Does the failure to acquire helminthic parasites predispose to Crohn's disease?

Elliott, David E.; Urban, Joe F.; Argo, Curtis K.; Weinstock, Joel V.

doi:10.1096/fj.99-0885hyp

Cited by 228 publications

(192 citation statements)

References 86 publications

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“…These observations may Europe PMC Funders Author Manuscripts also explain (together with genetic variations and dietary differences) the relatively low incidence of CD in non-developed countries. For example, the carriage rates of helminths such as Trichurus suis are greater in areas with a low incidence of CD [107] and these worms have also been used successfully to treat active CD [108]. However, the mechanisms for this effect remain unclear and the hygiene hypothesis, while attractive, is unconfirmed.…”

Section: Lifestyle Factors May Influence Intestinal Barrier and Innate mentioning

confidence: 99%

Crohn’s disease as an immunodeficiency

Hayee

Rahman

Sewell

et al. 2010

Expert Review of Clinical Immunology

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The pathogenesis of Crohn's disease (CD) has widely been regarded as the consequence of a dysregulated T-cell-mediated response to intestinal microbes, and the majority of the worldwide research effort has focused on characterizing and treating the chronic inflammatory phase of the disease. However, recent molecular biological and clinical investigations indicate that CD is actually a primary immunodeficiency. At first counter-intuitive, the apparent paradox of a pathogenic innate immune defect can be linked mechanistically to the granulomatous chronic inflammation characteristic of the disease. Genome-wide association studies have corroborated the involvement of innate immune dysfunction in the pathogenesis of CD, but less than 20% of the heritable risk is accounted for. By contrast, in vitro and in vivo stimulation of the immune system has highlighted novel areas of interest that may lead to the development of targeted therapeutic and diagnostic tools. Keywordsbacteria; Crohn's disease; immunodeficiency; innate immunity; macrophage; neutrophil Established intestinal lesions in Crohn's disease (CD) contain a massive, mixed inflammatory cell infiltrate associated with a complex storm of cytokines in a selfperpetuating, chronic inflammatory response [1][2][3]. Most research to date has focused on the the immunological characteristics of established lesions and drawn inferences about their initiation. The predominance of a classically Th1-associated cytokine profile in these lesions led to the assumption that T lymphocytes were central to the initial pathogenesis. More recently, the role of regulatory (Treg) FoxP3 + and IL-23-induced responsive Th17-type T lymphocytes has gained popularity [2,4,5]. Treg cell populations are diminished in patients with CD [6] and, although the hypothesis of CD as an immunodeficiency does not necessarily exclude defects in T-cell function, to date, no convincing intrinsic (primary) defect has been identified to implicate these cells in the pathogenesis of human CD.The hypothesis that immunodeficiency underpins the development of CD seems, at first, to be in direct contrast with histological observations of established intestinal lesions and the † Author for correspondence: Tel.: +44 207 679 6170 Fax: +44 207 679 0967 b.hayee@nhs.net. Financial & competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Europe PMC Funders Group Association between immunodeficiency diseases & CDThere is a well-known and strong association between primary immunodeficiency disorders and non-infectious granulomatous intestinal inflammation. Chronic granulomatous disease (CGD), glycogen storage disease type 1b, leukocyte adhesion deficiency, Chediak-Higashi and Hermansky-Pudlak syndromes are all strongly associated with intestinal inflammation that is indistinguishable from CD [...

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Section: Lifestyle Factors May Influence Intestinal Barrier and Innate mentioning

confidence: 99%

Crohn’s disease as an immunodeficiency

Hayee

Rahman

Sewell

et al. 2010

Expert Review of Clinical Immunology

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“…In addition, in South Lower Saxony, Germany the incidence of multiple sclerosis doubled from 1969 to 1986 (Poser et al 1989), and increased four-fold in Japan over the last two decades (Itoh et al 2003). As well, Crohn's disease is more common in highly industrialized countries and less prevalent in Asia, Africa and South America (Elliott et al 2000). The incidence of the disease tripled in Europe from 1950 to 1990 (Farrokhyar et al 2001), appearing to correlate with decreasing prevalence of helminthic infections (Elliott et al 2000).…”

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confidence: 99%

“…As well, Crohn's disease is more common in highly industrialized countries and less prevalent in Asia, Africa and South America (Elliott et al 2000). The incidence of the disease tripled in Europe from 1950 to 1990 (Farrokhyar et al 2001), appearing to correlate with decreasing prevalence of helminthic infections (Elliott et al 2000). The incidence of type I diabetes among Pakistanis who migrated to the United States is the same as the rate among Americans and ten times higher than the incidence of the disease in Pakistan (Bodansky et al 1992, Staines et al 1997b, Bach 2002.…”

