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  • Review Article
  • Published:

Protective immune mechanisms in helminth infection

Nature Reviews Immunology volume 7, pages 975–987 (2007)Cite this article

Key Points

  • Helminth parasites cause chronic disease in billions of people, however, the immune response associated with helmith infection can also reduce the severity of certain harmful inflammatory autoimmune and allergic diseases.

  • Studies of tissue-dwelling parasites in murine models reveal the development of T helper 2 (TH2)-type granulomas consisting of cellular infiltrates that resemble TH1-type granulomas; however, the cells are activated differently and have distinct functions.

  • The TH2-type response can affect host protection by mediating helminth expulsion or by controlling otherwise pathological inflammatory responses that are driven by TH1 and TH17 cells.

  • TH2 cells are the primary source of TH2-type cytokines but innate cells can also produce these cytokines.

  • TH2-type cytokines, including interleukin-4 (IL-4) and IL-13, orchestrate a potent TH2-type response by direct stimulation of both bone-marrow-derived and non-bone-marrow-derived cell populations.

  • A similarly complex and multi-faceted TH2-type response is elicited following infection with a wide variety of helminths; however, only certain components of this broad response are effective against a particular species.

  • The discovery of new effector cell types and molecules contributing to the host protective TH2-type response provides additional targets for the development of novel therapies against helminths.

Abstract

Important insights have recently been gained in our understanding of how host immune responses mediate resistance to parasitic helminths and control associated pathological responses. Although similar cells and cytokines are evoked in response to infection by helminths as diverse as nematodes and schistosomes, the components of the response that mediate protection are dependent on the particular parasite. In this Review, we examine recent findings regarding the mechanisms of protection in helminth infections that have been elucidated in murine models and discuss the implications of these findings in terms of future therapies.

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Figure 1: Protective TH2-type response during intestinal nematode infection.
Figure 2: Functions of innate effector cells during the TH2-type response.
Figure 3: TH2-cell functions during helminth infection.
Figure 4: T helper and regulatory cells.

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Acknowledgements

We greatly appreciate the careful review and thoughtful suggestions provided by F.D. Finkelman and E.J. Pearce, and would like to thank T. Kreider for his help in editing the original manuscript and drawing the original figures. This work was supported by National Institutes of Health Grants AI031678 and AI066188.

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Authors and Affiliations

  1. The Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Robert M. Anthony

  2. Department of Pathology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, 02111, Massachusetts, USA

    Laura I. Rutitzky & Miguel J. Stadecker

  3. US Department of Agriculture, Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, 10300 Baltimore Avenue, Building 307-C BARC-East, Beltsville, 20705, Maryland, USA

    Joseph F. Urban Jr

  4. Department of Medicine, UMDNJ-New Jersey Medical School, 185 S. Orange Avenue, Newark, 07103, New Jersey, USA

    William C. Gause

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Glossary

Helminths

These are worms that are characterized by their body shape into cestodes (flat worms), nematodes (round worms) and trematodes (leaf-shaped worms).

Hygiene hypothesis

This hypothesis originally proposed that the increased incidence of atopic diseases in westernized countries was a consequence of living in an overly clean environment resulting in an under-stimulated immune system that responded inappropriately to harmless antigens. More recently it has been proposed that an absence of exposure to pathogens, in particular helminths, may predispose to both increased allergy and autoimmune disease.

TH2-type response

(T-helper-2-type response).An immune response including innate and adaptive components that is elicited by helminth infections and many allergic reactions. Common features include expression of TH2-type cytokines (IL-4, IL-5 and IL-13), eosinophilia, basophilia, mastocytosis, goblet-cell hyperplasia and IgE production.

TH1 cells

(T helper 1 cells). This is a CD4+ effector T cell mainly characterized by its expression of interferon-γ.

Heligmosomoides polygyrus

A natural mouse gastro-intestinal trichostrongylid nematode parasite, used as a model of human intestinal nematode infection. Primary infections become established and chronic, and can be cleared by helminth-specific drug treatment. Challenge infections are naturally cleared by the host by day 14 post-infection, making this an excellent model of protective memory T-helper-2-type responses.

Schistosoma mansoni

A blood-dwelling trematode parasite that causes a major form of human hepato-intestinal schistosomiasis. Infection of mice with this parasite represents a well-established murine model of this disease.

Granuloma

A circumscribed inflammatory cell infiltrate surrounding a nidus. Its composition usually includes T cells and macrophages, and in the case of helminth infection, eosinophils.

TH17 cell

(T helper 17 cell). This is a CD4+ effector T cell that expresses interleukin-17 (IL-17), IL-6, tumour necrosis factor, IL-21 and IL-22, but does not express interferon-γ nor IL-4.

Alternatively activated macrophage

A macrophage stimulated by interleukin-4 (IL-4) or IL-13 that expresses arginase-1, mannose receptor CD206 and IL-4 receptor α. There may be pathogen-associated molecular patterns expressed by helminths that can also drive alternative activation of macrophages.

Classically activated macrophage

A macrophage that is activated through Toll-like receptors and interferon-γ that expresses inducible nitric oxide synthase and nitric oxide.

Filarial parasites

These thread-like nematode parasites cause a wide range of diseases in humans, including River blindness (by Onchocerca volvulus) and elephantiasis (by Wuchereria bancrofti, Brugia malayi and Brugia timori).

Chitinase and FIZZ family member proteins

(ChaFFs). Proteins that are expressed by alternatively activated macrophages or goblet cells during TH2-type responses. They include acidic mammalian chitinase (AMCase), Ym1, Ym2, resistin-like molecule (RELMα also known as FIZZ1), RELMβ (also known as FIZZ 2) and RELMγ.

Strongyloides stercoralis

A parasitic roundworm (threadworm) of humans and other mammals.

Goblet cells

Mucus-producing cells found in the epithelial-cell lining of the intestine and lungs.

Allergic cascade

The sequence of events contributing to acute and chronic allergic reactions. Surface Fc receptors for IgE on mast cells are crosslinked, triggering the release of soluble mediators. Immediate vascular permeability and smooth muscle contractility is associated with acute allergic reactions, and eosinophils and T helper 2 cells are associated with chronic allergic reactions.

Nippostrongylus brasiliensis

A trichostrongylid intestinal nematode rodent parasite that is widely used as a model to study T-helper-2-type responses. In most inbred mouse strains, primary infection results in rapid expulsion of the parasite within 10–12 days.

Toll-like receptors

(TLRs). The best characterized family of receptors for pathogen-associated molecular patterns. Receptors in this family recognize bacterial cell-wall and membrane structures, flagella, bacterial DNA motifs, viral double-stranded RNA and other structures.

Pathogen-associated molecular patterns

(PAMPs). Conserved microbial structures recognized by innate receptors, including Toll-like receptors.

Regulatory T cell

(TReg cell). A type of CD4+ T cell that is characterized by its expression of forkhead box P3 (FOXP3) and high levels of CD25. TReg cells can downmodulate many types of immune responses.

Class switching

The somatic-recombination process by which the class of immunoglobulin is switched from IgM to IgG, IgA or IgE. During T helper 1 (TH1)-type responses, B cells can class-switch to produce IgG2a whereas during TH2-type responses B cells can switch to produce IgE.

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Anthony, R., Rutitzky, L., Urban, J. et al. Protective immune mechanisms in helminth infection. Nat Rev Immunol 7, 975–987 (2007). https://doi.org/10.1038/nri2199

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