Immunologic Research

, Volume 52, Issue 1–2, pp 111–119 | Cite as

Trichinella spiralis: shaping the immune response

  • Natasa Ilic
  • Alisa Gruden-Movsesijan
  • Ljiljana Sofronic-Milosavljevic
Immunology in Serbia


The co-evolution of a wide range of helminth parasites and vertebrates represented a constant pressure on the host’s immune system and a selective force for shaping the immune response. Modulation of the immune system by parasites is accomplished partly by dendritic cells. When exposed to helminth parasites or their products, dendritic cells do not become classically mature and are potent inducers of Th2 and regulatory responses. Treating animals with helminths (eggs, larvae, extracts) causes dampening or in some cases prevention of allergic or autoimmune diseases. Trichinellaspiralis (T. spiralis) possess a capacity to retune the immune cell repertoire, acting as a moderator of the host response not only to itself but also to third party antigens. In this review, we will focus on the ability of T. spiralis-stimulated dendritic cells to polarize the immune response toward Th2 and regulatory mode in vitro and in vivo and also on the capacity of this parasite to modulate autoimmune disease—such as experimental autoimmune encephalomyelitis.


Trichinella spiralis Dendritic cells Immune response Autoimmunity 


  1. 1.
    Allen JE, Maizels RM. Diversity and dialogue in immunity to helminths. Nat Rev Immunol. 2011;11:375–88.PubMedCrossRefGoogle Scholar
  2. 2.
    Matisz CE, McDougall JJ, Sharkey KA, McKay DM. Helminth parasite and the modulation of joint inflammation. J Parasitol Res. 2011;2022:942616.Google Scholar
  3. 3.
    Fleming JO. Helminths and multiple sclerosis: will old friend give us new treatment for MS? J Neuroimmunol. 2011;233:3–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Fleming JO, Issak A, Lee JE, Luzzio CC, Carrithers MD, Cook TD, Field AS, Boland J, Fabry Z. Probiotic helminth administration in relapsing-remiting multiple sclerosis: a phase 1 study. Mult Scler. 2011;17:743–54.PubMedCrossRefGoogle Scholar
  5. 5.
    He Y, Li Y, Zhuang W, Lin Y, Chen C, Li J, Chi F, Bai Y, Chen XP. The inhibitory effect against collagen-induced arthritis by Schistosoma japonicum infection is infection stage dependent. BMC Immunol. 2010;11:28–37.PubMedCrossRefGoogle Scholar
  6. 6.
    McKay DM. The therapeutic helminth? Trends Parasitol. 2009;25:109–14.PubMedCrossRefGoogle Scholar
  7. 7.
    Reis e Sousa C, Hieny S, Scharton-Kersten T, Jankovic D, Charest H, Germain R, Sher A. In vivo microbial stimulation induces rapid CD40L-independent production of IL-12 by dendritic cells and their re-distribution to T-cell areas. J Exp Med. 1997;186:1819–29.PubMedCrossRefGoogle Scholar
  8. 8.
    Maizels RM, Balic A, Gomez-Escobar N, Nair M, Taylor MD, Allen JE. Helminth parasites—masters of regulation. Immunol Rev. 2004;201:89–116.PubMedCrossRefGoogle Scholar
  9. 9.
    van Riet E, Everts B, Retra K, Phylipsen M, van Hellemond JJ, Tielens AGM, van der Kleij D, Hartgerts FC, Yazdanbakhsh M. Combined TLR-2 and TLR-4 ligation in the context of bacterial or helminth extracts in human monocyte derived dendritic cells: molecular correlation for Th1/Th2 polarization. BMC Immunol. 2009;10:9–20.PubMedCrossRefGoogle Scholar
  10. 10.
    Cervi L, MacDonald A, Kane C, Dzierszinski F, Pearce EJ. Cutting edge: dendritic cells copulsed with microbial and helminh antigens undergo modified maturation, segregate the antigens to distinct intracellular compartments, and concurrently induce microbe-specific Th1 and helminth-specific Th2 responses. J Immunol. 2004;172:2016–20.PubMedGoogle Scholar
  11. 11.
    Whelan M, Harnett MM, Houston KM, Patel V, Harnett W, Rigley KP. Filaral nematode-secreted product signals dendritic cells to acquire a phenotype that drives development of Th2 cells. J Immunol. 2000;164:6453–60.PubMedGoogle Scholar
  12. 12.