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confidence: 99%

Schistosoma mansoni infection modulates the immune response against allergic and auto-immune diseases

Araújo

Hoppe

Medeiros

et al. 2004

Mem. Inst. Oswaldo Cruz

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“…Our interest in understanding the mechanisms underlying the cross-talk between parasite and host arises because gastrointestinal roundworm parasites, including T. spiralis, infect approximately one billion people worldwide and are believed to cause approximately one million deaths annually (29). In addition, elucidation of the mechanisms could lead to the development of new strategies for the therapy of various inflammatory pathological conditions, such as inflammatory bowel disease (30), and could also offer more information on the hygiene hypothesis that has been very influential in directing strategies to prevent allergic diseases (4). We have previously demonstrated (8) that ongoing gut inflammatory reactions induced by certain roundworms can set into motion systemically operated mechanisms that downregulate NOS-2 expression.…”

Section: Discussionmentioning

confidence: 99%

Helminth regulation of host IL-4Rα/Stat6 signaling: Mechanism underlying NOS-2 inhibition byTrichinella spiralis

Bian¹,

Zhong²,

Harari³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Gastrointestinal nematode infection is known to alter host T cell activation and has been used to study immune and inflammatory reactions in which nitric oxide (NO) is a versatile player. We previously demonstrated that Trichinella spiralis infection inhibits host inducible NO synthase (NOS-2) expression. We now demonstrate that (i) an IL-4 receptor ␣-subunit (IL-4R␣)͞Stat6-dependent but T cell-independent pathway is the key for the nematodeinduced host NOS-2 inhibition; (ii) endogenous IL-4 and IL-13, the only known IL-4R␣ ligands, are not required for activating the pathway; and (iii) treatment of RAW264.7 cells with parasitecultured medium inhibits NOS-2 expression but not cyclooxygenase 2 expression. We propose that a yet-unidentified substance is released by the nematode during the host-parasite interaction.inflammation ͉ nematode ͉ immunoregulation ͉ nitric oxide ͉ endotoxin G astrointestinal nematode infection has served as a well established model to study parasite-induced host T cell activation and cytokine regulation (1, 2). Interaction within the cytokine network plays a key role in the control of immunity and inf lammation that mediates host protective responses (3, 4). Recently, nitric oxide (NO) has been recognized as one of the most versatile players in the immune system based on several findings. (i) Producing or responding to NO is a major feature of macrophages and many other immunesystem cells. (ii) All isoforms of NO synthase (NOS) are expressed in the immune system, and induction of inducible NOS (NOS-2) has been implicated in a variety of immunologic inf lammatory conditions. (iii) NOS-2 expression is upregulated by T helper 1 (Th1) cytokines and inhibited by Th2 cytokines. In addition, the effects of NO are not restricted to any single cytokine receptor. Thus, NO plays a very diverse role in the immune system. (iv) Activation of NOS-2 results in the production of a high concentration of NO. Highly diffusible ⅐ NO is rapidly oxidized to reactive nitrogen species that are detrimental in several immunopathologic processes [see reviews (5-7) for further information].We have previously demonstrated that Trichinella spiralis infection induces down-regulation of NOS-2 expression (8), which has the following characteristics. (i) Local jejunal infection by T. spiralis systemically inhibits NOS-2 gene transcription, protein expression, and enzyme activity in the ileum, jejunum, colon, kidney, lung, and uterus. (ii) The effect of inhibition is potent and can override endotoxin-induced NOS-2 expression. (iii) The inhibition does not extend to the expression of other isoforms of NOS; to paxillin, a housekeeper protein; or to cyclooxygenase 2 (COX-2), another protein induced by proinflammatory cytokines. (iv) The inhibition is not associated with a chemically induced intestinal inflammatory response. (v) The inhibition is unlikely related to the formation of specific antiparasite antibodies. (vi) The inhibition may involve substances other than stress-induced corticosteroids.The objective of the current...

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Does the failure to acquire helminthic parasites predispose to Crohn's disease?

Cited by 228 publications

References 86 publications

Crohn’s disease as an immunodeficiency

Crohn’s disease as an immunodeficiency

Schistosoma mansoni infection modulates the immune response against allergic and auto-immune diseases

Helminth regulation of host IL-4Rα/Stat6 signaling: Mechanism underlying NOS-2 inhibition byTrichinella spiralis

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