DQ2/DQ8 AND HLA-DQ Risk Assessment for Celiac Disease
Celiac disease (CD) is a chronic gluten-intolerance that occurs in genetically predisposed individuals. In gluten-sensitive individuals, the ingestion of gluten causes chronic inflammation of the small intestinal mucosa leading to villous atrophy and nutrient malabsorption. The prevalence of CD is estimated at about 1:100 in Caucasians, and it occurs more often in females with a gender ratio of about two-to-one. Furthermore, gluten intolerance is more frequent in at-risk groups, such as first-degree relatives of patients as well as individuals with specific genetic syndromes (Down, Turner, Williams) or autoimmune diseases (type I diabetes, thyroiditis and multiple sclerosis).
The close association between CD and these HLA alleles is due to the fact that these disease-associated HLA-DQ molecules expressed on antigen-presenting cells specifically bind gluten-derived peptides that are modified by the enzyme tissue transglutaminase (tTG) and present them to intestinal CD4+ T cells. The resulting T cell response leads to the production of auto-antibodies directed against tTG and to the secretion of pro-inflammatory cytokines (mainly TNF-α and IFN-γ) with consequent mucosa atrophy and clinical manifestations.
Chart 1: Risk gradient, considering a disease prevalence of 1:100. Refer to Figure 1 for nomenclature (from Megiorni F et al, 2009).
Figure 1: CD at-risk heterodimers encoded by different combinations of DQA1 and DQB1 alleles (from Megiorni and Pizzuti, 2012).