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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Muller, R. In Worms and Human Disease. 1–161 (CABI Publishing, Wallingford, UK, 2002).
King, C. L. et al. Cytokine control of parasite-specific anergy in human lymphatic filariasis. Preferential induction of a regulatory T helper type 2 lymphocyte subset. J. Clin. Invest. 92, 1667–1673 (1993).
Yazdanbakhsh, M. et al. T cell responsiveness correlates differentially with antibody isotype levels in clinical and asymptomatic filariasis. J. Infect. Dis. 167, 925–931 (1993).
Grogan, J. L., Kremsner, P. G., Deelder, A. M. & Yazdanbakhsh, M. Antigen-specific proliferation and interferon-γ and interleukin-5 production are downregulated during Schistosoma haematobium infection. J. Infect. Dis. 177, 1433–1437 (1998).
Greene, B. M., Fanning, M. M. & Ellner, J. J. Nonspecific suppression of antigen-induced lymphocyte blastogenesis in Onchocerca volvulus infection in man. Clin. Exp. Immunol. 52, 259–265 (1983).
Sabin, E. A., Araujo, M. I., Carvalho, E. M. & Pearce, E. J. Impairment of tetanus toxoid-specific TH1-like immune responses in humans infected with Schistosoma mansoni. J. Infect. Dis. 173, 269–272 (1996).
Cooper, P. J., Espinel, I., Paredes, W., Guderian, R. H. & Nutman, T. B. Impaired tetanus-specific cellular and humoral responses following tetanus vaccination in human onchocerciasis: a possible role for interleukin-10. J. Infect. Dis. 178, 1133–1138 (1998).
Liwski, R., Zhou, J., McAlister, V. & Lee, T. D. Prolongation of allograft survival by Nippostrongylus brasiliensis is associated with decreased allospecific cytotoxic T lymphocyte activity and development of T cytotoxic cell type 2 cells. Transplantation 69, 1912–1922 (2000).
King, C. L., Connelly, M., Alpers, M. P., Bockarie, M. & Kazura, J. W. Transmission intensity determines lymphocyte responsiveness and cytokine bias in human lymphatic filariasis. J. Immunol. 166, 7427–7436 (2001).
Fox, J. G. et al. Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy. Nature Med. 6, 536–542 (2000).
Nacher, M. et al. Helminth infections are associated with protection from malaria-related acute renal failure and jaundice in Thailand. Am. J. Trop. Med. Hyg. 65, 834–836 (2001).
van den Biggelaar, A. et al. Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet 356, 1723–1727 (2000). The first report to link interleukin-10 (IL-10) responses to parasites with a downregulation of allergic responses in helminth-infected humans.
Yazdanbakhsh, M., van den Biggelaar, A. & Maizels, R. M. TH2 responses without atopy: immunoregulation in chronic helminth infections and reduced allergic disease. Trends Immunol. 22, 372–377 (2001).
Yazdanbakhsh, M., Kremsner, P. G. & van Ree, R. Allergy, parasites, and the hygiene hypothesis. Science 296, 490–494 (2002).
Sher, A. F. & Coffman, R. L. Regulation of immunity to parasites by T cells and T cell-derived cytokines. Annu. Rev. Immunol. 10, 385–409 (1992).
Maizels, R. M., Bundy, D. A. P., Selkirk, M. E., Smith, D. F. & Anderson, R. M. Immunological modulation and evasion by helminth parasites in human populations. Nature 365, 797–805 (1993).
Mohrs, M., Shinkai, K., Mohrs, K. & Locksley, R. M. Analysis of type 2 immunity in vivo with a bicistronic IL-4 reporter. Immunity 15, 303–311 (2001).
Pearce, E. J. & MacDonald, A. S. The immunobiology of schistosomiasis. Nature Rev. Immunol. 2, 499–511 (2002).
Osborne, J. & Devaney, E. The L3 of Brugia induces a TH2-polarized response following activation of an IL-4-producing CD4− CD8− αβ T cell population. Int. Immunol. 10, 1583–1590 (1998).
