Differential Mucosal IL-17 Expression in Two Gliadin-Induced Disorders: Gluten Sensitivity and the Autoimmune Enteropathy Celiac Disease

Sezione Biotecnologia e Biologia Molecolare, Dipartimento di Medicina Sperimentale, Seconda Università degli Studi di Napoli, Naples, Italy.
International Archives of Allergy and Immunology (Impact Factor: 2.67). 11/2009; 152(1):75-80. DOI: 10.1159/000260087
Source: PubMed


The immune-mediated enteropathy, celiac disease (CD), and gluten sensitivity (GS) are two distinct clinical conditions that are both triggered by the ingestion of wheat gliadin. CD, but not GS, is associated with and possibly mediated by an autoimmune process. Recent studies show that gliadin may induce the activation of IL-17-producing T cells and that IL-17 expression in the CD mucosa correlates with gluten intake.
The small-intestinal mucosa of patients with CD and GS and dyspeptic controls was analyzed for expression of IL-17A mRNA by quantitative RT-PCR. The number of CD3+ and TCR-gammadelta lymphocytes and the proportion of CD3+ cells coexpressing the Th17 marker CCR6 were examined by in situ small-intestinal immunohistochemistry.
Mucosal expression of IL-17A was significantly increased in CD but not in GS patients, compared to controls. This difference was due to enhanced IL-17A levels in >50% of CD patients, with the remainder expressing levels similar to GS patients or controls, and was paralleled by a trend toward increased proportions of CD3+CCR6+ cells in intestinal mucosal specimens from these subjects.
We conclude that GS, albeit gluten-induced, is different from CD not only with respect to the genetic makeup and clinical and functional parameters, but also with respect to the nature of the immune response. Our findings also suggest that two subgroups of CD, IL-17-dependent and IL-17-independent, may be identified based on differential mucosal expression of this cytokine.

Download full-text


Available from: Vincenzo Casolaro,
  • Source
    • "Gliadin peptides have been shown induce a significant innate immune response in epithelium, mucosal macrophages and dendritic cells in humans, both with and without coeliac disease, as well as in murine cells [45],[48]–[55]. We propose that elements of this innate response contribute to the characteristic architectural disturbance in coeliac disease in a fashion analogous to the insect encapsulation reaction, through cell recruitment and induced matrix expansion. In refractory coeliac disease, where villous atrophy persists despite gluten free diet, mucosal IL-6 expression is further increased [56] and its systemic release enhanced, especially in enteropathy associated T cell lymphoma [57]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background We studied the expression of sulphated glycosaminoglycans (GAGs) in coeliac disease (CD) mucosa, as they are critical determinants of tissue volume, which increases in active disease. We also examined mucosal expression of IL-6, which stimulates excess GAG synthesis in disorders such as Grave's ophthalmopathy. Methods We stained archival jejunal biopsies from 5 children with CD at diagnosis, on gluten-free diet and challenge for sulphated GAGs. We then examined duodenal biopsies from 9 children with CD compared to 9 histological normal controls, staining for sulphated GAGs, heparan sulphate proteoglycans (HSPG), short-chain HSPG (Δ-HSPG) and the proteoglycan syndecan-1 (CD138), which is expressed on epithelium and plasma cells. We confirmed findings with a second monoclonal in another 12 coeliac children. We determined mucosal IL-6 expression by immunohistochemistry and PCR in 9 further cases and controls, and used quantitative real time PCR for other Th17 pathway cytokines in an additional 10 cases and controls. Results In CD, HSPG expression was lost in the epithelial compartment but contrastingly maintained within an expanded lamina propria. Within the upper lamina propria, clusters of syndecan-1+ plasma cells formed extensive syncytial sheets, comprising adherent plasma cells, lysed cells with punctate cytoplasmic staining and shed syndecan ectodomains. A dense infiltrate of IL-6+ mononuclear cells was detected in active coeliac disease, also localised to the upper lamina propria, with significantly increased mRNA expression of IL-6 and IL-17A but not IL-23 p19. Conclusions Matrix expansion, through syndecan-1+ cell recruitment and lamina propria GAG increase, underpins villous atrophy in coeliac disease. The syndecan-1+ cell syncytia and excess GAG production recapitulate elements of the invertebrate encapsulation reaction, itself dependent on insect transglutaminase and glutaminated early response proteins. As in other matrix expansion disorders, IL-6 is upregulated and represents a logical target for immunotherapy in patients with coeliac disease refractory to gluten-free diet.
    PLoS ONE 09/2014; 9(9):e106005. DOI:10.1371/journal.pone.0106005 · 3.23 Impact Factor
  • Source
    • "Symptoms may include pain, bloating or fatigue [8] [9]. The mechanism of symptom development in non-celiac gluten sensitivity is unclear; although an innate immune response to gluten in the intestine has been suggested [10]. The only treatment for non-celiac gluten Correspondence: Ryan T. Demmer PhD, Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 W. 168th St, New York, NY 10032, USA. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Clinical inference suggests the prevalence of non-celiac gluten sensitivity is substantially higher than that of celiac disease in the USA. Unfortunately, there are currently no data supporting these claims. The authors analyzed nationally representative data to estimate the prevalence of adherence to a gluten-free diet among participants without celiac disease and also to characterize the demographics and general health status of these participants. Study design and setting: The Continuous National Health and Nutrition Examination Survey (NHANES) 2009-2010 enrolled 7762 individuals representing the civilian, non-institutionalized, US population free of celiac disease. Participants responded to interviewer administered questionnaires regarding current adherence to a gluten-free diet. Prevalence estimates were computed using SAS survey procedures. Results: There were 49 individuals who reported current adherence to a gluten-free diet reflecting a weighted prevalence of 0.548% (95% CI 0.206-0.889). The prevalence of a gluten-free diet was higher in females (0.58%) than males (0.37%), although this was not statistically significant (p = 0.34). Participants reporting a gluten-free diet were older (46.6 vs. 40.5 years, p = 0.005), had higher high-density lipoprotein, lower iron and lower body mass index. Conclusions: The estimated national prevalence of non-celiac gluten sensitivity is 0.548%, approximately half that of celiac disease. Future studies are merited in order to better understand the population burden of non-celiac gluten sensitivity.
    Scandinavian Journal of Gastroenterology 07/2013; 48(8). DOI:10.3109/00365521.2013.809598 · 2.36 Impact Factor
    • "Gluten is the trigger of three heterogeneous sets of conditions: 1) immune-mediated enteropathy (celiac disease), 2) wheat allergy, 3) non-celiac gluten sensitivity [1]. These three distinct diseases can induce many different and specific manifestations, mediated by innate and adaptive immune pathways which are not common to all three conditions [2]. "
    Dataset: case report

Show more