Suppression of Inflammatory Immune Responses in Celiac Disease by Experimental Hookworm Infection

Henry J Mcsorley,Henry J Mcsorley,Richard Speare,James Daveson,Andrew Clouston,Alex Loukas,Alex Loukas,John Croese,Christian R Engwerda,Christian R Engwerda,Soraya Gaze,Soraya Gaze,Nathalie E Ruyssers,Nathalie E Ruyssers,Dianne Jones,James S Mccarthy,James S Mccarthy,Robert P Anderson

doi:10.1371/journal.pone.0024092

Abstract

We present immunological data from two clinical trials where the effect of experimental human hookworm (Necator americanus) infection on the pathology of celiac disease was evaluated. We found that basal production of Interferon- (IFN-)γ and Interleukin- (IL-)17A from duodenal biopsy culture was suppressed in hookworm-infected participants compared to uninfected controls. Increased levels of CD4+CD25+Foxp3+ cells in the circulation and mucosa are associated with active celiac disease. We show that this accumulation also occurs during a short-term (1 week) oral gluten challenge, and that hookworm infection suppressed the increase of circulating CD4+CD25+Foxp3+ cells during this challenge period. When duodenal biopsies from hookworm-infected participants were restimulated with the immunodominant gliadin peptide QE65, robust production of IL-2, IFN-γ and IL-17A was detected, even prior to gluten challenge while participants were strictly adhering to a gluten-free diet. Intriguingly, IL-5 was produced only after hookworm infection in response to QE65. Thus we hypothesise that hookworm-induced TH2 and IL-10 cross-regulation of the TH1/TH17 inflammatory response may be responsible for the suppression of these responses during experimental hookworm infection.

Highlights

Celiac disease is an immune-mediated intestinal inflammatory condition
The immunopathology of celiac disease is well understood and allows researchers to focus on the specific population of CD4+ T cells that are responsible for inflammation
Only the control group showed an increase in the overall proportion of circulating CD4+ T cells (Figure 2A), a trend for increased proportions of CD25+Foxp3+ CD4+ cells (Figure 2B) and increased CD25 (Figure 2C) and Foxp3 (Figure 2D) expression (MFI) in the CD4+CD25+ Foxp3+ population (p = 0.016 and p = 0.007 respectively), while no change was seen in the hookworm group (p = 0.69 and p = 0.88 respectively)

Summary

Introduction

Celiac disease is an immune-mediated intestinal inflammatory condition. To inflammatory gastrointestinal disease, the stimulatory antigen (dietary gluten) and even the MHC restriction are known [1]. The immunopathology of celiac disease is well understood and allows researchers to focus on the specific population of CD4+ T cells that are responsible for inflammation. Predisposition to celiac disease is believed to depend on multiple genetic, immunological and environmental factors [2]. Expression of tTG is upregulated by the presence of gliadin and in active celiac disease patients produce diagnostic autoantibodies to tTG [3]. Deamidated gliadin peptides bind strongly to HLA-DQ2 or HLA-DQ8 MHC molecules, allowing efficient presentation to CD4+ T cells, and the presence of these MHC haplotypes is the most important genetic risk factor predisposing to disease [4]

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Results

Conclusion