Jarrett, E. E. E. Potentiation of rat reagenic (IgE) antibody to ovalbumin in the rat following sequential trematode and nematode infections. Immunol. 22, 1099–1101 (1972).
Kullberg, M. C., Pearce, E. J., Hieny, S. E., Sher, A. & Berzofsky, J. A. Infection with Schistosoma mansoni alters TH1/TH2 cytokine responses to a non-parasite antigen. J. Immunol. 148, 3264–3270 (1992).
Liu, Z., et al. Nippostrongylus brasiliensis can induce B7-independent antigen-specific development of IL-4-producing T cells from naive CD4+ T cells in vivo. J. Immunol. 169, 6959–6968 (2002).
Lawrence, R. A., Allen, J. E., Osborne, J. & Maizels, R. M. Adult and microfilarial stages of the filarial parasite Brugia malayi stimulate contrasting cytokine and immunoglobulin isotype responses in BALB/c mice. J. Immunol. 153, 1216–1224 (1994).
Else, K. J., Finkelman, F. D., Maliszewski, C. R. & Grencis, R. K. Cytokine-mediated regulation of chronic intestinal helminth infection. J. Exp. Med. 179, 347–351 (1994).
Hagan, P., Blumenthal, U. J., Dunn, D., Simpson, A. J. G. & Wilkins, H. A. Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium. Nature 349, 243–245 (1991).
Elson, L. H., et al. Immunity to onchocerciasis: putative immune persons produce a TH1-like response to Onchocerca volvulus. J. Infect. Dis. 171, 652–658 (1995).
Finkelman, F. D., et al. Cytokine regulation of host defense against parasitic gastrointestinal nematodes: lessons from studies with rodent models. Annu. Rev. Immunol. 15, 505–533 (1997).
Maizels, R. M. & Holland, M. J. Parasite immunity: pathways for expelling intestinal parasites. Curr. Biol. 8, R711–R714 (1998).
Urban, J. F., Jr. et al. IL-13, IL-4Rα and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8, 255–264 (1998). A definitive study of the type-2 mediators and signalling components that generate protective immunity to a gut nematode.
Vallance, B. A. & Collins, S. M. The effect of nematode infection upon intestinal smooth muscle function. Parasite Immunol. 20, 249–253 (1998).
Faulkner, H., Renauld, J. -C., Van Snick, J. & Grencis, R. K. Interleukin-9 enhances resistance to the intestinal nematode Trichuris muris. Infect. Immun. 66, 3832–3840 (1998).
Urban, J. F., Jr, Noben-Trauth, N., Schopf, L., Madden, K. B. & Finkelman, F. D. IL-4 receptor expression by non-bone marrow-derived cells is required to expel gastrointestinal nematode parasites. J. Immunol. 167, 6078–6081 (2001).
Lawrence, R. A., Allen, J. E., Gregory, W. F., Kopf, M. & Maizels, R. M. Infection of IL-4 deficient mice with the parasitic nematode Brugia malayi demonstrates that host resistance is not dependent on a TH2 dominated immune response. J. Immunol. 154, 5995–6001 (1995).
Dent, L. A., et al. Interleukin-5 transgenic mice show enhanced resistance to primary infections with Nippostrongylus brasiliensis but not primary infections with Toxocara canis. Infect. Immun. 67, 989–993 (1999).
Herbert, D. R. et al. Role of IL-5 in innate and adaptive immunity to larval Strongyloides stercoralis in mice. J. Immunol. 165, 4544–4551 (2000).
Meeusen, E. N. T. & Balic, A. Do eosinophils have a role in the killing of helminth parasites? Parasitol. Today 16, 95–101 (2000).
Caulada-Benedetti, Z., Al-Zamel, F., Sher, A. & James, S. Comparison of TH1- and TH2-associated immune reactivities stimulated by single versus multiple vaccination of mice with irradiated Schistosoma mansoni cercariae. J. Immunol. 146, 1655–1660 (1991).
