Estilos de aprendizaje (VAK)

This thesis has investigated the cellular immunopathogenesis and cereal toxicity of coeliac disease. Evidence has been presented and discussed suggesting that upregulated expression of ICAM-1 is of importance in the development of the mucosal lesion of coeliac disease and that such upregulation may be cytokine driven.. The lack of expression of ICAM-1 by the intestinal epithelium emphasises the importance of the lamina propria as probably the major site of immune activation within the intestinal mucosa of coeliac patients. The significance of T cell mechanisms in the pathogenesis of coeliac disease is suggested by the tight HLA class II linkage and the recent cloning of gliadin-reactive T cells. The ICAM-l-LFA-1 molecular interaction is of considerable importance to most T cell functions and thus the evidence from this thesis supports the hypothesis that T cell activation within the lamina propria is fundamental to the coeliac lesion. The ICAM-l-LFA-1 interaction, however, faciltates other non-T cell immune interactions which may have considerable importance, particularly in the generation of enterocyte damage and the acute mucosal lesion after gluten challenge. The immediately subepithelial localisation of upregulated ICAM-1 expression suggests that immune events, including presentation of antigen and generation of effector responses, occur within this intestinal microenviroment

Increased numbers of intraepithélial lymphocytes relative to the numbers of enterocytes is recognised as a hallmark of the coeliac intestinal lesion, yet their functional role in the pathogenesis of the condition remains unclear. y/5+IEL are found in increased numbers in the intestinal mucosa of patients who are gluten sensitive. Evidence has been presented of a correlation between y/ô+IEL num bers and enteropathy which together with evidence from functional studies demonstrating that y/5+IEL are capable of cytotoxicity, suggests that they form a component part of the epithelial mucosal immune response to gluten, perhaps as enterocytolytic cells. Direct evidence for this role, however is lacking. Certainly they do not seem to be involved in the early response to gluten challenge.

A p p en d ices

The recognition that certain cereals were toxic to coeliac patients, revolutionised the treatment of the condition and initiated a search for the precise toxic factor within the toxic cereals and in particular, w heat The availability of automated peptide synthesisers has allowed the synthesis of chemically pure gliadin peptides in sufficient quantity to use in in vivo challenge experiments. This thesis has presented evidence for the toxicity of a synthetic peptide homologous to residues 31-49 of A-gliadin. Definition of cereal toxicity at a molecular level is now possible and is a major step in dissecting the precise events in the pathogenesis of the condition.

Many questions remain to be answered regarding coeliac disease but a key one is why some individuals with apparently the same genetic susceptibities develop coeliac disease and some do not. Healthy individuals can mount an immune response to gliadin, as evidenced by the presence of gliadin-antibodies in the serum and is likely that, in these individuals, gliadin-specific T cells are present in the intestine of these individuals. Clearly, individuals with a normal intestine are tolerant to gliadin; the development of enteropathy presumably reflects abrogation of this tolerance rather than the presence of gliadin-specific T cells in the intestinal mucosa. It is possible that other, as yet unidentified, genetic susceptibilities exist for coeliac disease. Abrogation of tolerance and unidentified genetic suceptibilities are relevant to the question of variation in the expression of gluten sensitivity which varies through truly latent coeliac patients to aymptomatic mild enteropathy to symptomatic patients with severe enteropathy. Coeliac disease continues to pose questions for investigators.

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