    Balic A, Harcus Y, Holland MJ, Maizels RM. Selective maturation of dendritic cells by Nippostongylus brasiliensis-secreted proteins drives Th2 immune responses. Eur J Immunol. 2004;34:3047–59.PubMedCrossRefGoogle Scholar
  13. 13.
    Grainger JR, Smith KA, Hewitson JP, McSorley HJ, Harcus Y, Filbey KJ, Finney CA, Greenwood EJ, Knox DP, Wilson MS, Belkaid Y, Rudensky AY, Maizels RM. Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-b pathway. J Exp Med. 2010;207:2331–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Beiting DP, Gagliardo LF, Hesse M, Bliss SK, Meskill D, Appleton JA. Coordinated control of immunity to muscle stage Trichinella spiralis by IL-10, regulatory T Cells, and TGF-b. J Immunol. 2007;178:1039–47.PubMedGoogle Scholar
  15. 15.
    Wu Z, Sofronic-Milosavljevic Lj, Nagano, Takahashi Y. Trichinella spiralis: nurse cell formation with emphasis on analogy to muscle cell repair. Parasit Vectors. 2008;1:27.PubMedCrossRefGoogle Scholar
  16. 16.
    Nagano I, Wu Y, Takahashi Y. Functional genes and proteins of Trichinella spp. Parasitol Res. 2009;104:197–207.PubMedCrossRefGoogle Scholar
  17. 17.
    Else KJ. Have gastrointestinal nematode outwitted the immune system? Parasite Immunol. 2005;27:407–15.PubMedCrossRefGoogle Scholar
  18. 18.
    Mosmann TR. Cytokine secretion patterns and cross-regulation of T cell subsets. Immunol Res. 1991;10:183–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Ishikawa N, Goyal PK, Mahida YR, Li FP, Wakelin D. Early cytokine responses during intestinal parasitic infections. Immunology. 1998;93:257–63.PubMedCrossRefGoogle Scholar
  20. 20.
    Finney CAM, Taylor MD, Wilson MS, Maizels RM. Expansion and activation of CD4+CD25+ regulatory T cells in Heligmosomoides polygyrus infection. Eur J Immunol. 2007;37:1874–86.PubMedCrossRefGoogle Scholar
  21. 21.
    Taylor JJ, Mohrs M, Pearce EJ. Regulatory T cell responses develop in parallel to Th responses, and control the magnitude and phenotype of the Th effector population. J Immunol. 2006;176:5839–47.PubMedGoogle Scholar
  22. 22.
    Sher A, Pearce E, Kaye P. Shaping the immune response to parasites: role of dendritic cells. Curr Opin Immunol. 2003;15:421–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Kane CM, Cervi L, Sun J, McKee AS, Masek KS, Shapira S, Hunter CA, Pearce EJ. Helminth antigens modulate TLR-initiated dendritic cell activation. J Immunol. 2004;173:7454–61.PubMedGoogle Scholar
  24. 24.
    Segura M, Su Z, Piccirillo C, Stevenson MM. Impairment of dendritic cell function by excretory-secretory products: a potentiaol mechanism for nematode-induced immunosuppression. Eur J Immunol. 2007;37:1887–904.PubMedCrossRefGoogle Scholar
  25. 25.
    van Riet E, Hartgers FC, Yazdanbakhsh M. Chronic helminth infections induce immuno-modulation: consequences and mechanisms. Immunobiology. 2007;212:475–90.PubMedCrossRefGoogle Scholar
  26. 26.
    MacDonald AS, Maizels RM. Allarming dendritic cells for Th2 induction. J Exp Med. 2008;205:13–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Ilic N, Colic M, Gruden-Movsesijan A, Majstorovic I, Vasilev S, Sofronic-Milosavljevic Lj. Characterization of rat bone marrow dendritic cells initially primed by Trichinella spiralis antigens. Parasite Immunol. 2008;30:491–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Ilic N, Worthington JJ, Gruden-Movsesijan A, Travis MA, Sofronic-Milosavljevic Lj, Grencis RK. Trichinella spiralis antigens prime mixed Th1/Th2 response but do not induce de novo generation of Foxp3+ T cells in vitro. Parasite Immunol. 2011;33:572–82.PubMedCrossRefGoogle Scholar
  29. 29.