Hoffmann, K. F., James, S. L., Cheever, A. W. & Wynn, T. A. Studies with double cytokine-deficient mice reveal that highly polarized TH1- and TH2-type cytokine and antibody responses contribute equally to vaccine-induced immunity to Schistosoma mansoni. J. Immunol. 163, 927–938 (1999).
Allen, J. E. & Maizels, R. M. TH1–TH2: reliable paradigm or dangerous dogma? Immunol. Today 18, 387–392 (1997).
Artis, D. et al. Tumor necrosis factor-α is a critical component of interleukin 13-mediated protective T helper cell type 2 responses during helminth infection. J. Exp. Med. 190, 953–962 (1999).
Lawrence, C. E. et al. IL-4-regulated enteropathy in an intestinal nematode infection. Eur. J. Immunol. 28, 2672–2684 (1998).
Brunet, L. R., Dunne, D. W. & Pearce, E. J. Cytokine interaction and immune responses during Schistosoma mansoni infection. Parasitol. Today 14, 422–427 (1998).
Hoffmann, K. F., Cheever, A. W. & Wynn, T. A. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J. Immunol. 164, 6406–6416 (2000). Important experimental evidence showing that regulation protects infected animals against 'over-zealous' immune responses of either type 1 or type 2.
Hoffmann, K. F., Wynn, T. A. & Dunne, D. W. Cytokine-mediated host responses during schistosome infections; walking the fine line between immunological control and immunopathology. Adv. Parasitol. 52, 265–307 (2002).
Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nature Immunol. 3, 135–142 (2002).
Shevach, E. M. CD4+ CD25+ suppressor T cells: more questions than answers. Nature Rev. Immunol. 2, 389–400 (2002).
Brunet, L. R., Finkelman, F. D., Cheever, A. W., Kopf, M. A. & Pearce, E. J. IL-4 protects against TNF-α-mediated cachexia and death during acute schistosomiasis. J. Immunol. 159, 777–785 (1997).
MacDonald, A. S., Araujo, M. I. & Pearce, E. J. Immunology of parasitic helminth infections. Infect. Immun. 70, 427–433 (2002).
Chiaramonte, M. G., et al. IL-13 is a key regulatory cytokine for TH2 cell-mediated pulmonary granuloma formation and IgE responses induced by Schistosoma mansoni eggs. J. Immunol. 162, 920–930 (1999).
Fallon, P. G., Richardson, E. J., McKenzie, G. J. & McKenzie, A. N. J. Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J. Immunol. 164, 2585–2591 (2000).
Platts-Mills, T., Vaughan, J., Squillace, S., Woodfolk, J. & Sporik, R. Sensitisation, asthma, and a modified TH2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 357, 752–756 (2001). Conceptually important work in allergy, which might indicate parallels for the immunology of helminth infection.
Jeannin, P., Lecoanet, S., Delneste, Y., Gauchat, J. -F. & Bonnefoy, J. -Y. IgE versus IgG4 production can be differentially regulated by IL-10. J. Immunol. 160, 3555–3561 (1998).
Maizels, R. M. et al. T cell activation and the balance of antibody isotypes in human filariasis. Parasitol. Today 11, 50–56 (1995).
Sartono, E., Kruize, Y. C. M., Kurniawan-Atmadja, A., Maizels, R. M. & Yazdanbakhsh, M. Depression of antigen-specific interleukin-5 and interferon-γ responses in human lymphatic filariasis as a function of clinical status and age. J. Infect. Dis. 175, 1276–1280 (1997).
Cooper, P. J. et al. Early human infection with Onchocerca volvulus is associated with an enhanced parasite-specific cellular immune response. J. Infect. Dis. 183, 1662–1668 (2001).
Boros, D. L., Pelley, R. P. & Warren, K. S. Spontaneous modulation of granulomatous hypersensitivity in Schistosomiasis mansoni. J. Immunol. 114, 1437–1441 (1975).
Chiaramonte, M. G. et al. Regulation and function of the interleukin 13 receptor α2 during a T helper cell type 2-dominant immune response. J. Exp. Med. 197, 687–701 (2003).
