Q J Med 1999; 92: 119-122
© 1999 Association of Physicians
Commentary |
Is gliadin mispresented to the immune system in coeliac disease? A hypothesis
From the Gastroentrology Unit (GKT), The Rayne Institute, St Thomas' Hospital, London, UK and 1 University Children's Hospital, 48149 Münster, Germany
Professor P.J. Ciclitira, Department of Gastroenterology, The Rayne Institute, St. Thomas' Hospital, Lambeth Palace Road, London SE1 7EH
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Summary |
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 Top Summary IntroductionThe enterocyte and CDA different metabolic pathway?A precarious balanceWhat of tissue transglutaminase?ConclusionsAcknowledgementsReferences |
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The primary pathogenic trigger in coeliac disease (CD) is still unknown. We present the hypothesis that in CD the enterocytes could metabolize gliadin through an immunogenic pathway instead of a tolerogenic one. The result of this abnormal presentation of gliadin to the immune system would be the activation of lamina propria T cells, followed by the onset of enteropathy.
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Introduction |
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TopSummaryIntroductionThe enterocyte and CDA different metabolic pathway?A precarious balanceWhat of tissue transglutaminase?ConclusionsAcknowledgementsReferences |
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Coeliac disease (CD) can be considered as an aberrant immune response to gliadin which, in genetically susceptible individuals, triggers a cascade of events that results in a chronic enteropathy (for the purposes of this paper we will refer simply to `gliadin' and not to the various pathogenic epitopes).
Although in recent times many of the processes involved in the immune response to gliadin in CD have become better understood,1–9 the reason why coeliac patients are intolerant to gliadin remains unclear. HLA-DQ2-restricted gliadin-specific T cells are very important for the pathogenesis of CD7 and their presence in the small bowel is specific to CD patients.1,2 However, gliadin-specific T cells that are HLA-DR, -DP, or -DQ restricted have been demonstrated in the peripheral blood of not only CD patients, but also healthy controls.3,4 To explain these puzzling findings, we suggest that only the small-bowel mucosa of CD patients expresses the `signals' necessary for both intestinal recruitment and activation of HLA-DQ2-restricted gliadin-specific T cells. The primary pathogenic event of CD could thus be the expression in the small-bowel mucosa of an abnormal signal, which would consequently trigger the immunological response.
On the basis of recent evidence on the role of enterocytes (i.e. the intestinal epithelial cell of the small-bowel mucosa) in CD,10–12 we present here the hypothesis that the primary defect of CD could be related to the antigen-presenting cells (APC) and the way they metabolize and present gliadin to the immune system.
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The enterocyte and CD |
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TopSummaryIntroductionThe enterocyte and CDA different metabolic pathway?A precarious balanceWhat of tissue transglutaminase?ConclusionsAcknowledgementsReferences |
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The APC involved in the processing and presentation of gliadin to the immune system in CD remain unknown. Few publications have focussed on the role of the enterocytes in CD,10–13 probably because it has only recently been considered possible for enterocytes to act as APC.14,15
Zimmer et al. have suggested that enterocytes might have a role in the induction of the immune response in CD, and have shown that gliadin is translocated into vacuoles positive for MHC II antigens in enterocytes of untreated CD patients, but not in those of healthy controls.10
Friis et al. used an immunofluorescent method with gliadin polyclonal antibodies to show that the enterocytes of healthy controls and treated CD patients have different staining pattern just 20 min after the start of an infusion of gliadin.12 The enterocytes of healthy controls are characterized by a diffuse, homogeneous staining pattern, whereas the enterocytes of CD show a much more intense granular staining pattern in the apical region, and a conspicuous fluorescence in the intercellular space.