    Leech MD, Grencis RK. Induction of enhanced immunity to intestinal nematodes using IL-9-producing dendritic cells. J Immunol. 2006;176:2505–11.PubMedGoogle Scholar
  30. 30.
    Langelaar M, Aranzamendi C, Franssen F, van der Giessen J, Rutten V, van der Ley P, Pinelli E. Suppresion of dendritic cells matiuration by Trichinella spiralis excretory/secretory products. Parasite Immunol. 2009;31:641–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Thomas PG, Carter MR, Atochina O, Da’Dara AA, Piskorska D, McGuire E, Harn DA. Maturation of dendritic cell 2 phenotype by a helminth glycan uses a Toll-like receptor 4-dependent mechanism. J Immunol. 2003;171:5837–41.PubMedGoogle Scholar
  32. 32.
    Jenkins SJ, Mountford AP. Dendritic cells activated with product released by Shistosome larvae drive Th2 type immune response which can be inhibited by manipulation of CD40 costimulation. Infect Immun. 2005;73:395–402.PubMedCrossRefGoogle Scholar
  33. 33.
    Marshall FA, Pearce EJ. Uncoupling of induced protein processing from maturation in dendritic cells exposed to a highly antigenic preparation from a helminth parasite. J Immunol. 2008;181:7562–70.PubMedGoogle Scholar
  34. 34.
    Poncini CV, Soto CDA, Batalla E, Solana ME, Gonzalez Cappa SM. Trypanosoma cruzi induces regulatory dendritic cells in vitro≯. Infect Immun. 2008;76:2633–41.PubMedCrossRefGoogle Scholar
  35. 35.
    Bousheri S, Cao H. New insight into the role of dendritic cells in malaria immune pathogenesis. Trends Parasitol. 2008;24:199–200.PubMedCrossRefGoogle Scholar
  36. 36.
    Revest M, Donaghy L, Cabilic F, Guiguen C, Gangneux JP. Comparison of the immunomodulatory effects of L. donovani and L. major excreted–secreted antigens, particulate and soluble extracts and viable parasites on human dendritic cells. Vaccine. 2008;26:6119–23.PubMedCrossRefGoogle Scholar
  37. 37.
    Wiethe C, Debus A, Mohrs M, Steinkasserer A, Lutz M, Gessner A. Dendritic cell differentiation state and their interaction with NKT cells determine Th1/Th2 differentiation in the murine model of Leishmania major infection1. J Immunol. 2008;180:4371–81.PubMedGoogle Scholar
  38. 38.
    Manickasingham SP, Edwards AD, Schulz O, Reis e Sousa C. The ability of murine dendritic cell subsets to direct T helper cell differentiation is dependent on microbial signals. Eur J Immunol. 2003;33:101–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Chang JH, Kunkel SL, Chang CH. Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells. PNAS. 2009;106:18327–32.PubMedCrossRefGoogle Scholar
  40. 40.
    Xio CQ, Kao KJ. Suppression of interleukin-12 production through endogenously secreted interleukin-10 in activated dendritic cells: involvement of activation of extracellular signal-regulated protein kinase. Scand J Immunol. 2003;58:23–32.CrossRefGoogle Scholar
  41. 41.
    Muthana M, Fairburn B, Mirza S, Slack LK, Hopkinson K, Pockley AG. Identification of a rat bone marrow-derived dendritic cell population which secretes both IL-10 and IL-12: evidence against a reciprocal relationship between IL-10 and IL-12 secretion. Immunobiology. 2006;211:391–402.PubMedCrossRefGoogle Scholar
  42. 42.
    Sallusto F, Lanzavecchia A. The instructive role of dendritic cells on T-cell responses. Arthritis Res. 2002;4(suppl3):S127–32.PubMedCrossRefGoogle Scholar
  43. 43.
    Carvalho LP, Pearce EJ, Scott P. Functional dichotomy of dendritic cells following interaction with Leishmania braziliensis: infected cells produce high levels of TNF-α, whereas bystander dendritic cells are activated to promote T cell responses. J Immunol. 2008;181:6473–80.PubMedGoogle Scholar
  44. 44.
    Vasquez RE, Xin L, Soong L. Effects of CXCL10 on dendritic cell and CD4+ T-Cell functions during Leishmania amazonensis infection. Infect Immun. 2008;76:161–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Shaw J, Grund V, Durling L, Crane D, Caldwell HD. Dendritic cells pulsed with recombinant Chlamydial major outer membrane protein antigen elicit a CD4+ type 2 rather than type 1 immune response that is not protective. Infect Immun. 2002;70:1097–105.PubMedCrossRefGoogle Scholar
  46. 46.
