Identification of coeliac disease triggering glutenin peptides and their measurement in foods

• Main Author: Donnelly, Suzanne
• Published: King's College London (University of London) 2013
• Subjects: 616.3
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.628216

Coeliac disease is a common small intestinal disorder affecting approximately 1% of the Northern European population. It is caused by an inappropriate immune response to dietary gluten found in wheat, rye, barley and, for a small minority of patients, oats. There is mounting evidence to suggest that the immune response of coeliac disease is not purely driven by gluten-sensitive T lymphocytes but also by an innate immune response mediated through interleukin-15. Dietary gluten comprises of two major protein fractions, gliadins and glutenins. Considerable research has been carried out on the immunostimulatory components in wheat gliadin. Glutenins, newly discovered to be toxic to coeliac individuals, have limited evidence describing their immunostimulatory potential in coeliac disease. Glutenins can be further differentiated by their molecular weight into low and high molecular weight fractions. Small intestinal T-cell studies suggest that an in vitro response to certain high molecular weight glutenin proteins may occur in some, but not all, coeliac individuals. There is even less evidence available concerning the coeliac disease toxicity of low molecular weight glutenin proteins. The stimulating epitopes within these proteins are not fully understood. This thesis describes the immunostimulatory potential of peptides contained in high molecular weight glutenins, glut 04 p721-735, and in low molecular weight glutenins, glt 156 p44-59, that have been implicated in a small number of coeliac individuals. The adaptive immune response to these peptides has been measured by proliferation assays using gluten-sensitive small intestinal lymphocytes and measurement of their interferon-γ secretion. The innate immune response has been assessed by morphometric measurement of small intestinal biopsies following overnight incubation with these peptides, followed by interleukin-15 assessment via secretion into the tissue culture supernatant. A number of attempts have been made to raise monoclonal antibodies to these peptides. A variety of immunisation schedules have been attempted in host mice. A number of cell fusion experiments have been performed without success. The possible reasons for this lack of success are discussed. Results generated by in vitro studies of coeliac small intestinal explants and isolated cells have improved our understanding of the pathogenesis of coeliac disease.