serotyping.
Isoform functionality is dependent on αβ composition. Most studies indicate a chromosomal linkage between disease causing
DQA1 and DQB1 genes. Therefore the DQA1, α, component is as important as DQB1. An example of this is DQ2, DQ2 mediates Coeliac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
and Type 1 diabetes but only if the α5 subunit is present. This subunit can be encoded by either DQA1*0501 or DQA1*0505. When the DQ2 encoding β-chain gene is on the same chromosome as the α5 subunit isoform, then individuals
who have this chromosome have a much higher risk of these two disease. When DQA1 and DQB1 alleles are linked in this way
they form a haplotype. The DQA1*0501-DQB1*0201 haplotype is called the DQ2.5 haplotype, and the DQ that results α5β² is the "cis-haplotype" or "cis-chromosomal" isoform of DQ2.5
To detect these potential combinations one uses a technique called SSP-PCR (Sequence specific primer polymerase chain reaction). This techniques works because, outside of a few areas of Africa, we know the overwhelming majority of all DQ alleles in the world. The primers are specific for known DQ and thus, if a product is seen it means that gene motif is present. This results in nearly 100% accurate typing of DQA1 and DQB1 alleles.
'How does one know which isoforms are functionally unique and which isoforms are functionally synonymous with other isoforms'?. The IMGT/HLA database also provides alignments for various alleles, these alignments show the variable regions and conserved regions. By examining the structure of these variable regions with different ligands bound
(such as the MMDB) one can see which residues come into close contact with peptides and those the have side chains that are distal. Those changes more than 10 Angstoms away generally do not affect binding of peptides. The structure of HLA-DQ8/insulin peptide at NCBI can be view with Cn3D
Cn3D
Cn3D is a Windows, Macintosh and Unix-based software from the United States National Library of Medicine that acts as a helper application for web browsers to view three-dimensional structures from The National Center for Biotechnology Information's Entrez retrieval service...
or Rasmol
RasMol
RasMol is a computer program written for molecular graphics visualization intended and used primarily for the depiction and exploration of biological macromolecule structures, such as those found in the Protein Data Bank...
. In Cn3D one can highlight the peptide and then select for amino acids within 3 or more Angstroms of the peptide. Side chains that come close to the peptide can be identified and then examined on the sequence alignments at IMGT/HLA database. Anyone can download software and sequence. Have fun!
Effects of heterogeneity of isoform pairing
As an MHC class II antigen-presenting receptor, DQ functions as a dimerProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
containing two protein subunits, alpha (DQA1 gene product) and beta (DQB1 gene product), a DQ heterodimer. These receptors can be made from alpha+beta sets of two different DQ haplotype
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
s, one set from the maternal and paternal chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
. If one carries haplotype -A-B- from one parent and -a-b- from the other, that person makes 2 alpha isoforms (A and a) and 2 beta isoforms (B and b). This can produce 4 slightly different receptor heterodimers (or more simply, DQ isoforms). Two isoforms are in the cis
Cis
Cis may have the following meanings:* "Cis-" as a prefix of Latin origin, meaning "on the same side [as]" or "on this side [of]", with several derived usages:** In chemistry, cis- refers to cis-trans isomerism...
-haplotype pairing (AB and ab) and 2 are in the trans
Trans
Trans is a Latin noun or prefix, meaning "across", "beyond" or "on the opposite side".Trans may refer to:- Science and technology :* Cis-trans isomerism, in chemistry, a form of stereoisomerism...
