Infection with a Helminth Parasite Attenuates Autoimmunity through TGF-β-Mediated Suppression of Th17 and Th1 Responses

Walsh, Kevin; Brady, Miriam T.; Finlay, Conor M.; Boon, Louis; Mills, Kingston H. G.

doi:10.4049/jimmunol.0803803

Cited by 258 publications

(228 citation statements)

References 38 publications

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“…These studies support the hypothesis that the induction of Treg cells by respiratory or enteric pathogens may play an important role in the protective effect of infections against the development of allergic disorders [76]. Furthermore, identification of immunomodulatory molecules, such as FHA from B. pertussis or products of helminth parasites [77] [78] that promote the development of Treg cells in vivo, may provide us with novel immunotherapeutic drugs for the prevention and treatment of autoimmune diseases and allergy (Fig 1). Support for this possibility stems from the demonstration that parenteral administration of FHA to mice significantly ameliorated disease in a T-cell mediated model of In contrast to PBS-treated mice, FHA-treated mice had significantly reduced weight loss, reduced colon shrinkage and lower levels of inflammatory cytokines [79].…”

Section: Implications For Allergy and Asthmasupporting

confidence: 51%

The Role of Regulatory T Cells in Respiratory Infections and Allergy and Asthma

McGuirk

Higgins²,

Mills³

2010

Curr Allergy Asthma Rep

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Section: Implications For Allergy and Asthmasupporting

confidence: 51%

The Role of Regulatory T Cells in Respiratory Infections and Allergy and Asthma

McGuirk

Higgins²,

Mills³

2010

Curr Allergy Asthma Rep

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“…Recently, growing evidence indicates that concomitant parasitic infections can reduce disease severity in different models of human autoimmune diseases (Tadokoro et al, 2004;Stevenson and Zavala, 2006;Walsh et al, 2009;Farias et al, 2011). For example, regulatory mechanisms induced during Plasmodium infection ameliorate the clinical course and immune responses of EAE (Farias et al, 2011) and co-infection with Trypanosoma species interferes with the development of EAE through a modulatory effect exerted by IL-10 that limits Th1 cells expansion (Tadokoro et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Puentes

Dickhaut

Hofstätter

et al. 2016

J Neuroimmune Pharmacol

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Parasite proteins containing repeats are essential invasion ligands, important for their ability to evade the host immune system and to induce immunosuppression. Here, the intrinsic suppressive potential of repetitive structures within parasite proteins was exploited to induce immunomodulation in order to establish self-tolerance in an animal model of autoimmune neurological disease.We tested the tolerogenic potential of fusion proteins containing repeat sequences of parasites linked to self-antigens. The fusion constructs consist of a recombinant protein containing repeat sequences derived from the S-antigen protein (SAg) of Plasmodium falciparum linked to a CD4 T cell epitope of myelin. They were tested for their efficacy to control the development of experimental autoimmune encephalomyelitis (EAE), In addition, we used the DO11.10 transgenic mouse model to study the immune mechanisms involved in tolerance induced by SAg fusion proteins.We found that repeated sequences of P. falciparum SAg protein linked to self-epitopes markedly protected mice from EAE. These fusion constructs were powerful tolerizing agents not only in a preventive setting but also in the treatment of ongoing disease. The tolerogenic effect was shown to be antigen-specific and strongly dependent on the physical linkage of the T cell epitope to the parasite structure and on the action of anti-inflammatory cytokines like IL-10 and TGF-β. Other mechanisms include down-regulation of TNF-α accompanied by increased numbers of FoxP3 + cells. This study describes the use of repetitive structures from parasites linked to defined T cell epitopes as an effective method to induce antigen-specific tolerance with potential applicability for the treatment and prevention of autoimmune diseases.

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“…This idea could explain the failure of F. hepatica coinfected mice to clear B. pertussis infection because mast cells secrete proinflammatory mediators like TNF-a and IFN-g that mediate host defense against B. pertussis (3, 4). Similarly, mast cells have a critical role during EAE in mice, as mast cell knockout mice are protected from developing this disease (42); this could also explain how Fasciola could attenuate EAE in mice (20). Further studies are required to determine the role of mast cells in this process, which would shed further light on the impact of helminths on communicable and noncommunicable diseases.…”

Section: Discussionmentioning

confidence: 99%

“…It can also attenuate experimental autoimmune encephalomyelitis (EAE) through the suppression of Th17 and Th1 immune responses (20).…”

Section: Ast Cells Are Associated With Helminth Infection Butmentioning

confidence: 99%

Fasciola hepatica Tegumental Coat Impairs Mast Cells’ Ability To Drive Th1 Immune Responses

Vukman

Adams

Metz

et al. 2013

The Journal of Immunology

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The parasitic worm Fasciola hepatica induces strong Th2 and T-regulatory immune responses while simultaneously suppressing Th1-driven immune responses to bystander microbial infections. It also prevents the initiation of Th1-mediated autoimmune disorders in mice through the suppression of Th17 and Th1 immune responses, and this can be mimicked by parasite-derived molecules. We have isolated F. hepatica tegumental coat Ag (FhTeg) and demonstrated its suppressive effect in vivo by directly targeting dendritic cells, impairing their ability to drive Th1 responses. Mast cells are critical in promoting Th1 protective immunity during bacterial infection and in driving Th1-mediated pathological conditions in autoimmune diseases. In this article, we show that FhTeg inhibits the ability of mast cells to drive the Th1 immune response by suppressing cytokine secretion (TNF-α, IL-6, IFN-γ, and IL-10) and ICAM1 expression in mast cells stimulated with LPS or heat-inactivated Bordetella pertussis Ag. These heat-inactivated B. pertussis Ag/LPS–stimulated mast cells fail to promote Th1 immune responses in CD4+ T cells when pretreated with FhTeg, and a role for ICAM1 in this process was demonstrated. FhTeg suppresses the activation of transcription factors in the TLR signaling pathway, which explains the decrease in cytokine production and cell surface marker expression. We demonstrated that FhTeg suppresses MAPK and NF-κB activation and enhances SOCS3 expression, which could explain its negative effect on the TLR pathways. We conclude that FhTeg targets innate immune cells, inhibiting their ability to drive Th1 immune responses.

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Infection with a Helminth Parasite Attenuates Autoimmunity through TGF-β-Mediated Suppression of Th17 and Th1 Responses

Cited by 258 publications

References 38 publications

The Role of Regulatory T Cells in Respiratory Infections and Allergy and Asthma

The Role of Regulatory T Cells in Respiratory Infections and Allergy and Asthma

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Fasciola hepatica Tegumental Coat Impairs Mast Cells’ Ability To Drive Th1 Immune Responses

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