HLA-DQ2 - in Coeliac Disease - DQ2.2 and Gluten

DQ2.2 and Gluten

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. The gliadin peptides that bind DQ2.5 are enriched in the amino acid glutamine. 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 however can present less pathogenic epitopes such as proteolytic peptides of gamma-gliadin. This appears to be the mediator of disease in 1% of coeliacs that are homozygotes for DQ2.2.

The DQ2.2/DQ7.5 phenotype. Also called DQ2.5_trans in some publications. DQ7.5 haplotype is the DQA1*0505:DQB1*0301 haplotype. The DQA1*0505 allele is similar to the DQA1*0501 allele of the DQ2.5 haplotype. When DQA1*0505 or DQA1*0501 gene products are processed to the cell surface they become α5. The gene products of DQB1*0202 and DQB1*0201 are almost identical and function similarly. As a result one isoform produced by the phenotype of two haplotypes, DQ2.2/DQ7.5, is HLA DQ α5β2. A small percentage of coeliac disease patients have this haplotype. The other 3 isoforms are α2β2(DQ2.2), α2β7 (DQ7.2), and α5β7 (DQ7.5).

DQ2.2/DQ2.5. Random pairing of heterologous DQ alpha and beta isoforms produces 4 different isoforms at 1:1:1:1 ratios. The fraction of DQ2.5 can be 25%. 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 1:1. 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%, as compared to a randomly expected 3% indicating a sevenfold enrichment.

DQ2.2/DQ8. Among DQ8 positive celiacs without DQ2.5, 1/3 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. This fraction of coeliacs is important because they can only produce α2β2 and are useful for determining the role of DQ2.2 in coeliac disease.