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Immune Regulation by helminth parasites: cellular and molecular mechanisms

Key Points

  • Helminths are multicellular worms that presently infect more than two billion humans worldwide. A large proportion of infections are clinically aysmptomatic, indicating that parasite-mediated downmodulation of immunity might reduce pathology.

  • The typical features of the immune response to helminths are those of the T helper 2 (TH2) type — high levels of interleukin-4 (IL-4) and low levels of interferon-γ. However, the response might be more accurately described as a 'modified TH2-cell response', with high IL-10 and IgG4 antibody isotypes, and low IgE reactions.

  • Studies in humans and experimental animal models indicate that regulatory T cells and suppressive macrophage populations might be important in downmodulating immune responses and pathology. We suggest that the regulatory environment results in the modified TH2-cell response.

  • Molecular studies, involving both genomics and glycobiology, are identifying mediators from helminth parasites that are associated with immune regulation.

  • One category of mediators are those that directly interfere with specific processes of immunity, for example a cysteine protease inhibitor that blocks MHC class II processing. Parasite cytokine homologues are also thought to be important.

  • A second group of molecules are those, such as schistosome lipids, that interact with host dendritic cells to initiate a regulatory loop. So, helminths intervene from the first events in immune recognition to favour the development of a regulatory environment in which host and parasite can remain in a long-term homeostatic relationship.

Abstract

Immunology was founded by studying the body's response to infectious microorganisms, and yet microbial prokaryotes only tell half the story of the immune system. Eukaryotic pathogens — protozoa, helminths, fungi and ectoparasites — have all been powerful selective forces for immune evolution. Often, as with lethal protozoal parasites, the focus has been on acute infections and the inflammatory responses they evoke. Long-lived parasites such as the helminths, however, are more remarkable for their ability to downregulate host immunity, protecting themselves from elimination and minimizing severe pathology in the host.

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Figure 1: System-wide effects of helminth immunomodulation.
Figure 2: Rodent models of infection with intestinal nematodes.
Figure 3: Alternatively activated macrophages.
Figure 4: The regulatory environment that we propose might develop during helminth infection.
Figure 5: Immune modulators.
Figure 6: Blocking efferent immune mechanisms and effector cells.

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Acknowledgements

We express our gratitude to J. Allen, A. Balic, N. Gomez, M. Taylor and M. Wilson for discussions, criticism and permission to quote unpublished data. We thank A. van den Biggelaar and E. Sartono for immunoepidemiological data. We thank the Wellcome Trust and the Medical Research Council for funding, the European Union framework 5 and the Netherlands Organization for Scientific Research for support.

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Correspondence to Rick M. Maizels.

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DATABASES

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CCL19

CTLA4

IFN-γ

STAT6

TGF-β

TLR2

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Maria Yazdanbakhsh's

Filarial genome network

Filarial genome network

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Glossary

T HELPER 1/T HELPER 2 CELL

(TH1/TH2). A classification of CD4+ T cells on the basis of the patterns of cytokines that they secrete. TH1 cells secrete large amounts of interferon-γ and associated pro-inflammatory cytokines. TH2 cells secrete large amounts of interleukin-4 and associated cytokines that promote antibody production by B cells. TH1/TH2 cytokines can cross-regulate each other's responses. An imbalance of TH1/TH2-cell responses is thought to contribute to the pathogenesis of various infections, allergic responses and autoimmune diseases.

IDIOTYPIC NETWORK

The antigen-binding site of an antibody is an idiotype. As an immune response develops and clonal expansion of B cells occurs, the prevalence of this previously rare idiotype increases and can lead to the development of an anti-idiotypic T- and B-cell response.

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Maizels, R., Yazdanbakhsh, M. Immune Regulation by helminth parasites: cellular and molecular mechanisms. Nat Rev Immunol 3, 733–744 (2003). https://doi.org/10.1038/nri1183

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