Le Goff, L., Lamb, T. J., Graham, A. L., Harcus, Y. & Allen, J. E. IL-4 is required to prevent filarial nematode development in resistant but not susceptible strains of mice. Int. J. Parasitol. 32, 1277–1284 (2002).
Maizels, R. M. & Lawrence, R. A. Immunological tolerance: the key feature in human filariasis? Parasitol. Today 7, 271–276 (1991).
Sher, A. et al. Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection. Immunol. Rev. 127, 183–204 (1992).
Schopf, L. R., Hoffmann, K. F., Cheever, A. W., Urban, J. F., Jr & Wynn, T. A. IL-10 is critical for host resistance and survival during gastrointestinal helminth infection. J. Immunol. 168, 2383–2392 (2002).
Wynn, T. A. et al. IL-10 regulates liver pathology in acute murine Schistosomiasis mansoni but is not required for immune down-modulation of chronic disease. J. Immunol. 159, 4473–4480 (1998).
Sadler, C. H., Rutitzky, L. I., Stadecker, M. J. & Wilson, R. A. IL-10 is crucial for the transition from acute to chronic disease state during infection of mice with Schistosoma mansoni. Eur. J. Immunol. 33, 880–888 (2003).
Mahanty, S. et al. High levels of spontaneous and parasite antigen-driven interleukin-10 production are associated with antigen-specific hyporesponsiveness in human lymphatic filariasis. J. Infect. Dis. 173, 769–773 (1996).
Mahanty, S. et al. Regulation of parasite antigen-driven immune responses by interleukin-10 (IL-10) and IL-12 in lymphatic filariasis. Infect. Immun. 65, 1742–1747 (1997).
Doetze, A. et al. Antigen-specific cellular hyporesponsiveness in a chronic human helminth infection is mediated by TH3/TR1-type cytokines IL-10 and transforming growth factor-β but not by a TH1 to TH2 shift. Int. Immunol. 12, 623–630 (2000). The first evidence for regulatory T-cell activity in human helminth infection.
Araújo, M. I. et al. Evidence of a T helper type 2 activation in human schistosomiasis. Eur. J. Immunol. 26, 1399–1403 (1996).
King, C. L. et al. Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity. J. Immunol. 156, 4715–4721 (1996). One of the most comprehensive studies on cellular and cytokine responses in a human helminth-infected population, emphasizing the role of IL-10 at an early stage.
Grogan, J. L., Kremsner, P. G., Deelder, A. M. & Yazdanbakhsh, M. The effect of anti-IL-10 on proliferation and cytokine production in human schistosomiasis: fresh versus cryopreserved cells. Parasite Immunol. 20, 345–349 (1998).
Satoguina, J. et al. Antigen-specific T regulatory-1 cells are associated with immunosuppression in a chronic helminth infection (onchocerciasis). Microbes Infect. 4, 1291–1300 (2002).
Steel, C. & Nutman, T. B. CTLA-4 in filarial infections: implications for a role in diminished T cell reactivity. J. Immunol. 170, 1930–1938 (2003).
Bluestone, J. A. & Abbas, A. K. Natural versus adaptive regulatory T cells. Nature Rev. Immunol. 3, 253–257 (2003).
Cong, Y., Weaver, C. T., Lazenby, A. & Elson, C. O. Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J. Immunol. 169, 6112–6119 (2002).
McGuirk, P. & Mills, K. Pathogen-specific regulatory T cells provoke a shift in the TH1/TH2 paradigm in immunity to infectious diseases. Trends Immunol. 23, 450–455 (2002).
McGuirk, P., McCann, C. & Mills, K. H. G. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin-10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J. Exp. Med. 195, 221–231 (2002).
Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. M. & Sacks, D. L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002).
Reis e Sousa, C. Dendritic cells as sensors of infection. Immunity 14, 495–498 (2001).
Piessens, W. F. et al. Antigen specific suppressor cells and suppressor factors in human filariasis with Brugia malayi. New. Eng. J. Med. 302, 833–837 (1980).
