Pathogenesis

  1. Dr.Schär Institute
  2. Dr. Schär Institute
  3. Pathogenesis
DNA, Genetik, Exogene Ursachen, Pathogenese

Coeliac disease has a complex pathology resulting from interaction between a number of genetic and exogenous factors.

Genetic factors

A high incidence of coeliac disease within affected families (approximately 10% among first-degree relatives and 80% among twins) suggests a genetic involvement in the pathogenesis of coeliac disease. An important genetic factor is the human leukocyte antigen (HLA) system, a gene complex whose task is to recognise foreign molecules. 90% of coeliac patients carry genes encoding HLA DQ2 whilst most of the remainder carry the HLA DQ8 haplotype [1]. Although these are necessary for the disease to develop, they are not solely responsible for it. It is known that these genes are also present in up to 40% of individuals in Western populations, however, the frequency is population dependent [2]. Genome wide studies have also demonstrated that 39 non-HLA regions are associated with an increased risk of coeliac disease [3].
 

Exogenous factors

The presence of gluten in the diet is clearly a pre-requisite for the development of coeliac disease. People with coeliac disease develop an immune response to some, but not all gluten proteins in wheat [4]. Studies have failed to show that breastfeeding has an effect on the incidence of coeliac disease [5]. A high quantity of gluten ingestion has been proposed as a proposed risk factor for coeliac disease, but current studies are conflicting. Currently, there are a lack of prevention strategies, with gluten being suggested to be consumed at small amounts at initial introduction, suggested to be commenced between 4 to 12 months of age [6]. Other risk factors, such as mode of delivery [7,8], or season of birth [9,10] have also been proposed in the pathogenesis of coeliac disease, as well as gastrointestinal infections [11].

Connection to other diseases

There are some autoimmune diseases, e.g. Type 1 diabetes, that have a high occurrence among coeliac disease patients when compared to non-affected persons. For these conditions, screening is advisable in order to detect possible coeliac disease, even if there are no clear symptoms.

 

Reference

  1. Karrell K, Louka AS, Moodie SJ et al. HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) hererodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol 2003; 64:469-77
  2. Abadie V, Sollid LM, Barreiro LB et al. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol 2011; 29:493-525
  3. Gutierrez-Achury J, Zhernakova A, Pulit SL, et al. Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease. Nat Genet 2015; 47: 577–78
  4. Huebener S, Tanaka CK, Uhde M, et al. Specific nongluten proteins of wheat are novel target antigens in celiac disease humoral response. J Proteome Res 2015; 14: 503–11
  5. Welander A, Tjernberg AR, Montgomery SM, Ludvigsson J, Ludvigsson JF. Infectious disease and risk of later celiac disease in childhood. Pediatrics 2010; 125: e530–36
  6. Szajewska H, Shamir R, Mearin L, et al. Gluten introduction and the risk of coeliac disease: a position paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.
J Pediatr Gastroenterol Nutr 2016; 62: 507–13
  7. Mårild K, Stephansson O, Montgomery S, Murray JA, et al. Pregnancy outcome and risk of celiac disease in offspring:
a nationwide case-control study. Gastroenterology 2012; 142: 39–45
  8. Lionetti E, Castellaneta S, Francavilla R, et alPulvirenti A, Catassi C, Mode of delivery and risk of celiac disease: risk of celiac disease and age at gluten introduction cohort study. J Pediatr 2017; 184: 81–86
  9. Lebwohl B, Green PH, Murray JA, et al. Season of birth in a nationwide cohort of coeliac disease patients. Arch Dis Child 2013; 98: 48–51

  10. Tanpowpong P, Obuch JC, Jiang H, et al. Multicenter study on season of birth and celiac disease: evidence for a new theoretical model of pathogenesis. J Pediatr 2013; 162: 501–04

  11. Stene LC, Honeyman MC, Hoffenberg EJ, et al. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study. Am J Gastroenterol 2006; 101: 2333–40