major histocompatibility complex, class II, DQ2
|Haplotypes||DQA1*0201:DQB1*0202 DQA1*0303:DQB1*0202 DQA1*0501:DQB1*0201|
|Structure (See HLA-DQ)|
alpha *0201 *0303 *0501
beta 1 *0201 or *0202
HLA-DQ2 is a serotype group within HLA-DQ serotyping system which is determined by the antibody recognition of the HLA-DQB1*02 group of HLA-DQB1 alleles. HLA-DQ2 and HLA-DQB1*02 are almost synonymous in meaning. DQ2 cell surface antigens are encoded by DQB1*02 alleles in combination with other alpha alleles. The two most common DQ2 β chains, which are produced by the DQB1*0201 and DQB1*0202 alleles, function similarly.
DQ2 is most common in Western Europe, North and Western Africa. Highest frequencies are observed in parts of Spain and Ireland, this distribution correlates with the frequency of two of the most prevalent autoimmune diseases.
Serotyping efficiency. The serotyping efficiency of HLA-DQ2 is among the highest of the antisera. DQ2 antiboides can be used to effectively type DQ2 bearing individuals, however antibody may detect DQB1*0303.
DQB1*0201 (*0201) is in strong linkage disequilibrium with HLA-DQA1*0501 and HLA-DRB1*03, therefore, *0201 is almost always found in the DQ2.5 (A1:B1) genetically defined haplotype, or the DR3-DQ2 (DR-DQ) serologically defined haplotype. This beta chain allele shares stongest genetic linkage to coeliac disease, the beta chain product is one of three DQ beta chains (DQB1*0201, *0202, and *0302) that effectively present the disease causing gluten epitopes of Triticeae glutens. There are ambiguities regarding DQB1*0201 in the literature, some low resolution typing kits detect *0202 as *0201 and are presented as *0202 in the literature without distinction. DQB1*0201 is part of the multilocus HLA haplotype:
A*0101 : Cw*0701 : B*0801 : DRB1*0301 : DQA1*0501 : DQB1*0201
This haplotype is known as "Super B8" or "European ancestral haplotype"
This allele is linked to several DQA1* alleles, the linkage with DQA1*0201 forms the DQ2.2 haplotype and linkage with DQA1*0303 forms the DQ2.33 haplotype. In Africa the DQA1*0501 haplotype is also linked rarely to DQ2.2 and may represent that ancestral form of the DQ2.5 haplotype.
What is DQ2.5? DQ2.5 is referred to as both an isoform and a haplotype. To be correct the haplotype is actually DQ2.5cis, referring to the cis chromosomal arrangement of the DQA1*05 and DQB1*02 on the same chromosome. DQ2.5 isoform is actually DQ α5β2 (also DQ α1*05 β1*02).
DQA1*0501:DQB1*0201 (DQ2.5) is linked to DRB1*03, primarily DRB1*0301. This haplotype is one of the most important factors in autoimmune disease in the western world, and its distribution also of importance. HLA DR3-DQ2 distribution is described separately.
DQ2.5 and the linked DR3 are associated with probably the greatest frequency of autoimmune occurrence relative to any other haplotype. The haplotype is positively associated with coeliac disease, Juvenile diabetes, Lambert-Eaton myasthenic syndrome (LEMS), Sjögren's syndrome, and autoimmune hepatitis although significant proportion of the risk is secondary to coeliac disease. DR3 and/or DQ2.5 are linked to the following diseases: Moreen's ulceration, "bout onset" multiple schlerosis, Grave's disease and systemic lupus erythematosus
DQA1*0201:DQB1*0202 (DQ2.2) is most common isoform produced is DQ α2β2. The haplotyped is linked to DR7. is found at high frequencies in the Mediterranean and Western Africa. The Eurasian geographic distribution of DQ2.2 is slightly greater than DQ2.5. Compared to DQ2.5, the freqeuncy in Sardinia is low, but in Iberia it is high reaching a maximum frequency of ~30% in Northern Iberia, and half that in the British Ilses. It extends along the Mediterranean and Africa at relatively high frequency and is found in high freqeucies in some Central Asian, Mongolians, and Han. It does not appear to have an indigenous presence in the West Pacific Rim or the New World and DQ2.2 presence in Southeast Asia and Indonesia is likely the result of gene flow from India and China in post-neolithic times. The haplotype shows considerable diversity in Africa and this has translated to Iberia with 2 addition haplotypes, DQA1*0303:DQB1*0202 and DR7:DQA1*0201:DQB1*0303. The expansion of DQ2.2 into Europe appears to have been slightly later or biased by some constriction between Iberia and the rest of the continent.
DQA1*0303:DQB1*0202 (DQ2.33) Most common isoform produced is α3β2, also part of the DR7-DQ2 serologically defined haplotypes. It is much less common than DQ2.2
Coeliac disease associations
DQ2 represents the second highest risk for celiac disease, the first being a family member with the disease. It is one of the clearist links between class II antigens and inherited dieases and most clear among disease mediated by HLA-DQ The relationship of DQ2 and coeliac disease (CD) is an example of potential complexity The DQ isoform that is most strongly associated with CD is the DQ α5β2 isoform. This isoform is partially encoded by the DQB1 genes in HLA-DQ2 positive individuals. The DQB1*0201 and its linked DQA1* gene (DQ2.5 haplotype) encodes both α5 and β2 subunits, and therefore confers highest risk haplotype for CD in humans. The HLA DQB1*0202 and its linked DQA1* alleles (DQ2.2 haplotype) do not produce the α5 subunit and therefore cannot, by itself, increase risk of CD. Dependent on other haplotypes, DQ2.2 can produce risk or increase risk by transisoform pairing to DQ7.5 and DQ2.5, respectively.