Lammie, P. J. & Katz, S. P. Immunoregulation in experimental filariasis. I. In vitro suppression of mitogen-induced blastogenesis by adherent cells from jirds chronically infected with Brugia pahangi. J. Immunol. 130, 1381–1385 (1983).
Osborne, J. & Devaney, E. Interleukin-10 and antigen-presenting cells actively suppress TH1 cells in BALB/c mice infected with the filarial parasite Brugia pahangi. Infect. Immun. 67, 1599–1604 (1999).
Flores Villanueva, P. O., Harris, T. S., Ricklan, D. E. & Stadecker, M. J. Macrophages from schistosomal egg granulomas induce unresponsiveness in specific cloned TH1 lymphocytes in vitro and downregulate schistosomal granulomatous disease in vivo. J. Immunol. 152, 1847–1855 (1994).
Allen, J. E. & Loke, P. Divergent roles for macrophages in lymphatic filariasis. Parasite Immunol. 23, 345–352 (2001).
MacDonald, A. S., Maizels, R. M., Lawrence, R. A., Dransfield, I. & Allen, J. E. Requirement for in vivo production of IL-4, but not IL-10, in the induction of proliferative suppression by filarial parasites. J. Immunol. 160, 4124–4132 (1998).
Allen, J. E. & MacDonald, A. S. Profound suppression of cellular proliferation mediated by the secretions of nematodes. Parasite Immunol. 20, 241–247 (1998).
Loke, P. et al. IL-4 dependent alternatively activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol. 3, 7 (2002). This paper describes a new gene-expression profile, including YM1 and FIZZ1, in nematode-elicited (alternatively activated) macrophages with the functional capacity to suppress target-cell proliferation.
Nair, M. G., Cochrane, D. W. & Allen, J. E. Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Immunol. Lett. 85, 173–180 (2003).
Loke, P., MacDonald, A. S., Robb, A., Maizels, R. M. & Allen, J. E. Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell to cell contact. Eur. J. Immunol. 30, 2669–2678 (2000).
Allen, J. E., Lawrence, R. A. & Maizels, R. M. Antigen presenting cells from mice harboring the filarial nematode, Brugia malayi, prevent cellular proliferaton but not cytokine production. Int. Immunol. 8, 143–151 (1996).
Gordon, S. Alternative activation of macrophages. Nature Rev. Immunol. 3, 23–35 (2003).
Jankovic, D., Liu, Z. & Gause, W. C. TH1- and TH2-cell commitment during infectious disease: asymmetry in divergent pathways. Trends Immunol. 22, 450–457 (2001).
MacDonald, A. S., Straw, A. D., Bauman, B. & Pearce, E. J. CD8− dendritic cell activation status plays an integral role in influencing TH2 response development. J. Immunol. 167, 1982–1988 (2001).
de Jong, E. C. et al. Microbial compounds selectively induce TH1 cell-promoting or TH2 cell-promoting dendritic cells in vitro with diverse TH cell-polarizing signals. J. Immunol. 168, 1704–1709 (2002).
Flynn, S., Toellner, K. -M., Raykundalia, C., Goodall, M. & Lane, P. CD4+ T cell cytokine differentiation: the B cell activation molecule, OX40 ligand, instructs CD4+ T cells to express interleukin 4 and upregulates expression of the chemokine receptor, Blr-1. J. Exp. Med. 188, 297–304 (1998).
MacDonald, A. S. & Pearce, E. J. Polarized TH cell response induction by transferred antigen-pulsed dendritic cells is dependent on IL-4 or IL-12 production by recipient cells. J. Immunol. 168, 3127–3130 (2002).
Chaussabel, D. et al. Unique gene expression profiles of human macrophages and dendritic cells to phylogenetically distinct parasites. Blood 102, 672–681 (2003).
van der Kleij, D. et al. A novel host — parasite lipid cross talk: schistosomal lysophosphatidylserine activates Toll-like receptor 2 and affects immune polarization. J. Biol. Chem. 277, 48122–48129 (2002). Evidence for the induction of both T helper 2 (T H 2) cells and regulatory T cells through Toll-like receptor (TLR) signalling in response to schistosome-specific lipid structures.
