Immunologic Research

, Volume 42, Issue 1–3, pp 197–209

A detrimental role for IgG and FcgammaR in Leishmania mexicana infection

Article

Abstract

The intracellular protozoan parasite Leishmania causes leishmaniasis, which is the second biggest killer worldwide among parasitic diseases, after malaria. As drug therapy for leishmaniasis is toxic and resistance is growing, a vaccine is an important weapon against this disease. Unfortunately, no effective vaccine exists for any human parasitic infection. Worse yet, nearly all effective vaccines whose mechanisms are known work through the induction of protective antibodies. Leishmania mexicana causes primarily chronic cutaneous disease. Not only are antibodies not effective at killing Leishmania, as it hides inside the parasitophorous vacuole of the host cell, but new research indicates that IgG antibodies may be crucial in suppressing the host immune response by generating an immunosuppressive interleukin-10 response. IL-10 is able to decrease the needed Th1-generated IFN-γ and downregulates production of nitric oxide, a required effector mechanism of parasite killing. We have been studying the pathways that the host uses to partially control L. mexicana infection, which include STAT4, IFN-γ, and inducible nitric oxide synthase, but found that the IL-12 pathway is suppressed by IL-10. We are now studying the mechanisms by which IgG, bound to parasites, can induce IL-10 through FcγR ligation and how this suppresses a healing immune response. We are examining which IgG isotypes bind to which FcγRs and whether macrophages are the necessary source of IL-10 for chronic disease. Elucidation of these mechanisms may help us to design vaccines that will not induce antibody-mediated immunosuppressive IL-10 responses.

Keywords

Immunoglobulin G Protozoan parasite Leishmania FcgammaR IL-10 IL-12 Macrophage Immune complex 

References

  1. 1.
    WHO. World health report: reducing risks, promoting healthy life. 2002. p. 186.Google Scholar
  2. 2.
    WHO. WHO: leishmaniasis. 2005. http://www.who.int/leishmaniasis/en.
  3. 3.
    WHO. TDR disease portfolio. 2004. http://www.who.int/tdr/diseases/default.htm.
  4. 4.
    Hewitt S, Reyburn H, Ashford R, Rowland M. Anthroponotic cutaneous leishmaniasis in Kabul, Afghanistan: vertical distribution of cases in apartment blocks. Trans R Soc Trop Med Hyg. 1998;92:273–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Rowland M, Munir A, Durrani N, Noyes H, Reyburn H. An outbreak of cutaneous leishmaniasis in an Afghan refugee settlement in north-west Pakistan. Trans R Soc Trop Med Hyg. 1999;93:133–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Roberts LJ, Handman E, Foote SJ. Science, medicine, and the future: Leishmaniasis. BMJ. 2000;321:801–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Magill AJ, Grogl M, Gasser RA Jr, Sun W, Oster CN. Visceral infection caused by Leishmania tropica in veterans of Operation Desert Storm. N Engl J Med. 1993;328:1383–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Bryceson AD, Chulay JD, Ho M, Mugambii M, Were JB, Muigai R, et al. Visceral leishmaniasis unresponsive to antimonial drugs. I. Clinical and immunological studies. Trans R Soc Trop Med Hyg. 1985;79:700–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Jha TK, Sundar S, Thakur CP, Bachmann P, Karbwang J, Fischer C, et al. Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. N Engl J Med. 1999;341:1795–800.PubMedCrossRefGoogle Scholar
  10. 10.
    Escobar P, Matu S, Marques C, Croft SL. Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH(3) (edelfosine) and amphotericin B. Acta Trop. 2002;81:151–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Soto J, Arana BA, Toledo J, Rizzo N, Vega JC, Diaz A, et al. Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis. 2004;38:1266–72.PubMedCrossRefGoogle Scholar
  12. 12.
    Roberts LS, Janovy J Jr, editors. Kinetaplasta: trypanosomes and their kin. In: Gerald D Schmidt and Larry S Roberts’ Foundations of parasitology. 6th ed. New York: McGraw Hill; 2000, p. 70–8.Google Scholar
  13. 13.
    Preston PM, DuMonde DC. Immunology of clinical and experimental leishmaniasis. In: Cohen S, Sadun EH, editors. Immunology of parasitic infections. Oxford: Blackwell Scientific Publications; 1976. p. 168–202.Google Scholar
  14. 14.
    Locksley RM, Scott P. Helper T-cell subsets in mouse leishmaniasis: induction, expansion and effector function. Immunol Today. 1991;12:A58–61.PubMedCrossRefGoogle Scholar
  15. 15.
    Childs GE, Lightner LK, McKinney L, Groves MG, Price EE, Hendricks LD. Inbred mice as model hosts for cutaneous leishmaniasis. I. Resistance and susceptibility to infection with Leishmania braziliensis, L. mexicana, and L. aethiopica. Ann Trop Med Parasitol. 1984;78:25–34.PubMedGoogle Scholar
  16. 16.
    Buxbaum LU, Uzonna JE, Goldschmidt MH, Scott P. Control of New World cutaneous leishmaniasis is interleukin-12 independent but STAT4 dependent. Eur J Immunol. 2002;32:3206–15.PubMedCrossRefGoogle Scholar
  17. 17.
    Wei XQ, Charles IG, Smith A, Ure J, Feng GJ, Huang FP, et al. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature. 1995;375:408–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Diefenbach A, Schindler H, Donhauser N, Lorenz E, Laskay T, MacMicking J, et al. Type 1 interferon (IFNalpha/beta) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite. Immunity. 1998;8:77–87.PubMedCrossRefGoogle Scholar
  19. 19.
    Heinzel FP, Rerko RM, Ahmed F, Pearlman E. Endogenous IL-12 is required for control of Th2 cytokine responses capable of exacerbating leishmaniasis in normally resistant mice. J Immunol. 1995;155:730–9.PubMedGoogle Scholar
  20. 20.
    Jones DE, Buxbaum LU, Scott P. IL-4-independent inhibition of IL-12 responsiveness during Leishmania amazonensis infection. J Immunol. 2000;165:364–72.PubMedGoogle Scholar
  21. 21.
    Heinzel FP, Schoenhaut DS, Rerko RM, Rosser LE, Gately MK. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993;177:1505–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Jones D, Ellosso MM, Showe L, Williams D, Trinchieri G, Scott P. Differential regulation of the interleukin-12 receptor during the innate immune response to Leishmania major. Infect Immun. 1998;66:3818–24.PubMedGoogle Scholar
  23. 23.
    Buxbaum LU, Scott P. Interleukin 10- and Fcgamma receptor-deficient mice resolve Leishmania mexicana lesions. Infect Immun. 2005;73:2101–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.PubMedCrossRefGoogle Scholar
  25. 25.
    Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989;170:2081–95.PubMedCrossRefGoogle Scholar
  26. 26.
    Sad S, Marcotte R, Mosmann TR. Cytokine-induced differentiation of precursor mouse CD8+ T cells into cytotoxic CD8+ T cells secreting Th1 or Th2 cytokines. Immunity. 1995;2:271–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol. 2001;2:816–22.PubMedCrossRefGoogle Scholar
  28. 28.
    Roncarolo MG, Levings MK, Traversari C. Differentiation of T regulatory cells by immature dendritic cells. J Exp Med. 2001;193:F5–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Uhlig HH, Coombes J, Mottet C, Izcue A, Thompson C, Fanger A, et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol. 2006;177:5852–60.PubMedGoogle Scholar
  30. 30.
    Anderson CF, Oukka M, Kuchroo VJ, Sacks D. CD4+CD25-Foxp3- Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J Exp Med. 2007;204:285–97.PubMedCrossRefGoogle Scholar
  31. 31.
    Taga K, Mostowski H, Tosato G. Human interleukin-10 can directly inhibit T-cell growth. Blood. 1993;81:2964–71.PubMedGoogle Scholar
  32. 32.
    Villegas EN, Wille U, Craig L, Linsley PS, Rennick DM, Peach R, et al. Blockade of costimulation prevents infection-induced immunopathology in interleukin-10-deficient mice. Infect Immun. 2000;68:2837–44.PubMedCrossRefGoogle Scholar
  33. 33.
    Murphy ML, Wille U, Villegas EN, Hunter CA, Farrell JP. IL-10 mediates susceptibility to Leishmania donovani infection. Eur J Immunol. 2001;31:2848–56.PubMedCrossRefGoogle Scholar
  34. 34.
    Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–74.PubMedCrossRefGoogle Scholar
  35. 35.
    Louzir H, Melby PC, Ben Salah A, Marrakchi H, Aoun K, Ben Ismail R, et al. Immunologic determinants of disease evolution in localized cutaneous leishmaniasis due to Leishmania major. J Infect Dis. 1998;177:1687–95.PubMedCrossRefGoogle Scholar
  36. 36.
    Karp CL, el-Safi SH, Wynn TA, Satti MM, Kordofani AM, Hashim FA, et al. In vivo cytokine profiles in patients with kala-azar. Marked elevation of both interleukin-10 and interferon-gamma. J Clin Invest. 1993;91:1644–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Ghalib HW, Piuvezam MR, Skeiky YA, Siddig M, Hashim FA, el-Hassan AM, et al. Interleukin 10 production correlates with pathology in human Leishmania donovani infections. J Clin Invest. 1993;92:324–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Kane MM, Mosser DM. The role of IL-10 in promoting disease progression in leishmaniasis. J Immunol. 2001;166:1141–7.PubMedGoogle Scholar
  39. 39.
    Stober CB, Lange UG, Roberts MT, Alcami A, Blackwell JM. IL-10 from regulatory T cells determines vaccine efficacy in murine Leishmania major infection. J Immunol. 2005;175:2517–24.PubMedGoogle Scholar
  40. 40.
    Padigel UM, Alexander J, Farrell JP. The role of interleukin-10 in susceptibility of BALB/c mice to infection with Leishmania mexicana and Leishmania amazonensis. J Immunol. 2003;171:3705–10.PubMedGoogle Scholar
  41. 41.
    Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature. 2002;420:502–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Thomas BN, Buxbaum LU. FcgammaRIII mediates immunoglobulin G-induced interleukin-10 and is required for chronic Leishmania mexicana lesions. Infect Immun. 2008;76:623–31.PubMedCrossRefGoogle Scholar
  43. 43.
    Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV. FcgammaRIV: a novel FcR with distinct IgG subclass specificity. Immunity. 2005;23:41–51.PubMedCrossRefGoogle Scholar
  44. 44.
    Ravetch JV, Bolland S. IgG Fc receptors. Annu Rev Immunol. 2001;19:275–90.PubMedCrossRefGoogle Scholar
  45. 45.
    Gerber JS, Mosser DM. Stimulatory and inhibitory signals originating from the macrophage Fcgamma receptors. Microbes Infect. 2001;3:131–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Snapper CM, Paul WE. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science. 1987;236:944–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Berton MT, Uhr JW, Vitetta ES. Synthesis of germ-line gamma 1 immunoglobulin heavy-chain transcripts in resting B cells: induction by interleukin 4 and inhibition by interferon gamma. Proc Natl Acad Sci USA. 1989;86:2829–33.PubMedCrossRefGoogle Scholar
  48. 48.
    Hazenbos WL, Gessner JE, Hofhuis FM, Kuipers H, Meyer D, Heijnen IA, et al. Impaired IgG-dependent anaphylaxis and Arthus reaction in Fc gamma RIII (CD16) deficient mice. Immunity. 1996;5:181–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Hazenbos WL, Heijnen IA, Meyer D, Hofhuis FM, Renardel de Lavalette CR, Schmidt RE, et al. Murine IgG1 complexes trigger immune effector functions predominantly via Fc gamma RIII (CD16). J Immunol. 1998;161:3026–32.PubMedGoogle Scholar
  50. 50.
    Meyer D, Schiller C, Westermann J, Izui S, Hazenbos WL, Verbeek JS, et al. FcgammaRIII (CD16)-deficient mice show IgG isotype-dependent protection to experimental autoimmune hemolytic anemia. Blood. 1998;92:3997–4002.PubMedGoogle Scholar
  51. 51.
    Fossati-Jimack L, Ioan-Facsinay A, Reininger L, Chicheportiche Y, Watanabe N, Saito T, et al. Markedly different pathogenicity of four immunoglobulin G isotype-switch variants of an antierythrocyte autoantibody is based on their capacity to interact in vivo with the low-affinity Fcgamma receptor III. J Exp Med. 2000;191:1293–302.PubMedCrossRefGoogle Scholar
  52. 52.
    Taube C, Dakhama A, Rha YH, Takeda K, Joetham A, Park JW, et al. Transient neutrophil infiltration after allergen challenge is dependent on specific antibodies and Fc gamma III receptors. J Immunol. 2003;170:4301–9.PubMedGoogle Scholar
  53. 53.
    Sadick MD, Raff HV. Differences in expression and exposure of promastigote and amastigote membrane molecules in Leishmania tropica. Infect Immun. 1985;47:395–400.PubMedGoogle Scholar
  54. 54.
    Medina-Acosta E, Karess RE, Schwartz H, Russell DG. The promastigote surface protease (gp63) of Leishmania is expressed but differentially processed and localized in the amastigote stage. Mol Biochem Parasitol. 1989;37:263–73.PubMedCrossRefGoogle Scholar
  55. 55.
    Winter G, Fuchs M, McConville MJ, Stierhof YD, Overath P. Surface antigens of Leishmania mexicana amastigotes: characterization of glycoinositol phospholipids and a macrophage-derived glycosphingolipid. J Cell Sci. 1994;107(Pt 9):2471–82.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  1. 1.Division of Infectious Diseases, Department of MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Veterans Affairs Medical Center of PhiladelphiaPhiladelphiaUSA

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