DQ2.5 and coeliac disease
The highest risk for celiac disease (CD) is in Western Ireland and overlaps one of three global nodes of DQ2.5 in Western Europe. DQ2.5 (cis) haplotype is linked to DR3 but DR3 is not linked to DQ2.2, therefore using both serotyping and genotyping studies it is possible to follow risk of celiac disease according to HLA DR3-DQ2 frequency. The debate over whether CD is a DQ2 or DQ2.5 mediated disease supports DQ2.5 as the primary risk factor, a genome wide survey of markers linked to CD reveals that highest linkage is for a marker within the DQA1*0501 allele. and the significance of the DQB1*0201 association is nearly as high. The structure of DQ2.5 haplotype in autosomes in the DQ2.5cis chromosomal configuration allows DQ isoform homogeneity. This occurs when a person inherits 2 DQ2.5cis bearing chromosomes from each parent. CD patients show a large increase of DQ2 homozygotes relative to expectation given ~80% of patients have DQ2.5cis, and, although multiple copies of DQ2.5 do not cause apparent increases of severity, DQ2.5/DQ2 increases risk of life threatening complications and more severe histological findings. DQ2.5 provides the opportunity, individually, for 2 gene copies of DQA1*05 and/or DQB1*02 within the same diploid cell. However, analysis of risk indicates that DQ2.5/2.5 genotype has approximately the same risks as DQ2.5/DQ2.2 genotype but 3 fold higher risk than the DQ2.5/DQ7.5 genotype suggesting that DQB1*02 predominate risk association with CD.
The increases the compliment of DQ2.5 bearing isoforms from 25% to 50% (single homozygote). DQ2.5/DQ2.5 homozygotes represent approximately 30% of Dutch celiacs random expectation within a cluster of 80(%) DQ2.5 is 8%. DQ2.5/DQ2.2 is also elevated, approximately 20% of Dutch CD have this phenotype. Based on this study DQ2.5/DQ7.5 would also be elevated (since it carries the DQA1*05 allele, however it is not. approximately 3% of celiacs have this phenotype.
DQ2.5 (haplotype product is DQ α5-β2) and DQ8 (DQ α3-β302) produce susceptibility to coeliac disease in their cis-haplotype pair. These two haplotypes share in common EBV peptide binding capacity and they both prefer acidic side chains at the P9 binding position. and the tTG induced deamidation (Changing glutamine to glutamic acid) improves the binding to DQ2.5 isoform, but not DQ2.2.
DQ2.2 and coeliac disease
DQ2.2 does not produce all the necessary subunits to efficiently present pathogenic gluten epitopes to the immune system. With the DQ2.2 isoform (DQ α2-β2), polar substitutions (amino acids such as asparagine, glutamine, glycine, serine, and threonine) are not bound well to DQ2.2. The gliadin peptides that bind DQ2.5 are enriched in glutamin. Since the β2 provides half the structural information for gluten presentation, other haplotypes might provide the rest. Such haplotypes are known to exist and these haplotypes confer different risk on DQ2.2.
DQ2.2/DQ7.5. DQ7.5 haplotype is the DQA1*0505:DQB1*0301 haplotype. The DQA1*0505 gene product is similar to DQA1*0501 gene product of DQ2.5's DQA1 gene. When DQA1*0505 gene product is processed to the cell surface it becomes α5. The gene products of DQB1*0202 and DQB1*0201 are similar and function similarly. As a result one isoform produced by DQ2.2/DQ7.5 is HLA DQ α5β2. A small percentage of coeliac disease patients have this haplotype.
DQ2.2/DQ2.5. Random pairing of heterologous DQ alpha and beta isoforms produces 4 different isoforms with at 25:25:25:25 ratios. In the case of this phenotype, HLA DQB1*02 alleles are encoded by both chromosome 6 (maternal and paternal derived). Since DQB1*0201 and *0202 function similarly, only two types of isoforms can be produced and the ratio becomes 50:50. This increases the random number of isoforms from 25% to 50% that can cause disease, and as a result increases risk of celiac disease and probably increases risk of severe complications such as refractory celiac disease and lymphoma.. These partial homozygotes in the Dutch CD population are approximately 20%.
DQ2.2/DQ8. Among DQ8 positive celiacs without DQ2.5, 1/3rd bear DQ2.2 haplotype, about 3 fold higher than random expectation.
DQ2.2/DQ2.2 DQ2.2 homozygotes represent about 1.1% of the celiac population, this is not high relative to controls, but it is very high with the DQ2.5(isoform)-,DQ8-,DQ2+ cohort at 30%. The random expectation is much lower.
DQ2.2/X. Three percent of Europeans that have DQ2.2, in this group DQ2.2/DQ5 (DQA1*01:DQB1*05) is enriched. 1/2 of the DQ2.5(isoform)-, DQ8-, DQ2.2+, DQ2.2/DQ2.2- group are DQ5. A significant proportion of these are DQA1*01:DQA1*0503. However DQ6 was reduced in this set.
Juvenile diabetes association
Juvenile diabetes (T1D) has a high association with DQ2.5 and there appears to be link between GSE and early onset male T1D. Anti-tTG antibodies are found elevated in a 1/3rd of T1D pateints and there are indicators that Triticeae may be involved but the gluten protein is a type of globulin (Glb1). Recent studies indicate a combination of DQ2.5 and DQ8 (both acid peptide presenters) greatly increase the risk of adult onset Type 1 Diabetes and ambiguous type I/II Diabetes. HLA-DR3 plays a prominent role in autoimmune diabetes. However, DQ2 presence with DR3 decreases the age of onset and the severity of the autoimmune disorder.
- derived from IMGT/HLA
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