Blaxter, M. L., Aslett, M., Guiliano, D. & Daub, J. Parasitic helminth genomics. Filarial genome project. Parasitol. 118, S39–S51 (1999).
Manoury, B., Gregory, W. F., Maizels, R. M. & Watts, C. Bm-CPI-2, a cystatin homolog secreted by the filarial parasite Brugia malayi, inhibits class II MHC-restricted antigen processing. Curr. Biol. 11, 447–451 (2001).
Schönemeyer, A. et al. Modulation of human T cell responses and macrophage functions by onchocystatin, a secreted protein of the filarial nematode Onchocerca volvulus. J. Immunol. 167, 3207–3215 (2001).
Dainichi, T. et al. Nippocystatin, a cysteine protease inhibitor from Nippostrongylus brasiliensis, inhibits antigen processing and modulates antigen-specific immune response. Infect. Immun. 69, 7380–7386 (2001).
Pierre, P. & Mellman, I. Developmental regulation of invariant chain proteolysis controls MHC class II trafficking in mouse dendritic cells. Cell 93, 1135–1145 (1998).
Hartmann, S., Kyewski, B., Sonnenburg, B. & Lucius, R. A filarial cysteine protease inhibitor downregulates T cell proliferation and enhances interleukin-10 production. Eur. J. Immunol. 27, 2253–2260 (1997).
Aliberti, J., Hieny, S., Reis e Sousa, C., Serhan, C. N. & Sher, A. Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nature Immunol. 3, 76–82 (2002).
Kalinski, P., Hilkens, C. M., Snijders, A., Snijdewint, F. G. & Kapsenberg, M. L. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J. Immunol. 159, 28–35 (1997).
Angeli, V. et al. Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection. J. Exp. Med. 193, 1135–1147 (2001).
Leid, R. W. & McConnell, L. A. PGE2 generation and release by the larval stage of the cestode, Taenia taeniaeformis. Prostaglandins Leukot. Med. 11, 317–323 (1983).
Liu, L. X., Buhlmann, J. E. & Weller, P. F. Release of prostaglandin E2 by microfilariae of Wuchereria bancrofti and Brugia malayi. Am. J. Trop. Med. Hyg. 46, 520–523 (1992).
Goodridge, H. S. et al. Modulation of macrophage cytokine production by ES-62, a secreted product of the filarial nematode Acanthocheilonema viteae. J. Immunol. 167, 940–945 (2001).
Atochina, O., Daly-Engel, T., Piskorska, D., McGuire, E. & Harn, D. A. A schistosome-expressed immunomodulatory glycoconjugate expands peritoneal Gr1+ macrophages that suppress naive CD4+ T cell proliferation via an IFN-γ and nitric oxide-dependent mechanism. J. Immunol. 167, 4293–4302 (2001).
Terrazas, L. I., Walsh, K. L., Piskorska, D., McGuire, E. & Harn, D. A., Jr. The schistosome oligosaccharide lacto-n-neotetraose expands Gr1+ cells that secrete anti-inflammatory cytokines and inhibit proliferation of naive CD4+ cells: a potential mechanism for immune polarization in helminth infections. J. Immunol. 167, 5294–5303 (2001).
Whelan, M. et al. A filarial nematode-secreted product signals dendritic cells to acquire a phenotype that drives development of TH2 cells. J. Immunol. 164, 6453–6460 (2000).
Van Die, I. et al. The dendritic cell specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis-x. Glycobiol. 13, 471–478 (2003).
Loukas, A. & Maizels, R. M. Helminth C-type lectins and host-parasite interactions. Parasitol. Today 16, 333–339 (2000).
Gomez-Escobar, N., Lewis, E. & Maizels, R. M. A novel member of the transforming growth factor-β (TGF-β) superfamily from the filarial nematodes Brugia malayi and B. pahangi. Exp. Parasitol. 88, 200–209 (1998).