This different staining pattern might mean a different distribution of the gliadin in the enterocytes of healthy controls and CD patients. In healthy controls (diffuse pattern), gliadin appears to be in the cytoplasm of the enterocytes, but in CD (granular pattern), it appears to be in an endocytic compartment, that resembles the MHC-class-II-positive vacuoles containing gliadin described by Zimmer et al.10
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A different metabolic pathway? |
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TopSummaryIntroductionThe enterocyte and CDA different metabolic pathway?A precarious balanceWhat of tissue transglutaminase?ConclusionsAcknowledgementsReferences |
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It is generally accepted that the factor that determines whether a peptide is processed either in the MHC I (endogenous) pathway or in the MHC II (exogenous) pathway is its site within the cell (reviewed in reference 16). To be processed in an endogenous pathway the antigen has to be in the cytoplasm, but to be processed in an exogenous pathway it has to be in an endocytic compartment. Thus, the evidence from Friis et al. suggests that in healthy individuals gliadin might be metabolized through an endogenous pathway, whereas in CD it might be metabolized through an exogenous pathway. This could be relevant for the loss of oral tolerance to gliadin in CD.
Antigen presentation through the MHC II pathway of an APC is one of the first steps in the induction of an immune response driven by CD4+ helper T cells.16 Furthermore, in the presence of 
-IFN, enterocytes too can process antigens through the MHC II pathway to activate CD4+ T cells in the lamina propria.17 Activation of the CD4+ gliadin-specific T cells of the lamina propria,1 the basis of the -IFN-dominated response of CD,7 could therefore be due to gliadin being metabolized through an exogenous MHC II pathway in CD. On the other hand, although the involved metabolic pathways are only partially understood, some evidence suggests that a tolerogenic response to dietary antigens may be due to an interaction between enterocytes and CD8+ suppressor T cells.15,18,19 Therefore, we hypothesize that in CD the abnormal intracellular distribution of gliadin favours its metabolism through the immunogenic pathway, and hampers the onset of a tolerogenic response by preventing its presentation to CD8+ suppressor T cells.
To be internalized into an endocytic compartment, the peptide has to be bound at the apical membrane, either through a specific receptor or in a non-specific manner.20 Therefore, the role of the still unknown and HLA-unrelated gene involved in the pathogenesis of CD, currently the subject of much interest,21–23 could be related to the capacity of the enterocytes to bind gliadin at the apical surface. Once gliadin is internalized in the endocytic compartment, it could meet the vacuoles transporting the DQ2 molecules. The fusion of these two vacuoles could cause the binding of gliadin to DQ2, and could allow the expression of the gliadin-DQ2 complex at the basolateral membrane. Although it is still controversial whether CD enterocytes can express DQ2 molecules, some evidence shows that this can occur, at least in some patients.9 Thus, the presentation to the immune system of the gliadin-DQ2 complex would trigger CD. If a DQ2-negative patient's enterocytes were genetically able to bind gliadin, we would expect that gliadin-containing vacuoles would cross the enterocytes towards the basolateral membrane, and that gliadin would be released in the intercellular space.20 APCs of the lamina propria would then metabolize and present gliadin correctly to the immune system to induce oral tolerance.
