HLA-DQ

heteropolypeptide
heteropolymer = MHC class II, DQ
polymer_type = heterodimer
protein_type = cell surface receptor
function = Immune recognition and
antigen presentation


image_source = DQ1 binding pocket with ligand
SubunitCount = 2
subunit1 = α
gene1 = HLA-DQA1
locus1 = Chromosome 6p21.31
subunit2 = β
gene2 = HLA-DQB1
locus2 = Chromosome 6p21.31HLA-DQ (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 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 and thus 4 DQ . 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 ). 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 disease 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 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.

tructure, Functions, Genetics

Function

The name 'HLA DQ' originally describes a transplantation antigen of MHC class II category of the major histocompatibility complex 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

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). TheDQ 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).

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 polymorphisms (SNP). SomeSNP 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 generallychange in the peptides they bind and present to T-cells. Much ofthe 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 serotypes.

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, resultingserotyping errors. Because of this mistyping serotyping is not as reliable as gene sequencingor SSP-PCR.

While the DQ2 isoforms are recognized by the same antibodies, and allDQB1*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.

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 witha more severe course of disease.

References

External links

* [http://tech.groups.yahoo.com/group/DNAanthro/ Molecular Anthropology Yahoo Group]
* [http://www.allelefrequencies.net HLA Allele and Haplotype Frequency Database]
* [http://www.ebi.ac.uk/imgt/hla/ IMGT-HLA Database]