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Oral Paracoccidioidomycosis Granulomas are Predominantly Populated by CD163+ Multinucleated Giant Cells

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Abstract

Multinucleated giant cells (MGC) are considered to be a hallmark of granulomatous inflammation; thus, they may play an essential role in the host response against pathogens, particularly Paracoccidioides brasiliensis. This study characterizes the MGC found in oral paracoccidioidomycosis and assesses the correlation of MGC with the amount of fungi within oral tissues. Twenty-six cases were included. They were classified as loose or dense granulomas, and the total MGC, including foreign-body and Langhans giant cells, besides the total and intracellular fungi, were taken into consideration. CD163 immunoexpression was performed, and CD163+ multinucleated giant cells were also quantified. Dense granulomas revealed more foreign-body type and total giant cells than loose granulomas (P < 0.05). Total giant cells showed a positive linear correlation with the CD163+ cells (P = 0.003; r = 0.56) and intracellular fungi quantification (P = 0.045; r = 0.40). Oral paracoccidioidomycosis lesions contain MGC that mainly belong to a CD163+ phenotype, also showing both Langhans and foreign-body arrangements. Additionally, the higher the presence of MGC, the higher the amount of phagocytized fungi.

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References

  1. Ramos-e-Silva M, Saraiva LE. Paracoccidioidomycosis. Dermatol Clin. 2008;26:257–69 (vii).

    Article  CAS  PubMed  Google Scholar 

  2. Teixeira MM, Theodoro RC, de Carvalho MJ, Fernandes L, Paes HC, Hahn RC, et al. Phylogenetic analysis reveals a high level of speciation in the Paracoccidioides genus. Mol Phylogenet Evol. 2009;52:273–83.

    Article  PubMed  Google Scholar 

  3. Fortes MR, Miot HA, Kurokawa CS, Marques ME, Marques SA. Immunology of paracoccidioidomycosis. An Bras Dermatol. 2011;86:516–24.

    Article  PubMed  Google Scholar 

  4. Franco M, Bagagli E, Scapolio S, da Silva Lacaz CA. A critical analysis of isolation of Paracoccidioides brasiliensis from soil. Med Mycol. 2000;38:185–91.

    Article  CAS  PubMed  Google Scholar 

  5. Silva CO, Almeida AS, Pereira AA, Sallum AW, Hanemann JA, Tatakis DN. Gingival involvement in oral paracoccidioidomycosis. J Periodontol. 2007;78:1229–34.

    Article  PubMed  Google Scholar 

  6. Magalhaes EM, Ribeiro Cde F, Damaso CS, Coelho LF, Silva RR, Ferreira EB, et al. Prevalence of paracoccidioidomycosis infection by intradermal reaction in rural areas in Alfenas, Minas Gerais, Brazil. Rev Inst Med Trop Sao Paulo. 2014;56:281–5.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Coutinho ZF, Silva D, Lazera M, Petri V, Oliveira RM, Sabroza PC, et al. Paracoccidioidomycosis mortality in Brazil (1980–1995). Cad Saude Publica. 2002;18:1441–54.

    Article  PubMed  Google Scholar 

  8. Lenhard-Vidal A, Assolini JP, Ono MA, Bredt CS, Sano A, Itano EN. Paracoccidioides brasiliensis and P. lutzii antigens elicit different serum IgG responses in chronic paracoccidioidomycosis. Mycopathologia. 2013;176:345–52.

    Article  CAS  PubMed  Google Scholar 

  9. Shikanai-Yasuda MA, de Queiroz Telles Filho F, Mendes RP, Colombo AL, Moretti ML. Guidelines in paracoccidioidomycosis. Rev Soc Bras Med Trop. 2006;39:297–310.

    Article  PubMed  Google Scholar 

  10. Ferreira MS. Paracoccidioidomycosis. Paediatr Respir Rev. 2009;10:161–5.

    Article  PubMed  Google Scholar 

  11. Almeida OP, Jacks J Jr, Scully C. Paracoccidioidomycosis of the mouth: an emerging deep mycosis. Crit Rev Oral Biol Med. 2003;14:377–83.

