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

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.

Hookworm Excretory/Secretory Products Induce Interleukin-4 (IL-4)+IL-10+CD4+T Cell Responses and Suppress Pathology in a Mouse Model of Colitis

“…In a recent placebo-controlled clinical trial assessing the therapeutic effect of experimental N. americanus infection on the immunopathogenesis of celiac disease, hookworms reduced the systemic and mucosal expression of IL-17A and IFN-␥, which are signature cytokines involved in the pathogenesis of IBD, and caused elevated Th2 cytokine responses and eosinophilia (7,37). We observed a similar immune phenotype in mice injected with AcES, with reduced production of IL-17A and IFN-␥ and elevated levels of type 2 cytokines and eosinophilia.…”

Helminth Infections and Host Immune Regulation

“…Subsequently, trials for celiac disease (61) and allergic rhinoconjunctivitis (85) have been carried out. Although neither of these smallscale trials showed a significant suppression of pathology, the celiac disease trial did show some suppression of inflammatory cytokines in the gut (191), associated with a switch to a glutenspecific Th2 response (191). Thus, it remains to be seen whether human hookworm infection will be a viable option for the treatment of human immunopathologies.…”

“…First, in an ulcerative colitis patient with T. trichiura infection, parasite colonization was shown to modify IL-17 levels while inducing Th2 cytokines and IL-22 in the colonic mucosa, with associated goblet cell hyperplasia (36). Second, a clinical trial of hookworm infection in patients with celiac disease showed an upregulation of hookworm antigenspecific Th2 cytokines and basal levels of IL-22, with suppression of IL-23, IFN-␥, and IL-17A production (97,191). Thus, immune deviation in the gastrointestinal mucosa also occurs in human parasitic infections with respect to the suppression of inflammatory Th1/17 responses.…”

Nutrition in Celiac Disease

“…Increased incidence of celiac disease was found in children who have undergone diarrhea caused by rotavirus [8] or Campylobacter sp., but not other bacteria [9]. Conversely, a lower incidence of celiac disease has been detected in children colonized by Helicobacter pylori [10], an intentional infection by Necator americanus (hookworm) improved tolerance to gluten [11,12]. A theory of the influence damaged intestinal microbiome to a greater incidence of celiac disease is confirmed by the higher incidence of patients with celiac disease in a group of births by elective, but not emergency, caesarean section [13].…”