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A precarious balance |
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TopSummaryIntroductionThe enterocyte and CDA different metabolic pathway?A precarious balanceWhat of tissue transglutaminase?ConclusionsAcknowledgementsReferences |
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The fact that gliadin-MHC-class-I-positive vacuoles have been shown in the enterocytes of CD patients11 suggests that these two different and competing metabolic pathways for gliadin might both coexist in CD. Since it has been shown that peptides are more adherent to the apical surface of immature cells than to mature cells,24 the maturity of the enterocytes and the quantity of gluten in the diet could determine the rate of gliadin metabolism through either pathway and thus which one dominates. The frequent development of active CD in situations characterized by immaturity of the enterocytes, such as weaning or after gastrointestinal infections,25 could be due to the high capacity of the immature enterocytes to bind gliadin at the apical membrane, which would result in an enhanced endocytic pathway. On the other hand, in treated coeliac patients that reintroduce gluten in their diet, the maturity of enterocytes26 could hamper the adhesion of gliadin to the apical surface, and thus gliadin could be metabolized mostly on an endogenous pathway and only minimally on the MHC II pathway. This could result in the presentation of gliadin to tolerogenic intraepithelial CD8+ suppressor T cells. Moreover, it has been suggested that
T cells, which are increased in the intestinal epithelium of CD patients,27 may regulate the induction and maintenance of oral tolerance.28 We propose that the increased intraepithelial lymphocytes in CD27 have a tolerogenic effect that, at least initially, could balance the immune response against gliadin. This model could explain the reduced intolerance to gluten of treated coeliac teenagers and the lag time between a gluten challenge and the re-establishment of the enteropathy. However, this protective effect cannot last indefinitely. The immune response due to the presentation of gliadin by MHC II will increase both the immaturity of the enterocytes26 and the expression of MHC II molecules on the enterocytes,29 triggering a self-enhancing mechanism that leads to the Th1 response known to be involved in the pathogenesis of the coeliac enteropathy.30 |
What of tissue transglutaminase? |
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TopSummaryIntroductionThe enterocyte and CDA different metabolic pathway?A precarious balanceWhat of tissue transglutaminase?ConclusionsAcknowledgementsReferences |
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Tissue transglutaminase (tTG), a cytoplasmic enzyme for which gliadin is an excellent substrate, has recently been shown to be the antigen for endomysial antibodies.31 Endomysial antibodies may not be essential for the development of the disorder, since patients with hypogammaglobulinaemia and selective IgA deficiency can develop the condition.32,33 However, it has been suggested that tTG forms complexes with gliadin and that the neoepitopes trigger the immune response that causes CD.31 Very recently it has been suggested that gliadin-specific T cells could provide help for tTG-specific B cells.34 We think that the abnormal compartmentalization of gliadin in the enterocytes might be the predisposing factor for binding to tTG. Thus tTG might also be presented to the immune system in an abnormal way, which would produce antibodies against it. The withdrawal of gliadin from the diet would eliminate the abnormal presentation of tTG, by either of the above routes, to the immune system. This could explain the very high sensitivity of endomysial antibodies for CD.
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Conclusions |
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TopSummaryIntroductionThe enterocyte and CDA different metabolic pathway?A precarious balanceWhat of tissue transglutaminase?ConclusionsAcknowledgementsReferences |
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The reason why coeliac patients are intolerant to gluten is still unknown. We have presented here the hypothesis that the primary pathogenic event is related to the enterocytes that metabolize and present gliadin to the immune system through an immunogenic pathway instead of a tolerogenic one. As a result of this abnormal presentation, the immune system reacts with an immune response against gliadin that results in enteropathy.
To investigate our hypothesis, the study of the absorption of gliadin and other dietary peptides in the enterocytes of CD and healthy controls and its further metabolism is crucial. If our model is correct, it could shed new light on the pathogenesis not only of CD but also of other pathological conditions, such as inflammatory bowel disease, where the damage could be caused by an antigen, as yet unknown, being mispresented to the immune system.
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Acknowledgements |
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TopSummaryIntroductionThe enterocyte and CDA different metabolic pathway?A precarious balanceWhat of tissue transglutaminase?ConclusionsAcknowledgementsReferences |
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The co-authors wish to acknowledge the National Institute of Health (ref. R01DK47716), the St. Thomas' Hospital Research (endowments) committee, Nutricia UK and Semper AB, Sweden, and Associazione Italiana Celiachia (AIC) for financial support. Dr F Biagi is supported by the Instituto Superiore di Sanità research project `Prevention of risk factors of maternal and child health' art. 12 D.L. 502/92 and by a grant from Associazione Italiana Celiachia (AIC). Dr K.P. Zimmer is supported by the DFG (Az.:Zi294/6-1).
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References |
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TopSummaryIntroductionThe enterocyte and CDA different metabolic pathway?A precarious balanceWhat of tissue transglutaminase?ConclusionsAcknowledgementsReferences |
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