Anti-Inflammatory Mechanisms of Enteric<i>Heligmosomoides polygyrus</i>Infection against Trinitrobenzene Sulfonic Acid-Induced Colitis in a Murine Model

Sutton, Thomas L.; Zhao, Aiping; Madden, Kathleen B.; Elfrey, Justin; Tuft, Blaine; Sullivan, Connor; Urban, Joseph F.; Shea‐Donohue, Terez

doi:10.1128/iai.00744-07

Cited by 69 publications

(56 citation statements)

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“…These observations are supported by the results showing that intestinal helminth infection increases the intestinal translocation/ absorption of bacterial products such as lipopolysaccharide (LPS) into the portal circulation by altering barrier function (10) and that IL-4 treatment of keratinocytes significantly enhanced the permeability to high-molecular-mass material (40-kDa fluorescein isothiocyanate [FITC]-dextrans) through modification of intercellular adhesion molecules (23). In contrast, a recent study that used an Ussing chamber approach measured mucosal permeability and secretion ex vivo and showed that H. polygyrus infection increased colonic mucosal resistance (34). The differences in helminth-induced colonic permeability between this report (34) and our current study may be due to the differences in the experimental approaches used.…”

Section: Discussionmentioning

confidence: 93%

“…4). These (12), which may alter the host response to other pathogens or antigens (13,20,31,32,34). To directly demonstrate the role of the adaptive immune system in the immune modulation of colonic epithelial barrier function during intestinal helminth infection, we next adoptively transferred unfractionated lymphocytes isolated from the spleens and lymph nodes of normal BALB/c mice into SCID mice, which were infected with 200 third-stage H. polygyrus larvae or left uninfected.…”

Section: Resultsmentioning

confidence: 99%

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Duodenal Helminth Infection Alters Barrier Function of the Colonic Epithelium via Adaptive Immune Activation

Cao

Kaplan

et al. 2011

Infect Immun

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Chronic infection with intestinal helminth parasites is a major public health problem, particularly in the developing world, and can have significant effects on host physiology and the immune response to other enteric infections and antigens. The mechanisms underlying these effects are not well understood. In the current study, we investigated the impact of infection with the murine nematode parasite Heligmosomoides polygyrus, which resides in the duodenum, on epithelial barrier function in the colon. We found that H. polygyrus infection produced a significant increase in colonic epithelial permeability, as evidenced by detection of elevated serum levels of the tracer horseradish peroxidase following rectal administration. This loss of normal barrier function was associated with clear ultrastructural changes in the tight junctions of colonic epithelial cells and an alteration in the expression and distribution of the junctional protein E-cadherin. These parasite-induced abnormalities were not observed in SCID mice but did occur in SCID mice that were adoptively transferred with wild-type T cells, indicating a requirement for adaptive immunity. Furthermore, the helminth-induced increase in gut permeability was not seen in STAT6 knockout (KO) mice. Taken together, the results demonstrate that one of the mechanisms by which helminths exert their effects involves the lymphocyte-and STAT6-dependent breakdown of the intestinal epithelial barrier. This increase in epithelial permeability may facilitate the movement of lumenal contents across the mucosa, thus helping to explain how helminth infection can alter the immune response to enteric antigens.The integrity of the intestinal epithelium is essential for maintenance of the dynamic barrier that regulates absorption of nutrients and water and at the same time restricts uptake of luminal bacteria and bacterial products (3,40). The barrier function of the intestinal epithelium is maintained by the apical junctional (AJ) complex, which includes several distinct structures known as tight junctions (TJs), adherens junctions, desmosomes, and gap junctions. The TJ is the major paracellular barrier and functions as a "fence" separating apical and basolateral compartments. The adherens junction forms a continuous belt and is crucial for the maintenance of intercellular adhesion (9,24,28). The tight junction and adherens junction are regulated by (i) interactions between transmembrane TJ/AJ proteins on the opposing cell plasma membranes, (ii) interactions involving scaffolding proteins that cluster and stabilize transmembrane components of TJ and AJ proteins, and (iii) the interactions mediated by actin binding proteins such as those in the zonula occludin (ZO) family, catenin, etc., which link the AJ complex to actin microfilaments (9, 14, 24, 28). Major transmembrane proteins in the apical junctional complex include occludin, claudins, junction adhesion molecules, and E-cadherin (14). The list of proteins that constitute the intercellular junction complex has been expanding.L...

