Immunomodulation via Novel Use of TLR4 by the Filarial Nematode Phosphorylcholine-Containing Secreted Product, ES-62

Goodridge, Helen S.; Marshall, Fraser A.; Else, Kathryn J.; Houston, Katrina M.; Egan, C. A.; Al-Riyami, Lamyaa; Liew, Foo Y.; Harnett, William; Harnett, Margaret M.

doi:10.4049/jimmunol.174.1.284

Cited by 214 publications

(261 citation statements)

References 54 publications

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“…Among others, a phosphatidylserine with specific chain length expressed by S. mansoni eggs engages TLR2 expressed on dendritic cells, which in turn induces IL-10-producing regulatory T cells (53). A secreted glycoprotein of the filarial nematode A. viteae inhibited Fc RImediated mast cell responses by forming a complex with TLR4, which resulted in the sequestration of protein kinase C-␣, a molecule important for mast cell activation (54,55). We provide evidence that cystatin protects from inflammation in a systemic fashion, as reflected by its effects on remarkably different compartments, such as the lung and the gut.…”

Section: Discussionmentioning

confidence: 77%

A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages

Schnoeller

Rausch

Pillai

et al. 2008

The Journal of Immunology

226

196

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The coincidence between infections with parasitic worms and the reduced prevalence of allergic disease in humans and in animal models has prompted the search for helminth molecules with antiallergic and antiinflammatory potential. We report herein that filarial cystatin, a secreted protease inhibitor of filarial nematodes, suppresses Th2-related inflammation and the ensuing asthmatic disease in a murine model of OVA-induced allergic airway responsiveness. Treatment with recombinant filarial cystatin inhibited eosinophil recruitment, reduced levels of OVA-specific and total IgE, down-regulated IL-4 production, and suppressed allergic airway hyperreactivity when applied during or after sensitization and before challenge with the allergen. Depletion of macrophages by clodronate-containing liposomes prevented the curative effects and restored the levels of infiltrating cells, IgE, and allergic airway reactivity. Blocking of IL-10 by application of anti-IL-10 receptor Abs restored the reduced number of infiltrating cells and the levels of OVA-specific IgE. In contrast, depletion of regulatory T cells by anti-CD25 Abs had only limited effects. Cystatin also modulated macrophage-mediated inflammation in a murine model of dextran sulfate sodium-induced colitis, leading to reduction of inflammatory infiltrations and epithelial damage. Our data demonstrate that treatment with a single helminth protein can exert the antiallergic effects of helminth infections.

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Section: Discussionmentioning

confidence: 77%

A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages

Schnoeller

Rausch

Pillai

et al. 2008

The Journal of Immunology

226

196

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“…Thus, it targets cells of the innate immune system (DCs and ␥/␦ T cells) to inhibit initiation of pathogenic responses and also, by acting directly on Th17 cells, to suppress ongoing adaptive responses. Mechanistically, given the increasing evidence of TLR signaling in the initiation (DC) and amplification of Th17 cell-and ␥/␦ T cell-mediated IL-17 responses and autoimmune inflammation (28,31,48), it is pertinent that ES-62 rewires TLR-2-, TLR-4-, and TLR-9-driven maturation of DCs to an antiinflammatory phenotype in a TLR-4-dependent manner (19). This was reflected in the present study by the inhibition of LPS-induced TNF␣, IL-6, and IL-23 production, as well as by the release of increased levels of IL-27, resulting in the suppression of differentiation and/or maintenance of the Th17 phenotype.…”

Section: Discussionmentioning

confidence: 99%

The parasitic helminth product ES‐62 suppresses pathogenesis in collagen‐induced arthritis by targeting the interleukin‐17–producing cellular network at multiple sites

Pineda

McGrath

Smith

et al. 2012

Arthritis & Rheumatism

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146

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Objective. Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62.

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“…Nonetheless, some helminth products have also been shown to prime Th2 or regulatory responses through ligation of TLR. For instance, excretory/secretory-62 (ES-62), a phosphorylcholine-containing glycoprotein of the nematode Acanthocheilonema viteae, conditions DC to induce Th2 responses through TLR4 [7,8]. Moreover, the glycoconjugate LNFPIII, carrying a Lewis-X (Le x ) carbohydrate epitope found in schistosoma soluble egg antigens (SEA), has been implicated in TLR4-dependent priming of Th2 responses via DC [9].…”

Section: Modulation Of DC Function By Direct Interaction With Helmintmentioning

confidence: 99%

Helminths and dendritic cells: Sensing and regulating via pattern recognition receptors, Th2 and Treg responses

et al. 2010

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The classical reaction of the host to helminth infections is the induction of Th2 immune responses with a regulatory component. DC, as central players in the induction and maintenance of immune responses, play a prominent role in both these processes, and in recent years considerable progress has been made in elucidating the mechanisms behind the interplay between DC and helminths. It is becoming increasingly clear that helminths modulate DC function not only via direct interactions but also indirectly via host-derived cues. Furthermore, while studies have until recently focused on receptor signalingmediated DC modulation by helminths, evidence is emerging that DC may also respond to helminth infections by sensing stress signals or tissue damage inflicted by the worms or their products. Here, we will discuss these new insights and will link them to the origin and importance of Th2 and regulatory immune responses with respect to the survival of both parasite and host.Key words: DC . Helminth . Th cell polarization . Tissue damage IntroductionThe classical reaction of the host to helminth infections is the induction of Th2 responses. The induction of Th2 immunity has been shown to be important for resistance to helminth infections in various model systems; however, despite induction of a Th2 response, total clearance of the parasites rarely occurs in man (reviewed in [1,2]). This implies that helminths have evolved strategies, such as evasion or suppression of the host immune response that prevent their expulsion and permit their long-term survival. The immune modulatory effects are thought to arise from the helminth's capacity to exploit the host's own system of immune regulation, which is normally crucial for the maintenance of immune homeostasis and self tolerance. In this respect, the induction of Treg has been shown to be one of the most common mechanisms that restrains immune responses against the parasite while also preventing excessive inflammation and tissue damage inflicted by the worms (reviewed in [2,3]). Therefore, it is not surprising that among the variety of mechanisms developed by helminths to influence host immune responses, modulation of DC as pivotal players in the initiation and polarization of adaptive immune responses, including Treg modulation, may have a particularly important role (reviewed in [2,4,5] ) carbohydrate epitope found in schistosoma soluble egg antigens (SEA), has been implicated in TLR4-dependent priming of Th2 responses via DC [9]. However, SEA is also known to be capable of modulating DC for Th2 priming in the absence of TLR signaling [10]. Furthermore, phosphatidylserine (PS) lipids derived from schistosomes and ascaris worms, which carry TLR2-activating molecules, have been shown to promote Th2 responses via DC, but this is not TLR2 dependent [11], whereas monoacetylated PS lipids from schistosomes were found to specifically instruct DC to preferentially induce IL-10-producing Treg in a TLR2-dependent fashion [12]. Although TLR2 does not seem to be essential for Th2 polar...

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Immunomodulation via Novel Use of TLR4 by the Filarial Nematode Phosphorylcholine-Containing Secreted Product, ES-62

Cited by 214 publications

References 54 publications

A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages

A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages

The parasitic helminth product ES‐62 suppresses pathogenesis in collagen‐induced arthritis by targeting the interleukin‐17–producing cellular network at multiple sites

Helminths and dendritic cells: Sensing and regulating via pattern recognition receptors, Th2 and Treg responses

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