Diagnostics and genetics in coeliac disease

Abstract

Coeliac disease (CD) is an auto-immune disease triggered by ingestion of gluten, a protein found in wheat, rye and barley. In susceptible individuals the ingestion of gluten triggers an auto-immune reaction, giving chronic inflammation of the small intestinal mucosa, and generally resulting in villous atrophy. This thesis starts with an overview of CD including the history, pathogenesis, clinical characteristics, diagnosis and genetic factors. We subsequently investigated the reliability of new serological tests as well as the yield of gluten challenge in young children. Serum antibodies against tissue transglutaminase (IgA-tTG) were compared with serum antigliadin antibodies (IgA-AGA and IgG-AGA) and anti-endomysium antibodies (IgA-EMA) in the diagnosis of CD in a group of patients and controls who were all biopsied. Human IgA-tTG had a sensitivity of 96% and a specificity of 100% and is the serological screening method of choice. Thereafter we analyzed a new non-invasive marker for intestinal mucosal damage, the intestinal fatty acid binding protein (I-FABP). The serum levels of I-FABP were significantly elevated in children with biopsy proven CD and correlated significantly with the severity of villous atrophy. Furthermore, I-FABP was of additional value in the follow-up of CD. Thus, I-FABP improves the reliability of the current serologic parameters (IgA-tTG and IgA-EMA) both in the diagnosis of CD and in the follow-up. Then the diagnostic yield of routine gluten challenges was investigated in children diagnosed with CD under the age of two years. Based on our results we could conclude that routine gluten challenge in this group of patients is not necessary when villous atrophy at intestinal biopsy is present in combination with a raised serum IgA-EMA. In the second part an overview of the recent genetic developments is given. We subsequently showed that the newly found MYO9B gene is a risk factor for the development of refractory coeliac disease (RCD) type II and enteropathy-associated T-cell lymphoma (EATL). Both MYO9B and HLA-DQ2 homozygosity seem to be involved in the prognosis of CD and the development of RCD II and EATL. Thereafter three CD associated genes (MYO9B, MAGI2 and PARD3) were studied. These genes might encode tight junction proteins and thus might have a role in regulating intestinal permeability, but evidence for this function is far from complete. It was hypothesized that these three CD-associated genes are associated with an increased intestinal permeability as revealed by elevated antibodies against gliadin (AGA). However in a cohort of patients with Down syndrome we consistently found that AGA concentration was lower instead of increased in patients with a CD associated risk genotype. This might be due to different immunological mechanisms in this group of patients with Down syndrome, possibly involving altered induction and/or maintenance of tolerance. The field of genetics in CD and other autoimmune diseases is moving rapidly. Multiple genes seem to contribute to CD and to each of the major autoimmune disorders, with significant genetic overlap between them. Future studies will extend our knowledge both of the role of intestinal permeability and of associated genetic risk factors in CD and in other autoimmune diseases.