    Koyasu S, Moro K, Tanabe M, Takeuchi T. Natural helper cells: a new player in the innate immune response against helminth infection. Adv Immunol. 2010;108:21–44.PubMedCrossRefGoogle Scholar
  47. 47.
    Saenz SA, Noti M, Artis D. Innate immune cell populations function as initiators and effectors in Th2 cytokine responses. Trends Immunol. 2010;31:407–13.PubMedCrossRefGoogle Scholar
  48. 48.
    MacDonald AS, Arujo AI, Pearce EJ. Immunology of parasitic helminth infections. Infect Immun. 2002;70:427–33.PubMedCrossRefGoogle Scholar
  49. 49.
    Gruden-Movsesijan A, Ilic N, Colic M, Majstorovic I, Radovic I, Sofronic-Milosavljevic Lj. The impact of Trichinella spiralis excretory-secretory products on dendritic cells. Comp Immunol Microbiol Infect Dis. 2011;34:429–39.PubMedCrossRefGoogle Scholar
  50. 50.
    Gruden-Movsesijan A, Ilic N, Mostarica-Stojkovic M, Stosic-Grujicic S, Milic M, Sofronic-Milosavljevic Lj. Mechanisms of modulation of experimental autoimmune encephalomyelitis by Trichinella spiralis infection in Dark Agouti rats. Parasite Immunol. 2010;32:450–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Maldonado RA, von Andrian UH. How tolerogenic dendritic cells induce regulatory T cells. Adv Immunol. 2010;108:111–65.PubMedCrossRefGoogle Scholar
  52. 52.
    Babu S, Blauvelt CP, Kumaraswami V, Nutman TB. Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasite persistence. J Immunol. 2006;176:3248–56.PubMedGoogle Scholar
  53. 53.
    Sakagushi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T, Nomura T. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8–27.CrossRefGoogle Scholar
  54. 54.
    Okada H, Kuhn C, Feillet H, Bach JF. The “hygiene hypothesis” for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160:1–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Rook GAW. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Darwinian medicine and the ‘hygiene’ or ‘old friends’ hypothesis. Clin Exp Immunol. 2010;160:70–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Bach JF. Six questions about the hygiene hypothesis. Cell Immunol. 2005;233:158–61.PubMedCrossRefGoogle Scholar
  57. 57.
    Zaccone P, Fehervari Z, Jones FM, Sidobre S, Kronenberg M, Dunne DW, Cooke A. Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes. Eur J Immunol. 2003;33:1439–49.PubMedCrossRefGoogle Scholar
  58. 58.
    Correale J, Farez M. Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol. 2007;61:97–108.PubMedCrossRefGoogle Scholar
  59. 59.
    Zaccone P, Burton OT, Cooke A. Interplay of parasite-driven immune responses and autoimmunity. Trends Parasitol. 2008;24:35–42.PubMedCrossRefGoogle Scholar
  60. 60.
    Maizels RM. Infections and allergy—helminths, hygiene and host immune regulation. Curr Opin Immunol. 2005;17:656–61.PubMedCrossRefGoogle Scholar
  61. 61.
    Smits HH, Yazdanbakhsh M. Chronic helminth infections modulate allergen-specific immune responses: protection against development of allergic disorders? Ann Med. 2007;39:428–39.PubMedCrossRefGoogle Scholar
  62. 62.
    Maizels RM, Yazdanbakhsh M. Immune regulation by helminth parasites: cellular and molecular mechanisms. Nat Rev Immunol. 2003;3:733–44.PubMedCrossRefGoogle Scholar
  63. 63.
    Cooke A, Tonks P, Jones FM, O’Shea H, Hutchings P, Fulford AJ, Dunne DW. Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice. Parasite Immunol. 1999;21:169–76.PubMedCrossRefGoogle Scholar
  64. 64.
    La Flamme AC, Ruddenklau U, Backstrom BT. Schistosomiasis decreases central nervous system inflammation and alters the progression of experimental autoimmune encephalomyelitis. Infect Immun. 2003;71:4996–5004.PubMedCrossRefGoogle Scholar
  65. 65.