    Article  PubMed  Google Scholar 

  12. Garcia NG, Oliveira DT, Pereira AA, de Sa Magalhaes EM, Hanemann JA. Extensive cutaneous lesions in paracoccidioidomycosis successfully treated with itraconazole and beta-glucan. Int J Dermatol. 2014;53:e168–70.

    Article  CAS  PubMed  Google Scholar 

  13. Borges-Walmsley MI, Chen D, Shu X, Walmsley AR. The pathobiology of Paracoccidioides brasiliensis. Trends Microbiol. 2002;10:80–7.

    Article  CAS  PubMed  Google Scholar 

  14. Kurokawa CS, Araujo JP Jr, Soares AM, Sugizaki MF, Peracoli MT. Pro- and anti-inflammatory cytokines produced by human monocytes challenged in vitro with Paracoccidioides brasiliensis. Microbiol Immunol. 2007;51:421–8.

    Article  CAS  PubMed  Google Scholar 

  15. Benard G. An overview of the immunopathology of human paracoccidioidomycosis. Mycopathologia. 2008;165:209–21.

    Article  CAS  PubMed  Google Scholar 

  16. Helming L, Gordon S. Molecular mediators of macrophage fusion. Trends Cell Biol. 2009;19:514–22.

    Article  CAS  PubMed  Google Scholar 

  17. Williams GT, Williams WJ. Granulomatous inflammation—a review. J Clin Pathol. 1983;36:723–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhu XW, Friedland JS. Multinucleate giant cells and the control of chemokine secretion in response to Mycobacterium tuberculosis. Clin Immunol. 2006;120:10–20.

    Article  CAS  PubMed  Google Scholar 

  19. Anderson JM. Multinucleated giant cells. Curr Opin Hematol. 2000;7:40–7.

    Article  CAS  PubMed  Google Scholar 

  20. Varin A, Gordon S. Alternative activation of macrophages: immune function and cellular biology. Immunobiology. 2009;214:630–41.

    Article  CAS  PubMed  Google Scholar 

  21. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25:677–86.

    Article  CAS  PubMed  Google Scholar 

  22. Heusinkveld M, van der Burg SH. Identification and manipulation of tumor associated macrophages in human cancers. J Transl Med. 2011;9:216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. de Carli ML, Miyazawa M, Nonogaki S, Shirata NK, Oliveira DT, Pereira AA, et al. M2 macrophages and inflammatory cells in oral lesions of chronic paracoccidioidomycosis. J Oral Pathol Med. 2016;45:141–7.

    Article  PubMed  Google Scholar 

  24. Abreu e Silva MA, Salum FG, Figueiredo MA, Lopes TG, da Silva VD, Cherubini K. Interrelationship of clinical, histomorphometric and immunohistochemical features of oral lesions in chronic paracoccidioidomycosis. J Oral Pathol Med. 2013;42:235–42.

    Article  PubMed  Google Scholar 

  25. Quinn MT, Schepetkin IA. Role of NADPH oxidase in formation and function of multinucleated giant cells. J Innate Immun. 2009;1:509–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Batista AC, Soares CT, Lara VS. Failure of nitric oxide production by macrophages and decrease in CD4+ T cells in oral paracoccidioidomycosis: possible mechanisms that permit local fungal multiplication. Rev Inst Med Trop Sao Paulo. 2005;47:267–73.

    Article  PubMed  Google Scholar 

  27. Abreu e Silva MA, Salum FG, Figueiredo MA, Cherubini K. Important aspects of oral paracoccidioidomycosis—a literature review. Mycoses. 2013;56:189–99.

    Article  PubMed  Google Scholar 

  28. Muraille E, Leo O, Moser M. TH1/TH2 paradigm extended: macrophage polarization as an unappreciated pathogen-driven escape mechanism? Front Immunol. 2014;5:603.

