Skip to main content

Advertisement

SpringerLink
Log in

Immunopathological characterization of human cutaneous leishmaniasis lesions caused by Leishmania (Viannia) spp. in Amazonian Brazil

  • Original Paper
  • Published:
Parasitology Research Aims and scope Submit manuscript

Abstract

American cutaneous leishmaniasis (ACL) is a chronic infectious disease caused by different protozoan species of Leishmania, and it is endemic in both tropical and subtropical countries. Using immunohistochemistry, we investigate the density of CD68+, lysozyme+, CD1a+, factor XIIIa+, CD4+, CD8+, CD56+, interferon (IFN)-γ+, and inducible NO synthase (iNOS+) cells. These cells were analyzed from 22 biopsy samples obtained from the lesions of ACL patients, whose infection was caused by Leishmania (Viannia) spp. Histopathological analysis showed dense mononuclear inflammatory infiltration in the dermis, which was composed of lymphocytes, macrophages, plasma cells, and discrete tissue parasitism. Granulomatous reactions were also present in the majority of cases. The density of the activated macrophages was higher than that of inactivated macrophages in the lesions. The density of Langerhans cells (CD1a+) was lower than that of dermal dendrocytes (factor XIIIa+). The density of CD8+ T lymphocytes was higher than that of CD4+ T lymphocytes. The cellular density of these immunological markers in relation to the species of Leishmania demonstrated that L. (Viannia) sp. lesions had higher IFN-γ expression than that Leishmania (Viania) braziliensis lesions. The evaluation of these markers, according to disease progression, did not reveal any significant differences. L. (Viannia) sp. infection leads to a favorable immune response in the host, as predominantly represented by lysozyme+, factor XIIIa+, CD8+ T cells, and the expression of (IFN)-γ+ at the lesion site.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Anderson CF, Lira R, Kamhawi S, Belkaid Y, Wynn TA, Sacks D (2008) IL-10 and TGF-beta control the establishment of persistent and transmissible infections produced by Leishmania tropica in C57BL/6 mice. J Immunol 180:4090–4097

    Article  CAS  PubMed  Google Scholar 

  • Barral A, Costa JM, Bittencourt AL, Barral-Netto M, Carvalho EM (1995) Polar and subpolar diffuse cutaneous leishmaniasis in Brazil: clinical and immunopathologic aspects. Int J Dermatol 34:474–479

    Article  CAS  PubMed  Google Scholar 

  • Belkaid Y, Hoffmann KF, Mendez S, Kamhawi S, Udey MC, Wynn TA, Sacks DL (2001) The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J Exp Med 194:1497–1506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biedermann T, Zimmermann S, Himmelrich H, Gumy A, Egeter O, Sakrauski AK, Seegmüller I, Voigt H, Launois P, Levine AD, Wagner H, Heeg K, Louis JA, Röcken M (2001) IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice. Nat Immunol 2:1054–1060. doi:10.1038/ni725

    Article  CAS  PubMed  Google Scholar 

  • Bittencourt AL, Barral A (1991) Evaluation of the histopathological classifications of American cutaneous and mucocutaneous leishmaniasis. Mem Inst Oswaldo Cruz 86:51–56

    Article  CAS  PubMed  Google Scholar 

  • Bogdan C, Gessner A, Solbach W, Röllinghoff M (1996) Invasion, control and persistence of Leishmania parasites. Curr Opin Immunol 8:517–525

    Article  CAS  PubMed  Google Scholar 

  • Bogdan C, Röllinghoff M, Diefenbach A (2000) The role of nitric oxide in innate immunity. Immunol Rev 173:17–26

    Article  CAS  PubMed  Google Scholar 

  • Bosque F, Saravia NG, Valderrama L, Milon G (2000) Distinct innate and acquired immune responses to Leishmania in putative susceptible and resistant human populations endemically exposed to L. (Viannia) panamensis infection. Scand J Immunol 51:533–541

    Article  CAS  PubMed  Google Scholar 

  • Brodskyn CI, Barral A, Boaventura V, Carvalho E, Barral-Netto M (1997) Parasite-driven in vitro human lymphocyte cytotoxicity against autologous infected macrophages from mucosal leishmaniasis. J Immunol 159:4467–4473

    CAS  PubMed  Google Scholar 

  • Coutinho SG, Da-Cruz AM, Bertho AL, Santiago MA, De-Luca P (1998) Immunologic patterns associated with cure in human American cutaneous leishmaniasis. Braz J Med Biol Res 31:139–142