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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Duodenal Helminth Infection Alters Barrier Function of the Colonic Epithelium via Adaptive Immune Activation

Cao

Kaplan

et al. 2011

Infect Immun

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“…Despite the fact that the H. polygyrus life cycle takes place in the intestine (without entering the circulation), the parasite potently modulates systemic immune responses. It has been investigated in many animal models of inflammatory disease, including T1D, colitis, allergy, asthma, and gastric atrophy [39,[41][42][43][44][45][46][47][48] + T cells via ligation of the host TGF-β receptor [49].…”

Section: Abbreviationsmentioning

confidence: 99%

Helminth Infection and Type 1 Diabetes

Zaccone¹,

Hall²

2012

Rev Diabet Stud

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■ AbstractThe increasing incidence of type 1 diabetes (T1D) and autoimmune diseases in industrialized countries cannot be exclusively explained by genetic factors. Human epidemiological studies and animal experimental data provide accumulating evidence for the role of environmental factors, such as infections, in the regulation of allergy and autoimmune diseases. The hygiene hypothesis has formally provided a rationale for these observations, suggesting that our coevolution with pathogens has contributed to the shaping of the present-day human immune system. Therefore, improved sanitation, together with infection control, has removed immunoregulatory mechanisms on which our immune system may depend. Helminths are multicellular organisms that have developed a wide range of strategies to manipulate the host immune system to survive and complete their reproductive cycles successfully. Immunity to helminths involves profound changes in both the innate and adaptive immune compartments, which can have a protective effect in inflammation and autoimmunity. Recently, helminth-derived antigens and molecules have been tested in vitro and in vivo to explore possible applications in the treatment of inflammatory and autoimmune diseases, including T1D. This exciting approach presents numerous challenges that will need to be addressed before it can reach safe clinical application. This review outlines basic insight into the ability of helminths to modulate the onset and progression of T1D, and frames some of the challenges that helminth-derived therapies may face in the context of clinical translation.

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“…This protective effect could also be adoptively transferred with either regulatory T (Treg) cell [31], or B-cell transfer [32], in both cases in an IL-10 independent manner. Together with a number of other studies on H. polygyrus infection in allergy [33,34], colitis [35][36][37] and diabetes [38,39], it is clear that this helminth downregulates multiple effector pathways of the adaptive immune response [40].Therapy of human immune pathologies with live helminth parasites continues to be evaluated, but will remain an empirical process. Moreover, permitted doses of live parasites are minimal due to ethical and logistical constraints [41], such that exposure levels and duration do not approach those seen in endemic populations.…”

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confidence: 99%

Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminthHeligmosomoides polygyrus

McSorley

O'Gorman

Blair³

et al. 2012

Eur J Immunol

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Allergic asthma is less prevalent in countries with parasitic helminth infections, and mice infected with parasites such as Heligmosomoides polygyrus are protected from allergic airway inflammation. To establish whether suppression of allergy could be mediated by soluble products of this helminth, we tested H. polygyrus excretory-secretory (HES) material for its ability to impair allergic inflammation. When HES was added to sensitising doses of ovalbumin, the subsequent allergic airway response was suppressed, with ablated cell infiltration, a lower ratio of effector (CD4 + CD25 + Foxp3 − ) to regulatory (CD4 + Foxp3 + ) T (Treg) cells, and reduced Th1, Th2 and Th17 cytokine production. HES exposure reduced IL-5 responses and eosinophilia, abolished IgE production and inhibited the type 2 innate molecules arginase-1 and RELM-α (resistin-like molecule-α). Although HES contains a TGF-β-like activity, similar effects in modulating allergy were not observed when administering mammalian TGF-β alone. HES also protected previously sensitised mice, suppressing recruitment of eosinophils to the airways when given at challenge, but no change in Th or Treg cell populations was apparent. Because heat-treatment of HES did not impair suppression at sensitisation, but compromised its ability to suppress at challenge, we propose that HES contains distinct heat-stable and heat-labile immunomodulatory molecules, which modulate pro-allergic adaptive and innate cell populations.Keywords: Allergy r Eosinophils r IgE r Infection r Macrophages IntroductionAllergic asthma has dramatically increased in prevalence in developing countries, exceeding 5% of the Western European and North American populations [1]. This contrasts with much lower asthma incidence in tropical countries that have significant levels of parasite infections, and these observations have stimulated research into the effects of parasitic organisms on human allergy [2][3][4]. From these studies, it has emerged that allergic diseases are least common in parts of the world with high helminth endemicity, and that within endemic populations the prevalence of atopy is significantly lower in individuals with chronic worm infections [5][6][7][8][9][10].Correspondence: Dr. Rick M. Maizels e-mail: rick.maizels@ed.ac.ukWhile a causal link between human helminth infections and reduced allergy has yet to be proven [2], chemotherapeutic clearance of intestinal helminths can result in accentuated atopic responsiveness [11][12][13] and helminth infection blocks overt allergy in a number of animal models [14][15][16][17]. The degree to which helminths may influence allergy, however, is clearly variable between different parasite species [18], and is probably dependent upon the duration and intensity of infection [2,19], each factors that need to be taken into account in assessing this interaction.The concept that helminths may act in a beneficial way for therapy of immunological disorders is one that has been gaining * These author contributed equally to this work. Eur. J. Immunol. 20...

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Anti-Inflammatory Mechanisms of EntericHeligmosomoides polygyrusInfection against Trinitrobenzene Sulfonic Acid-Induced Colitis in a Murine Model

Cited by 69 publications

References 66 publications

Duodenal Helminth Infection Alters Barrier Function of the Colonic Epithelium via Adaptive Immune Activation

Duodenal Helminth Infection Alters Barrier Function of the Colonic Epithelium via Adaptive Immune Activation

Helminth Infection and Type 1 Diabetes

Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminthHeligmosomoides polygyrus

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