    PubMed  PubMed Central  Google Scholar 

  29. Kaye P. Granulomatous diseases. Int J Exp Pathol. 2000;81:289–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pedreira RP, Guimaraes EP, de Carli ML, Magalhaes EM, Pereira AA, Hanemann JA. Paracoccidioidomycosis mimicking squamous cell carcinoma on the dorsum of the tongue and review of published literature. Mycopathologia. 2014;177:325–9.

    Article  Google Scholar 

  31. Nascimento MP, Bannwart CF, Nakaira-Takahagi E, Peracoli MT. Granulocyte macrophage colony-stimulating factor enhances the modulatory effect of cytokines on monocyte-derived multinucleated giant cell formation and fungicidal activity against Paracoccidioides brasiliensis. Mem Inst Oswaldo Cruz. 2011;106:735–41.

    Article  PubMed  Google Scholar 

  32. Helming L, Gordon S. The molecular basis of macrophage fusion. Immunobiology. 2007;212:785–93.

    Article  CAS  PubMed  Google Scholar 

  33. Brodbeck WG, Anderson JM. Giant cell formation and function. Curr Opin Hematol. 2009;16:53–7.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593–604.

    Article  CAS  PubMed  Google Scholar 

  36. Wang N, Liang H, Zen K. Molecular mechanisms that influence the macrophage m1–m2 polarization balance. Front Immunol. 2014;5:614.

    PubMed  PubMed Central  Google Scholar 

  37. Fabriek BO, van Bruggen R, Deng DM, Ligtenberg AJ, Nazmi K, Schornagel K, et al. The macrophage scavenger receptor CD163 functions as an innate immune sensor for bacteria. Blood. 2009;113:887–92.

    Article  CAS  PubMed  Google Scholar 

  38. Gammelsrud A, Solhaug A, Dendele B, Sandberg WJ, Ivanova L, Kocbach Bolling A, et al. Enniatin B-induced cell death and inflammatory responses in RAW 267.4 murine macrophages. Toxicol Appl Pharmacol. 2012;261:74–87.

    Article  CAS  PubMed  Google Scholar 

  39. Tidwell WJ, Googe PB. Tissue histiocyte reactivity with CD31 is comparable to CD68 and CD163 in common skin lesions. J Cutan Pathol. 2014;41:489–93.

    Article  PubMed  Google Scholar 

  40. Fairweather D, Cihakova D. Alternatively activated macrophages in infection and autoimmunity. J Autoimmun. 2009;33:222–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kashino SS, Fazioli RA, Cafalli-Favati C, Meloni-Bruneri LH, Vaz CA, Burger E, et al. Resistance to Paracoccidioides brasiliensis infection is linked to a preferential Th1 immune response, whereas susceptibility is associated with absence of IFN-gamma production. J Interferon Cytokine Res. 2000;20:89–97.

    Article  CAS  PubMed  Google Scholar 

  42. Okamoto H, Mizuno K, Horio T. Monocyte-derived multinucleated giant cells and sarcoidosis. J Dermatol Sci. 2003;31:119–28.

    Article  CAS  PubMed  Google Scholar 

  43. Lay G, Poquet Y, Salek-Peyron P, Puissegur MP, Botanch C, Bon H, et al. Langhans giant cells from M. tuberculosis-induced human granulomas cannot mediate mycobacterial uptake. J Pathol. 2007;211:76–85.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are thankful to Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES AUX PE PNPD 2386/2011) for financially supporting this study.

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Correspondence to João Adolfo Costa Hanemann.

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All procedures performed in the present study involving human participants were in accordance with the ethical standards of the institutional research committee (protocol #814.059) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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do Prado Gomes Pedreira, R., de Carli, M.L., Beijo, L.A. et al. Oral Paracoccidioidomycosis Granulomas are Predominantly Populated by CD163+ Multinucleated Giant Cells. Mycopathologia 181, 709–716 (2016). https://doi.org/10.1007/s11046-016-0016-5

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  • DOI: https://doi.org/10.1007/s11046-016-0016-5

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