The immune recognition of gluten in coeliac disease

Abstract

SummaryCoeliac disease, the most common intestinal disorder of western populations, is an autoimmune enteropathy caused by an abnormal immune response to dietary gluten peptides that occurs in genetically susceptible individuals carrying the HLA-DQ2 or -DQ8 haplotype. Despite the recent progresses in understanding the molecular mechanisms of mucosal lesions, it remains unknown how increased amounts of gluten peptides can enter the intestinal mucosa to initiate the inflammatory cascade. Current knowledge indicates that different gluten peptides are involved in the disease process in a different manner, some fragments being 'toxic' and others 'immunogenic'. Those defined as 'toxic' are able to induce mucosal damage either when added in culture to duodenal endoscopic biopsy or when administered in vivo , while those defined as 'immunogenic' are able to specifically stimulate HLA-DQ2-or DQ8-restricted T cell clones isolated from jejunal mucosa or peripheral blood of coeliac patients. These peptides are able to trigger two immunological pathways: one is thought to be a rapid effect on the epithelium that involves the innate immune response and the other represents the adaptive immune response involving CD4 + + + + T cells in the lamina propria that recognize gluten epitopes processed and presented by antigen presenting cells. These findings are the subject of the present review. Keywords: coeliac disease, gluten, innate immunity, adaptive immunity Definition and clinical description of coeliac diseaseCoeliac disease (CD) may be considered the most common chronic inflammatory condition since the estimated prevalence in Western Countries is near to one per cent [1,2]. CD is an autoimmune enteropathy caused by an abnormal immune response to dietary gluten that occurs in genetically susceptible individuals [3]. The unique well established genetic factor is the HLA-DQ region at 6p21.3 [4] which, however, contributes no more than 40% of the risk, the non-HLA genes being the stronger determinant of CD susceptibility [5]. The broad spectrum of gluten-sensitive intestinal mucosal changes that are characteristic, albeit not pathognomonic of this condition, ranges from a complete disruption of the mucosal architecture with villous flattening and crypt hyperplasia, to a slight increase of inflammatory infiltrate in both the epithelium and lamina propria [6]. Furthermore, from in vivo and ex vivo challenges it has been shown that all the lesions comprise a dynamically interrelated series of events that, however, do not necessarily occur in the same patient [7][8][9]. The wide spectrum of clinical manifestations comprises the classical features of intestinal malabsorption to atypical or asyntomatic cases that now are believed to represent the majority of patients [10]. The only treatment currently available is a lifelong strict adherence to a gluten-free diet that is followed by an amelioration or a normalization of the histological lesions [3,6].As far as pathogenesis is concerned, CD represents a unique and privileged model sinc...

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“…18 Interestingly, some of these pathogenic bacteria previosly associated with the disease can produce toxins that disrupt the tight junction proteins and increase the intestinal permeability, 19-22 a condition linked to the break-down of gluten tolerance. 1 Although some potential candidates have been proposed, we lack strong evidence for pathogenic bacteria as trigger factors for CD development in humans.…”

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