The Comparison of the IFN-ɤ, TNF-α and IL-10 Cytokines in Healing and Non-healing Cutaneous Leishmaniasis
-
Mina Taraghian
,
Helena Hanif
,
Parisa Mousavi
,
Zahra Baharlooeyan cheshmeh
,
Azam Samei
,
Abbas Abdollahi
,
Hossein Vazini
Abstract
Background: Leishmaniasis is one of the main vectors borne and neglected tropical parasitic diseases. T cell cytokine responses are highly important in the presentations of disease such as control or progression, and understanding of the host immunological response is valuable in diagnosis, follow-up, and vaccine designs. In the current study, the profile of IFN-ɤ, TNF-α, and IL-10 cytokines was investigated through the ELISA technique in PBMCs isolated from antimony resistance and susceptible patients.
Methods: In this experimental study, 54 patients with healing (n=27) or non-healing (n=27) CL were recruited. Lesion samples were collected to determine the genotype of Leishmania spp. and peripheral blood mononuclear cells (PBMCs) were obtained to evaluate the cytokines profiles using soluble Leishmania antigen (SLA) and phytohaemagglutinin (PHA) mitogen. Cytokines were assessed by the ELISA technique
Results: The IFN-ɤ and TNF-α cytokines were significantly increased in the healing group treated with both SLA antigen and PHA mitogen (P<0.001). The level of IL-10 was significantly increased in non-healing and significantly declined in healing groups (P<0.001).
Conclusion: The profile of IFN-ɤ, TNF-α, and IL-10 cytokines are crucially associated with the response of treatment.
1. Ajdary S, Alimohammadian MH, Eslami MB, Kemp K, Kharazmi A. Comparison of the immune profile of nonhealing cutaneous leishmaniasis patients with those with active lesions and those who have recovered from infection. Infect Immun. 2000;68(4):1760-1764.
2. Akhoundi M, Kuhls K, Cannet A,et al . A historical overview of the classification, evolution, and dispersion of Leishmania parasites and sandflies. PLoS Negl Trop Dis. 2016;10(3):e0004349.
3. Alexander J, Bryson K. T helper (h) 1/th2 and Leishmania: Paradox rather than paradigm. Immunol Lett. 2005;99(1):17-23.
4. Antonelli LR, Dutra WO, Almeida RP, Bacellar O, Carvalho EM, Gollob KJ. Activated inflammatory t cells correlate with lesion size in human cutaneous leishmaniasis. Immunol Lett. 2005;101(2):226-230.
5. Bacellar M, Polari L, Carneiro PP, et al. Leishmania braziliensis infection enhances toll-like receptors 2 and 4 expression and triggers tnf-α and il-10 production in human cutaneous leishmaniasis. Front Cell Infect Microbiol. 2019;9:120.
6. Barbosa Júnior WL, Justo AM, Aguiar dos Santos AM, et al. Higher levels of tnf and il‐4 cytokines and low mir‐182 expression in visceral leishmaniasis‐hiv co‐infected patients. Parasite Immunol. 2020; 42(4):e12701.
7. Bunn PT, de Oca MM, de Labastida Rivera F,et al. Distinct roles for cd4+ foxp3+ regulatory t cells and il-10–mediated immunoregulatory mechanisms during experimental visceral leishmaniasis caused by Leishmania donovani. J Immunol. 2018;201(11):3362-3372.
8. Carneiro PP, Conceição J, Macedo M, Magalhães V, Carvalho EM, Bacellar O. The role of nitric oxide and reactive oxygen species in the killing of Leishmania braziliensis by monocytes from patients with cutaneous leishmaniasis. PLoS one. 2016;11(2):e0148084.
9. Castellano LR, Correia Filho D, Argiro L, et al. