Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Apr;91(4):1390–1395. doi: 10.1172/JCI116341

Cytokine patterns in the pathogenesis of human leishmaniasis.

C Pirmez 1, M Yamamura 1, K Uyemura 1, M Paes-Oliveira 1, F Conceição-Silva 1, R L Modlin 1
PMCID: PMC288111  PMID: 8473490

Abstract

The host response to infection appears to be regulated by specific patterns of local cytokine production. In the mouse, resistance to many pathogens including Leishmania is associated with a TH1 cytokine profile, IL-2 and IFN-gamma; whereas susceptibility to infection is associated with production of TH2 cytokines, IL-4, IL-5, and IL-10. To determine the cytokine patterns of the local immune response to Leishmania infection in humans, we used the polymerase chain reaction to compare cytokine mRNAs in biopsy specimens of American cutaneous leishmaniasis. In localized cutaneous leishmaniasis and the Montenegro delayed-type hypersensitivity reaction, type 1 cytokine mRNAs such as IL-2, IFN-gamma, and lymphotoxin were relatively predominant. In the chronic and destructive mucocutaneous form of leishmaniasis, there was a mixture of type 1 and type 2 cytokines, with a striking abundance of IL-4 mRNA in lesions. These results suggest that clinical course of infection with Leishmania braziliensis in man is associated with specific local patterns of cytokine production.

Full text

PDF
1393

Images in this article

1392Image
on p.1392
1392Image
on p.1392
1392Image
on p.1392
1392Image
on p.1392
1392Image
on p.1392
1393Image
on p.1393
1393Image
on p.1393
1393Image
on p.1393
1393Image
on p.1393
1393Image
on p.1393
1393Image
on p.1393
1393Image
on p.1393
1393Image
on p.1393
1393Image
on p.1393