    Sewell D, Qing Z, Reinke E, Elliott D, Weinstock J, Sandor M, Fabry Z. Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization. Int Immunol. 2003;15:59–69.PubMedCrossRefGoogle Scholar
  66. 66.
    Elliott DE, Li J, Blum A, Metwali A, Qadir K, Urban JF Jr, Weinstock JV. Exposure to schistosomiasis eggs protects mice from TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol. 2003;284:385–91.Google Scholar
  67. 67.
    Reardon C, Sanchez A, Hogaboam CM, McKay DM. Tapeworm infection reduces epithelial ion transport abnormalities in murine dextran sulfate sodium-induced colitis. Infect Immun. 2001;69:4417–23.PubMedCrossRefGoogle Scholar
  68. 68.
    McInnes IB, Leung BP, Harnett M, Gracie JA, Liew FI, Harnett W. A novel therapeutic approach targeting articular inflammation using the filarial nematode-derived phosphorylcholine-containing glycoprotein ES-62. J Immunol. 2003;171:2127–33.PubMedGoogle Scholar
  69. 69.
    Summers RW, Elliott DE, Qadir K, Urban JF Jr, Thomson R, Weinstock JV. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Am J Gastroenterol. 2003;98:2034–41.PubMedCrossRefGoogle Scholar
  70. 70.
    Summers RW, Elliott DE, Urban JF Jr, Thomson R, Weinstock JV. Trichuris suis therapy in Crohn’s disease. Gut. 2005;54:87–90.PubMedCrossRefGoogle Scholar
  71. 71.
    Elliot DE, Satiawan T, Metwali A, Blum A, Urban JF Jr, Weinstock JV. Heligmosomoides polygurus inhibits established colitis in IL10-deficient mice. Eur J Immunol. 2004;34:2690–8.CrossRefGoogle Scholar
  72. 72.
    Khan WI, Blennerhasset PA, Varqhese AK, Chowdhury CK, Omsted P, Deng Y, Collins SM. Intestinal nematode infection ameliorates experimental colitis in mice. Infect Immun. 2002;70:5931–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Motomura Y, Wang H, Deng Y, El-Sharkawy RT, Verdu EF, Khan WI. Helminth antigen-based strategy to ameliorate inflammation in an experimental model of colitis. Clin Exp Immunol. 2009;155:88–95.PubMedCrossRefGoogle Scholar
  74. 74.
    Saunders KA, Raine T, Cooke A, Lawrence CE. Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect Immun. 2007;75:397–407.PubMedCrossRefGoogle Scholar
  75. 75.
    Gruden-Movsesijan A, Ilic N, Mostarica-Stojkovic M, Stosic-Grujicic S, Milic M, Sofronic-Milosavljevic Lj. Trichinella spiralis: modulation of experimental autoimmune encephalomyelitis in DA rats. Exp Parasitol. 2008;188:641–7.CrossRefGoogle Scholar
  76. 76.
    Bettelli E, Nicholson LB, Kuchroo VK. IL-10, a key effector regulatory cytokine in experimental autoimmune encephalomyelitis. J Autoimmun. 2003;20:265–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Mangan NE, Fallon RE, Smith P, van Rooijen N, McKenzie AN, Fallon PG. Helminth infection protects mice from anaphylaxis via IL-10-producing B cells. J Immunol. 2004;173:6346–56.PubMedGoogle Scholar
  78. 78.
    Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol. 2008;9:239–44.PubMedCrossRefGoogle Scholar
  79. 79.
    Anderton SM, Liblau RS. Regulatory T cells in the control of inflammatory demyelinating diseases of the central nervous system. Curr Opin Neurol. 2008;21:248–54.PubMedCrossRefGoogle Scholar
  80. 80.
    Hewitson JP, Grainger JR, Maizels RM. Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity. Mol Biochem Parasitol. 2009;167:1–11.PubMedCrossRefGoogle Scholar
  81. 81.
    Gruden-Movsesijan A, Sofronic-Milosavljevic Lj. The involvement of macrophage mannose receptor in the innate immune response to infection with parasite Trichinella spiralis. Vet Immunol Immunoparasitol. 2006;109:57–67.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Natasa Ilic
    • 1
  • Alisa Gruden-Movsesijan
    • 1
  • Ljiljana Sofronic-Milosavljevic
    • 1
  1. 1.Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy – INEPUniversity of BelgradeBelgradeSerbia

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