    Article  CAS  PubMed  Google Scholar 

  • Cunha CF, Ferraz R, Pimentel MIF, Lyra MR, Schubach AO, Da-Cruz AM, Bertho AL (2016) Cytotoxic cell involvement in human cutaneous leishmaniasis: assessments in active disease, under therapy and after clinical cure. Parasite Immunol 38:244–254. doi:10.1111/pim.12312

    Article  CAS  PubMed  Google Scholar 

  • da Silva SC, Brodskyn CI (2014) The role of CD4 and CD8 T cells in human cutaneous leishmaniasis. Front Public Health 2:165. doi:10.3389/fpubh.2014.00165

    Google Scholar 

  • Da-Cruz AM, Bittar R, Mattos M, Oliveira-Neto MP, Nogueira R, Pinho-Ribeiro V, Azeredo-Coutinho RB, Coutinho SG (2002) T-cell-mediated immune responses in patients with cutaneous or mucosal leishmaniasis: long-term evaluation after therapy. Clin Diagn Lab Immunol 9:251–256

    PubMed  PubMed Central  Google Scholar 

  • Da-Cruz AM, Conceição-Silva F, Bertho AL, Coutinho SG (1994) Leishmania-reactive CD4+ and CD8+ T cells associated with cure of human cutaneous leishmaniasis. Infect Immun 62:2614–2618

    CAS  PubMed  PubMed Central  Google Scholar 

  • de Moura TR, Novais FO, Oliveira F, Clarêncio J, Noronha A, Barral A, Brodskyn C, de Oliveira CI (2005) Toward a novel experimental model of infection to study American cutaneous leishmaniasis caused by Leishmania braziliensis. Infect Immun 73:5827–5834. doi:10.1128/IAI.73.9.5827-5834.2005

    Article  PubMed  PubMed Central  Google Scholar 

  • Duarte ML, Rochael MC (2006) Histopathological and immunohistochemical profile of the American cutaneous leishmaniasis with emphasis on FXIIIa+ dermal dendrocytes Perfil histopatológico e imuno-histoquímico da leishmaniose tegumentar Americana com ênfase nos dendrócitos dérmicos FXIIIa+. An Bras Dermatol 81:541–548. doi:10.1590/s0365-05962006000600005

    Google Scholar 

  • Díaz NL, Arveláez FA, Zerpa O, Tapia FJ (2006) Inducible nitric oxide synthase and cytokine pattern in lesions of patients with American cutaneous leishmaniasis. Clin Exp Dermatol 31:114–117. doi:10.1111/j.1365-2230.2005.01991.x

    Article  PubMed  Google Scholar 

  • Favali C, Tavares N, Clarêncio J, Barral A, Barral-Netto M, Brodskyn C (2007) Leishmania amazonensis infection impairs differentiation and function of human dendritic cells. J Leukoc Biol 82:1401–1406. doi:10.1189/jlb.0307187

    Article  CAS  PubMed  Google Scholar 

  • Goto H, Lauletta Lindoso JA (2012) Cutaneous and mucocutaneous leishmaniasis. Infect Dis Clin N Am 26:293–307. doi:10.1016/j.idc.2012.03.001

    Article  Google Scholar 

  • Gutierrez Y, Salinas GH, Palma G, Valderrama LB, Santrich CV, Saravia NG (1991) Correlation between histopathology, immune response, clinical presentation, and evolution in Leishmania braziliensis infection. AmJTrop Med Hyg 45:281–289

    CAS  Google Scholar 

  • Hernández-Ruiz J, Becker I (2006) CD8+ cytotoxic lymphocytes in cutaneous leishmaniasis. Salud Publica Mex 48:430–439

    Article  PubMed  Google Scholar 

  • Hochrein H, O'Keeffe M, Luft T, Vandenabeele S, Grumont RJ, Maraskovsky E, Shortman K (2000) Interleukin (IL)-4 is a major regulatory cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J Exp Med 192:823–833. doi:10.1084/jem.192.6.823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jabbour MN, Issa G, Charafeddine K, Simaan Y, Karam M, Khalifeh H, Habib R, Khalifeh I (2015) The immune microenvironment in cutaneous leishmaniasis. J Eur Acad Dermatol Venereol 29:1170–1179. doi:10.1111/jdv.12781

    Article  CAS  PubMed  Google Scholar 

  • Kima PE, Soong L (2013) Interferon gamma in leishmaniasis. Front Immunol 4:156. doi:10.3389/fimmu.2013.00156