-haplotype pairing (Ab and aB). Such a person is a double heterozygote for these genes, for DQ the most popular situation. If a person carries haplotypes -A-B- and -A-b- then they can only make 2 DQ (AB and Ab), but if a person carries haplotypes -A-B- and -A-B- then they can only make DQ isoform AB, called a double homozygote. In coeliac disease, certain homozygotes and are at higher risk for disease and some specific complications of coeliac disease such as Gluten-sensitive enteropathy associated T-cell lymphoma
homozygotes and double homozygotes. Homozygotes at DQ loci can change risk for disease. In mice for instance, mice with 2 copies of the DQ-like Iab haplotype are more likely to progress toward fatal disease compared to mice that are heterozygotes only for the beta allele (MHC IAαb / IAαb, IAβb / IAβbm12). In humans, celiac disease DQ2.5/DQ2 homozygotes are several times more likely to have celiac disease versus DQ2.5/DQX individuals. DQ2/DQ2 homozygotes are at elevated risk for severe complications of disease. For an explanation of the risk association see:Talk:HLA-DQ#Effects of heterogeneity of isoform pairing-Expanded
Involvement of transhaplotypes in disease
There is some controversy in the literature whether trans-isoforms are relevant. Recent genetic studies into coeliac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
have revealed that the DQA1*0505:X/Y:DQB1*0202 gene products explain disease not linked to the haplotype that produces DQ8 and DQ2.5, strongly suggesting the trans-isoforms can be involved in disease. But, in this example, it is known that the transproduct is almost identical to a know cis-'isoform' produced by DQ2.5. There is other evidence that some haplotypes are linked to disease but show neutral linkage with other particular haplotypes are present. At present, the bias of relative isoform frequency toward cis pairing is unknown, it is known that some trans-isoforms occur.
see:Talk:HLA-DQ#Effects of heterogeneity of isoform pairing-Expanded
DQ Function in Autoimmunity
HLA D (-P,-Q,-R) genes are members of the Major histocompatibility complexMajor histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
(MHC) gene family and have analogs in other mammalian species. In mice the MHC locus known as IA is homologous to human HLA DQ. Several autoimmune diseases that occur in humans that are mediated by DQ also can be induced in mice and are mediated through IA. Myasthenia gravis
Myasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
is an example of one such disease. Linking specific sites on autoantigens is more difficult in humans due to the complex variation of heterologous humans, but subtle differences in T-cell stimulation associated with DQ-types has been observed. These studies indicate that potentially a small change or increase in the presentation of a potential self-antigen can result in autoimmunity. This may explain
why there is often linkage to DR or DQ, but the linkage is often weak.
Regional Evolution
| Known | HLA-DQ | Potential | |
|---|---|---|---|
| Locus: | A1 | B1 | Combinations |
| Alleles | 33 | 78 | 2475 |
| Subunit: | α | β | isoforms |
| Mature Chains | 24 | 58 | 1392 |
| Contact Variants* | ~9 | 40 | 360 |
| Caucasian (USA) | |||
| Contact Variants (CV) | 7 | 12 | 84 |
| CV-haplotypes | 30 | ||
| *Subunits vary within 9Â of peptide in DQ2.5 or DQ8 | |||
Many HLA DQ were under positive selection of 10,000s potentially 100,000s of years in some regions. As people moved they have tended to lose haplotypes and in the process lose
allelic diversity. On the other hand, on arrival at new distal locations, selection
would offer unknown selective forces that would have initially favored diversity in arrivals. By an unknown process, rapid evolution occurs, as has been seen in South Americas
indigeonous population (Parham and Ohta, 1996, Watkins 1995), and new alleles rapidly
appear. This process may be of immediate benefit of being positively selective in that new environment, but these new alleles might also be 'sloppy' in a selective perspective, having side effects if selection changed. The table to the left demonstrates how absolute diversity
at the global level translates into relative diversity at the regional level.
-
Heterozygous DQ Combinations and Disease
| DQ2.5 | DQ8 | DQ2.5/8 | |
|---|---|---|---|
| Sweden | 15.9 | 18.7 | 5.9 |
| Jalisco | 11.4 | 22.8 | 5.2 |
| England | 12.4 | 16.8 | 4.2 |
| Kazahk | 13.1 | 11 | 2.9 |
| Uygur | 12.6 | 11.4 | 2.9 |
| Finland | 9 | 15.7 | 2.8 |
| Poland | 10.7 | 9.9 | 2.1 |
DQ2.5/DQ8 Heterozygotes
The distribution of this phenotype is largely the result of admixtures between peoples of eastern or central Asian origin and peoples of western or central Asian origin. The highestfrequencies, by random mating, are expected in Sweden, but pockets of high levels also occur in Mexico, and a larger range risk exists in Central Asia.
Diseases that appear to be increased in Heterozygotes are Type 1 Diabetes. New evidence is showing an increased risk for late onset Type 1 diabetes in Heterozygotes (which includes ambiguous Type I/Type II diabetes). There is no evidence that celiac disease may have a slightly increased risk with
a more severe course of disease.