Gomez-Escobar, N., Gregory, W. F. & Maizels, R. M. Identification of Bm-tgh-2, a filarial nematode homolog of C. elegans daf-7 and human TGF-β, expressed in microfilarial and adult stages of Brugia malayi. Infect. Immun. 68, 6402–6410 (2000).
Gomez-Escobar, N., van den Biggelaar, A. & Maizels, R. M. A member of the TGF-β receptor gene family in the parasitic nematode Brugia. Gene 199, 101–109 (1997).
Davies, S. J., Shoemaker, C. B. & Pearce, E. J. A divergent member of the transforming growth factor-β receptor family from Schistosoma mansoni is expressed on the parasite surface membrane. J. Biol. Chem. 273, 11234–11240 (1998).
Pastrana, D. V. et al. Filarial nematode parasites secrete a homologue of the human cytokine macrophage migration inhibitory factor. Infect. Immun. 66, 5955–5963 (1998).
Pennock, J. L. et al. Rapid purification and characterization of L-dopachrome-methyl ester tautomerase (macrophage-migration-inhibitory factor) from Trichinella spiralis, Trichuris muris and Brugia pahangi. Biochem. J. 335, 495–498 (1998).
Zang, X. X. et al. Homologues of human macrophage migration inhibitory factor from a parasitic nematode: gene cloning, protein activity and crystal structure. J. Biol. Chem. 277, 44261–44267 (2002).
Kleemann, R. et al. Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 408, 211–216 (2000).
Falcone, F. H. et al. A Brugia malayi homolog of macrophage migration inhibitory factor reveals an important link between macrophages and eosinophil recruitment during nematode infection. J. Immunol. 167, 5348–5354 (2001).
Grencis, R. K. & Entwistle, G. M. Production of an interferon-γ homologue by an intestinal nematode: functionally significant or interesting artefact. Parasitol. 115, S101–S105 (1997).
Falcone, F. H. et al. Ascaris suum-derived products induce human neutrophil activation via a G protein-coupled receptor that interacts with the interleukin-8 receptor pathway. Infect. Immun. 69, 4007–4018 (2001).
Blackburn, C. C. & Selkirk, M. E. Inactivation of platelet activating factor by a putative acetylhydrolase from the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunol. 75, 41–46 (1992).
Culley, F. J. et al. Eotaxin is specifically cleaved by hookworm metalloproteases preventing its action in vitro and in vivo. J. Immunol. 165, 6447–6453 (2000).
Zang, X. X., Yazdanbakhsh, M., Kiang, H., Kanost, M. R. & Maizels, R. M. A novel serpin expressed by the blood-borne microfilariae of the parasitic nematode Brugia malayi inhibits human neutrophil serine proteinases. Blood 94, 1418–1428 (1999).
Zang, X. & Maizels, R. M. Serine proteinase inhibitors from nematodes and the arms race between host and pathogen. Trends Biochem. Sci. 26, 191–197 (2001).
Loukas, A., Jones, M. K., King, L. T., Brindley, P. J. & McManus, D. P. Receptor for Fc on the surfaces of schistosomes. Infect. Immun. 69, 3646–3651 (2001).
D'az, A., Ferreira, A. & Sim, R. B. Complement evasion by Echinococcus granulosus Sequestration of host factor H in the hydatid cell wall. J. Immunol. 158, 3779–3786 (1997).
Selkirk, M. E., Smith, V. P., Thomas, G. R. & Gounaris, K. Resistance of filarial nematode parasites to oxidative stress. Int. J. Parasitol. 28, 1315–1332 (1998).
Hussein, A. S., Kichenin, K. & Selkirk, M. E. Suppression of secreted acetylcholinesterase expression in Nippostrongylus brasiliensis by RNA interference. Mol. Biochem. Parasitol. 122, 91–94 (2002).
Aboobaker, A. A. & Blaxter, M. L. Use of RNA interference to investigate gene function in the human filarial nematode parasite Brugia malayi. Mol. Biochem. Parasitol. 129, 41–51 (2003).