    Article  PubMed  PubMed Central  Google Scholar 

  • Liew FY (1994) Regulation of nitric oxide synthesis in infectious and autoimmune diseases. Immunol Lett 43:95–98

    Article  CAS  PubMed  Google Scholar 

  • Liew FY, Li Y, Severn A, Millott S, Schmidt J, Salter M, Moncada S (1991) A possible novel pathway of regulation by murine T helper type-2 (Th2) cells of a Th1 cell activity via the modulation of the induction of nitric oxide synthase on macrophages. Eur J Immunol 21:2489–2494. doi:10.1002/eji.1830211027

    Article  CAS  PubMed  Google Scholar 

  • Maspi N, Abdoli A, Ghaffarifar F (2016) Pro- and anti-inflammatory cytokines in cutaneous leishmaniasis: a review. Pathog Glob Health 110:247–260. doi:10.1080/20477724.2016.1232042

    Article  CAS  PubMed  Google Scholar 

  • Meymandi S, Dabiri S, Dabiri D, Crawford RI, Kharazmi A (2004) A quantitative study of epidermal Langerhans cells in cutaneous leishmaniasis caused by Leishmania tropica. Int J Dermatol 43:819–823. doi:10.1111/j.1365-4632.2004.02359.x

    Article  PubMed  Google Scholar 

  • Ministério da Saúde SdVeS (2014) Guia de Vigilância em Saúde. Ministério da Saúde, Brasília-Distrito Federal-Brasil

    Google Scholar 

  • Morgado FN, Schubach A, Rosalino CM, Quintella LP, Santos G, Salgueiro M, Conceição-Silva F (2008) Is the in situ inflammatory reaction an important tool to understand the cellular immune response in American tegumentary leishmaniasis? Br J Dermatol 158:50–58. doi:10.1111/j.1365-2133.2007.08255.x

    CAS  PubMed  Google Scholar 

  • Murray HW, Berman JD, Davies CR, Saravia NG (2005) Advances in leishmaniasis. Lancet 366:1561–1577. doi:10.1016/S0140-6736(05)67629-5

    Article  CAS  PubMed  Google Scholar 

  • Nateghi Rostami M, Keshavarz H, Edalat R, Sarrafnejad A, Shahrestani T, Mahboudi F, Khamesipour A (2010) CD8+ T cells as a source of IFN-γ production in human cutaneous leishmaniasis. PLoS Negl Trop Dis 4:e845. doi:10.1371/journal.pntd.0000845

    Article  PubMed  PubMed Central  Google Scholar 

  • Qadoumi M, Becker I, Donhauser N, Röllinghoff M, Bogdan C (2002) Expression of inducible nitric oxide synthase in skin lesions of patients with american cutaneous leishmaniasis. Infect Immun 70:4638–4642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodrigues FM, Coelho Neto GT, Menezes JG, Gama ME, Gonçalves EG, Silva AR, Laurenti MD, Corbett CE, Silveira FT, Gomes CM (2014) Expression of Foxp3, TGF-β and IL-10 in American cutaneous leishmaniasis lesions. Arch Dermatol Res 306:163–171. doi:10.1007/s00403-013-1396-8

    Article  CAS  PubMed  Google Scholar 

  • Rogers KA, DeKrey GK, Mbow ML, Gillespie RD, Brodskyn CI, Titus RG (2002) Type 1 and type 2 responses to Leishmania major. FEMS Microbiol Lett 209:1–7

    Article  CAS  PubMed  Google Scholar 

  • Salud OPdl (2015) Informe Epidemiológico de las Américas. Leishmaniasis vol 1. World Health Organization. Regional Office for the Americas, Washington, DC

    Google Scholar 

  • Santos Cda S, Boaventura V, Ribeiro Cardoso C, Tavares N, Lordelo MJ, Noronha A, Costa J, Borges VM, de Oliveira CI, Van Weyenbergh J, Barral A, Barral-Netto M, Brodskyn CI (2013) CD8 (+) granzyme B (+)-mediated tissue injury vs. CD4 (+) IFNγ(+)-mediated parasite killing in human cutaneous leishmaniasis. J Invest Dermatol 133:1533–1540. doi:10.1038/jid.2013.4

    Article  PubMed  Google Scholar 

  • Silveira FT, Lainson R, Corbett CE (2004) Clinical and immunopathological spectrum of American cutaneous leishmaniasis with special reference to the disease in Amazonian Brazil: a review. Mem Inst Oswaldo Cruz 99:239–251. doi:10.1590/S0074-02762004000300001

