HLA-DQ2 - in Coeliac Disease

In Coeliac Disease

DQ2 represents the second highest risk factor for coeliac disease, the highest risk is a close family member with disease. Due to its link to coeliac disease, DQ2 has the highest association of any HLA serotype with autoimmune disease, close to 95% of all coeliacs have DQ2, of that 30% have 2 copies of DQ2. Of the DQ2 homozygotes who eat wheat, lifelong risk is between 20 and 40% for coeliac disease.

The relationship of DQ2 and coeliac disease, however, is complex because there are multiple DQ2 isoforms. The DQ α5β2 (DQ2.5) isoform is strongly associated with CD. This isoform is partially encoded by the DQB1*02 genes in HLA-DQ2 positive individuals. DQB1*0201 is genetically linked to DQA1*0501 forming the DQ2.5 haplotype that encodes both α5 and β2 subunits. The DQ2.5 haplotype confers the single highest genetic risk for disease, however comparable risk can also come from very similar alleles on different haplotypes.

The immunodominant site for DQ2.5 is on α2-gliadin. The site is a protease resistant 33mer that has 6 overlapping DQ2.5 restricted epitopes. This creates very strong binding of T-cells for DQ2.5-33mer complexes. DQ2.5 binds gliadin, but the binding is sensitive to deamidation caused by tissue transglutaminase. In almost all case the highest affinity sites of gluten are derived by deamidation. The HLA DQB1*0202 and its linked DQA1* alleles (the DQ2.2 haplotype) do not produce the α5 subunit. While the DQ2.2 heterodimer cannot effectively present α-2 gliadin, it can present other gliadins. In at least 1% of coeliacs DQ2.2 confers adaptive immunity to gliadin permitting coeliac disease.