HLA-DQ2

The serotype is determined by the antibody recognition of β2 subset of DQ β-chains.

DQ2 β-chains combine with α-chains, encoded by genetically linked HLA-DQA1 alleles, to form the cis-haplotype isoforms.

DQ antigen, a cell surface receptor, is composed of two polypeptide subunits.

These are more common isoforms encoded by haplotypes, almost all of the time, one passed without change from a person's mother and father from conception.

We also need information about beta chain, the best way to do this is to refer to common haplotypes.

(See image below) For coeliac disease however there appears to be one isoform that has a higher role.

The DQ isoform has a complex genetic involvement in coeliac disease.

DQ2.5 isoform or heterodimer is shorthand for the cell surface receptor HLA-DQ α5β2.

The haplotype encodes DQ2.5cis isoform, referring to the cis arrangement of the DQA1*0501 and DQB1*0201 on the same variant of chromosome 6.

DQ2.5 and the linked DR3 are associated with probably the greatest frequency of autoimmune occurrence relative to any other haplotypes.

The haplotype is positively associated with coeliac disease, dermatitis herpetiformis, juvenile diabetes, Lambert–Eaton myasthenic syndrome (LEMS), Sjögren syndrome, and autoimmune hepatitis (although significant proportion of the risk is secondary to coeliac disease).

The haplotype is found at high frequencies in the Mediterranean and West Africa.

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 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.

Of the DQ2 homozygotes who eat wheat, lifelong risk is between 20 and 40% for coeliac disease.

In almost all case the highest affinity sites of gluten are derived by deamidation.

As mentioned the DQA1*0501:DQB1*0201 haplotype produces DQ2.5cis which by frequency and efficiency in alpha-gliadin presentation is the major factor in adaptive immunity.

[8][9] Specifically, that this DQ2 heterodimer is responsible for presenting the α2-gliadin that most effectively stimulates pathogenic T-cells.

Greatly elevating risk is the ability of the DQ2.5 haplotype encoded isoforms to increase abundance on the cell surface in DQ2.5 double homozygotes.

DQ2.2 does not produce all the necessary subunits to efficiently present the most pathogenic gluten proteins 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.

[15] The gliadin peptides that bind DQ2.5 are enriched in the amino acid glutamine.

As a result, one isoform produced by the phenotype of two haplotypes, DQ2.2/DQ7.5, is HLA DQ α5β2.

In the case of this phenotype, HLA DQB1*02 alleles are encoded by both chromosome 6 (maternal and paternal derived).

[13] These partial homozygotes in the Dutch CD population are approximately 20%, as compared to a randomly expected 3% indicating a sevenfold enrichment.

Among DQ8 positive celiacs without DQ2.5, 1/3 bear DQ2.2 haplotype, about 3 fold higher than random expectation.

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 one-third of T1D patients[19][20] and there are indicators that Triticeae may be involved but the gluten protein is a type of globulin (Glb1).

[21] 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.

[24] However, DQ2 presence with DR3 decreases the age of onset and the severity of the autoimmune disorder.

Illustration of DQ antigen genetics, click image for details
Relationship of haplotypes to antigens
Isoform pairings in DQ2.5 homozygotes result in one isoform
Isoform pairings in DQ7.5/DQ2.2 result in 4 proteins isoforms, DQ2.5trans isoform is one(circled)
Illustration of deamidated alpha-2 gliadin's 33mer showing the overlapping of three varieties of T-cell epitope.
DQ α 5 2 -binding cleft with a deamidated gliadin peptide (yellow), modified from PDB : 1S9V [ 7 ]