    Article  PubMed  Google Scholar 

  • Silveira FT, Lainson R, De Castro Gomes CM, Laurenti MD, Corbett CE (2009) Immunopathogenic competences of Leishmania (V.) braziliensis and L. (L.) amazonensis in American cutaneous leishmaniasis. Parasite Immunol 31:423–431. doi:10.1111/j.1365-3024.2009.01116.x

    Article  CAS  PubMed  Google Scholar 

  • Silveira FT, Lainson R, Gomes CM, Laurenti MD, Corbett CE (2008) Reviewing the role of the dendritic Langerhans cells in the immunopathogenesis of American cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 102:1075–1080. doi:10.1016/j.trstmh.2008.05.020

    Article  PubMed  Google Scholar 

  • Soong L, Chang CH, Sun J, Longley BJ, Ruddle NH, Flavell RA, McMahon-Pratt D (1997) Role of CD4+ T cells in pathogenesis associated with Leishmania amazonensis infection. J Immunol 158:5374–5383

    CAS  PubMed  Google Scholar 

  • Soong L, Henard CA, Melby PC (2012) Immunopathogenesis of non-healing American cutaneous leishmaniasis and progressive visceral leishmaniasis. Semin Immunopathol 34:735–751. doi:10.1007/s00281-012-0350-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sotto MN, Halpern I, Kauffman MR, Pagliari C (2010) Factor XIIIa+ dermal dendrocyte parasitism in American tegumentary leishmaniasis skin lesions. Am J Dermatopathol 32:15–18. doi:10.1097/DAD.0b013e3181ab4695

    Article  PubMed  Google Scholar 

  • Stager S, Alexander J, Kirby AC, Botto M, Van Rooijen N, Smith DF, Brombacher F, Kaye PM (2003) Natural antibodies and complement are endogenous adjuvants for vaccine-induced CD8(+) T-cell responses. Nat Med 9:1287–1292. doi:10.1038/nm933

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors greatly acknowledge Thaíse Yumie Tomokane for editing the figures and performing the statistical analyses. Financial support was provided by the São Paulo Research Foundation (FAPESP) Grant #2006/56319-1, as well as by the Laboratório de Patologia de Moléstias Infecciosas (LIM-50/HCFMUSP). English-language editing of this manuscript was provided by Journal Prep.

Author information

Authors and Affiliations

  1. Pathology Department, Medical School of São Paulo University, São Paulo, São Paulo, Brazil

    Cláudia Maria Castro Gomes, Maria Gloria Teixeira Sousa, Joyce Prieto Bezerra Menezes, Ana Carolina Stocco Lima, Márcia Dalastra Laurenti & Carlos Eduardo Pereira Corbett

  2. Parasitology Department, Evandro Chagas Institute (Surveillance Secretary of Health, Ministry of Health), Belém, Pará, Brazil

    Marliane Campos Batista & Fernando Tobias Silveira

  3. Dermatology Department, Medical School of São Paulo University, São Paulo, São Paulo, Brazil

    Walter Belda Jr

  4. Chelsea and Westminster Hospital London, London, UK

    Daniel Bradshaw

  5. Pediatric Department, Federal University of Maranhão, São Luis, Maranhão, Brazil

    Monica Elinor Alves Gama

  6. Tropical Medicine Institute, Federal University of Pará, Belém, Pará, Brazil

    Fernando Tobias Silveira

Authors
  1. Cláudia Maria Castro Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Gloria Teixeira Sousa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joyce Prieto Bezerra Menezes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marliane Campos Batista
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana Carolina Stocco Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Walter Belda Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel Bradshaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Monica Elinor Alves Gama
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Márcia Dalastra Laurenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fernando Tobias Silveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Carlos Eduardo Pereira Corbett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cláudia Maria Castro Gomes.

Ethics declarations

This study was approved by the Ethics Committee of the Clinic’s Hospital, University of São Paulo Medical School (#0485/08). Informed consent was obtained from all participants in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Castro Gomes, C.M., Sousa, M.G.T., Menezes, J.P.B. et al. Immunopathological characterization of human cutaneous leishmaniasis lesions caused by Leishmania (Viannia) spp. in Amazonian Brazil. Parasitol Res 116, 1423–1431 (2017). https://doi.org/10.1007/s00436-017-5403-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00436-017-5403-4

Keywords

Search

Navigation