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Avila J. L., Rojas M., Rieber M. Antibodies to laminin in American cutaneous leishmaniasis. Infect Immun. 1984 Jan;43(1):402–406. doi: 10.1128/iai.43.1.402-406.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boom W. H., Liebster L., Abbas A. K., Titus R. G. Patterns of cytokine secretion in murine leishmaniasis: correlation with disease progression or resolution. Infect Immun. 1990 Dec;58(12):3863–3870. doi: 10.1128/iai.58.12.3863-3870.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Castes M., Agnelli A., Verde O., Rondón A. J. Characterization of the cellular immune response in American cutaneous leishmaniasis. Clin Immunol Immunopathol. 1983 May;27(2):176–186. doi: 10.1016/0090-1229(83)90068-5. [DOI] [PubMed] [Google Scholar]
  4. Castés M., Agnelli A., Rondón A. J. Mechanisms associated with immunoregulation in human American cutaneous leishmaniasis. Clin Exp Immunol. 1984 Aug;57(2):279–286. [PMC free article] [PubMed] [Google Scholar]
  5. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  6. Cooper C. L., Mueller C., Sinchaisri T. A., Pirmez C., Chan J., Kaplan G., Young S. M., Weissman I. L., Bloom B. R., Rea T. H. Analysis of naturally occurring delayed-type hypersensitivity reactions in leprosy by in situ hybridization. J Exp Med. 1989 May 1;169(5):1565–1581. doi: 10.1084/jem.169.5.1565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Daynes R. A., Araneo B. A., Dowell T. A., Huang K., Dudley D. Regulation of murine lymphokine production in vivo. III. The lymphoid tissue microenvironment exerts regulatory influences over T helper cell function. J Exp Med. 1990 Apr 1;171(4):979–996. doi: 10.1084/jem.171.4.979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Del Prete G. F., De Carli M., Mastromauro C., Biagiotti R., Macchia D., Falagiani P., Ricci M., Romagnani S. Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest. 1991 Jul;88(1):346–350. doi: 10.1172/JCI115300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Desjeux P., Santoro F., Afchain D., Loyens M., Capron A. Circulating immune complexes and anti-IgG antibodies in mucocutaneous leishmaniasis. Am J Trop Med Hyg. 1980 Mar;29(2):195–198. doi: 10.4269/ajtmh.1980.29.195. [DOI] [PubMed] [Google Scholar]
  10. Fernandez-Botran R., Sanders V. M., Mosmann T. R., Vitetta E. S. Lymphokine-mediated regulation of the proliferative response of clones of T helper 1 and T helper 2 cells. J Exp Med. 1988 Aug 1;168(2):543–558. doi: 10.1084/jem.168.2.543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Finkelman F. D., Holmes J., Katona I. M., Urban J. F., Jr, Beckmann M. P., Park L. S., Schooley K. A., Coffman R. L., Mosmann T. R., Paul W. E. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990;8:303–333. doi: 10.1146/annurev.iy.08.040190.001511. [DOI] [PubMed] [Google Scholar]
  12. Haanen J. B., de Waal Malefijt R., Res P. C., Kraakman E. M., Ottenhoff T. H., de Vries R. R., Spits H. Selection of a human T helper type 1-like T cell subset by mycobacteria. J Exp Med. 1991 Sep 1;174(3):583–592. doi: 10.1084/jem.174.3.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Heinzel F. P., Sadick M. D., Holaday B. J., Coffman R. L., Locksley R. M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. doi: 10.1084/jem.169.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. King C. L., Ottesen E. A., Nutman T. B. Cytokine regulation of antigen-driven immunoglobulin production in filarial parasite infections in humans. J Clin Invest. 1990 Jun;85(6):1810–1815. doi: 10.1172/JCI114639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lehn M., Weiser W. Y., Engelhorn S., Gillis S., Remold H. G. IL-4 inhibits H2O2 production and antileishmanial capacity of human cultured monocytes mediated by IFN-gamma. J Immunol. 1989 Nov 1;143(9):3020–3024. [PubMed] [Google Scholar]
  16. Liew F. Y., Millott S., Li Y., Lelchuk R., Chan W. L., Ziltener H. Macrophage activation by interferon-gamma from host-protective T cells is inhibited by interleukin (IL)3 and IL4 produced by disease-promoting T cells in leishmaniasis. Eur J Immunol. 1989 Jul;19(7):1227–1232. doi: 10.1002/eji.1830190712. [DOI] [PubMed] [Google Scholar]
  17. Limaye A. P., Abrams J. S., Silver J. E., Ottesen E. A., Nutman T. B. Regulation of parasite-induced eosinophilia: selectively increased interleukin 5 production in helminth-infected patients. J Exp Med. 1990 Jul 1;172(1):399–402. doi: 10.1084/jem.172.1.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Martinez O. M., Gibbons R. S., Garovoy M. R., Aronson F. R. IL-4 inhibits IL-2 receptor expression and IL-2-dependent proliferation of human T cells. J Immunol. 1990 Mar 15;144(6):2211–2215. [PubMed] [Google Scholar]