Boyle, J. P., Wu, X. J., Shoemaker, C. B. & Yoshino, T. P. Using RNA interference to manipulate endogenous gene expression in Schistosoma mansoni sporocysts. Mol. Biochem. Parasitol. 128, 205–215 (2003).
Karanja, D. M., Colley, D. G., Nahlen, B. L., Ouma, J. H. & Secor, W. E. Studies on schistosomiasis in western Kenya: I. Evidence for immune-facilitated excretion of schistosome eggs from patients with Schistosoma mansoni and human immunodeficiency virus coinfections. Am. J. Trop. Med. Hyg. 56, 515–521 (1997).
Fantappie, M. R., Gimba, E. R. & Rumjanek, F. D. Lack of DNA methylation in Schistosoma mansoni. Exp. Parasitol. 98, 162–166 (2001).
Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).
Holland, M. J., Harcus, Y. M., Riches, P. L. & Maizels, R. M. Proteins secreted by the parasitic nematode Nippostrongylus brasiliensis act as adjuvants for TH2 responses. Eur. J. Immunol. 30, 1977–1987 (2000).
van Die, I. et al. Core α1->3-fucose is a common modification of N-glycans in parasitic helminths and constitutes an important epitope for IgE from Haemonchus contortus infected sheep. FEBS Lett. 463, 189–193 (1999).
Faveeuw, C. et al. Schistosome N-glycans containing core α3-fucose and core β2-xylose epitopes are strong inducers of TH2 responses in mice. Eur. J. Immunol. 33, 1271–1281 (2003).
Schramm, G. et al. Molecular characterization of an interleukin-4-inducing factor from Schistosoma mansoni eggs. J. Biol. Chem. 278, 18384–18392 (2003). The first recombinant protein from helminths associated with the induction of T H 2 cells shown to operate by activating mast cells in an IgE-independent manner.
Rao, K. V., Chen, L., Gnanasekar, M. & Ramaswamy, K. Cloning and characterization of a calcium-binding, histamine-releasing protein from Schistosoma mansoni. J. Biol. Chem. 277, 31207–31213 (2002).
Okano, M., Satoskar, A. R., Nishizaki, K. & Harn, D. A., Jr. Lacto-N-fucopentaose III found on Schistosoma mansoni egg antigens functions as adjuvant for proteins by inducing TH2-type response. J. Immunol. 167, 442–450 (2001).
Montesano, M. A., Colley, D. G., Willard, M. T., Freeman, G. L., Jr. & Secor, W. E. Idiotypes expressed early in experimental Schistosoma mansoni infections predict clinical outcomes of chronic disease. J. Exp. Med. 195, 1223–1228 (2002).
Steel, C., Guinea, A., McCarthy, J. S. & Ottesen, E. A. Long-term effect of prenatal exposure to maternal microfilaraemia on immune responsiveness to filarial antigens. Lancet 343, 890–893 (1994).
Saint-André, A. v. et al. The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Science 295, 1892–1895 (2002).
LoVerde, P. T. Do antioxidants play a role in schistosome host–parasite interactions. Parasitol. Today 14, 284–289 (1998).
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.
Author information
Authors and Affiliations
Corresponding author
Related links
Related links
DATABASES
LocusLink
Further information
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.
Rights and permissions
About this article
Cite this article
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
Issue Date:
DOI: https://doi.org/10.1038/nri1183
This article is cited by
-
T helper cell responses to Opisthorchis viverrini infection associate with host susceptibility
Parasitology Research (2024)
-
IgG persistence showed weak clinical aspects in chronic schistosomiasis patients
Scientific Reports (2023)
-
Immunological factors linked to geographical variation in vaccine responses
Nature Reviews Immunology (2023)
-
Haematological indices and immune response profiles in dogs naturally infected and co-infected with Dirofilaria repens and Babesia canis
Scientific Reports (2023)
-
Lessons from helminths: what worms have taught us about mucosal immunology
Mucosal Immunology (2022)