  19. Mendonça S. C., Coutinho S. G., Amendoeira R. R., Marzochi M. C., Pirmez C. Human american cutaneous leishmaniasis (Leishmania b. braziliensis) in Brazil: lymphoproliferative responses and influence of therapy. Clin Exp Immunol. 1986 May;64(2):269–276. [PMC free article] [PubMed] [Google Scholar]
  20. Modlin R. L., Hofman F. M., Horwitz D. A., Husmann L. A., Gillis S., Taylor C. R., Rea T. H. In situ identification of cells in human leprosy granulomas with monoclonal antibodies to interleukin 2 and its receptor. J Immunol. 1984 Jun;132(6):3085–3090. [PubMed] [Google Scholar]
  21. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  22. Murray H. W., Rubin B. Y., Rothermel C. D. Killing of intracellular Leishmania donovani by lymphokine-stimulated human mononuclear phagocytes. Evidence that interferon-gamma is the activating lymphokine. J Clin Invest. 1983 Oct;72(4):1506–1510. doi: 10.1172/JCI111107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Murray H. W., Stern J. J., Welte K., Rubin B. Y., Carriero S. M., Nathan C. F. Experimental visceral leishmaniasis: production of interleukin 2 and interferon-gamma, tissue immune reaction, and response to treatment with interleukin 2 and interferon-gamma. J Immunol. 1987 Apr 1;138(7):2290–2297. [PubMed] [Google Scholar]
  24. Müller I., Pedrazzini T., Farrell J. P., Louis J. T-cell responses and immunity to experimental infection with leishmania major. Annu Rev Immunol. 1989;7:561–578. doi: 10.1146/annurev.iy.07.040189.003021. [DOI] [PubMed] [Google Scholar]
  25. Nacy C. A., Fortier A. H., Pappas M. G., Henry R. R. Susceptibility of inbred mice to Leishmania tropica infection: correlation of susceptibility with in vitro defective macrophage microbicidal activities. Cell Immunol. 1983 Apr 15;77(2):298–307. doi: 10.1016/0008-8749(83)90030-8. [DOI] [PubMed] [Google Scholar]
  26. Nathan C. F., Murray H. W., Wiebe M. E., Rubin B. Y. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med. 1983 Sep 1;158(3):670–689. doi: 10.1084/jem.158.3.670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Oliveira-Neto M. P., Pirmez C., Rangel E., Schubach A., Grimaldi Júnior G. An outbreak of American cutaneous leishmaniasis (Leishmania braziliensis braziliensis) in a periurban area of Rio de Janeiro city, Brazil: clinical and epidemiological studies. Mem Inst Oswaldo Cruz. 1988 Oct-Dec;83(4):427–435. doi: 10.1590/s0074-02761988000400006. [DOI] [PubMed] [Google Scholar]
  28. Pirmez C., Cooper C., Paes-Oliveira M., Schubach A., Torigian V. K., Modlin R. L. Immunologic responsiveness in American cutaneous leishmaniasis lesions. J Immunol. 1990 Nov 1;145(9):3100–3104. [PubMed] [Google Scholar]
  29. Sadick M. D., Heinzel F. P., Holaday B. J., Pu R. T., Dawkins R. S., Locksley R. M. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med. 1990 Jan 1;171(1):115–127. doi: 10.1084/jem.171.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sadick M. D., Locksley R. M., Tubbs C., Raff H. V. Murine cutaneous leishmaniasis: resistance correlates with the capacity to generate interferon-gamma in response to Leishmania antigens in vitro. J Immunol. 1986 Jan;136(2):655–661. [PubMed] [Google Scholar]
  31. Salgame P., Abrams J. S., Clayberger C., Goldstein H., Convit J., Modlin R. L., Bloom B. R. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science. 1991 Oct 11;254(5029):279–282. doi: 10.1126/science.254.5029.279. [DOI] [PubMed] [Google Scholar]
  32. Saravia N. G., Valderrama L., Labrada M., Holguín A. F., Navas C., Palma G., Weigle K. A. The relationship of Leishmania braziliensis subspecies and immune response to disease expression in New World leishmaniasis. J Infect Dis. 1989 Apr;159(4):725–735. doi: 10.1093/infdis/159.4.725. [DOI] [PubMed] [Google Scholar]
  33. Scott P., Natovitz P., Coffman R. L., Pearce E., Sher A. Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. J Exp Med. 1988 Nov 1;168(5):1675–1684. doi: 10.1084/jem.168.5.1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Yamamura M., Uyemura K., Deans R. J., Weinberg K., Rea T. H., Bloom B. R., Modlin R. L. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. doi: 10.1126/science.254.5029.277. [DOI] [PubMed] [Google Scholar]
  35. Yamamura M., Wang X. H., Ohmen J. D., Uyemura K., Rea T. H., Bloom B. R., Modlin R. L. Cytokine patterns of immunologically mediated tissue damage. J Immunol. 1992 Aug 15;149(4):1470–1475. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES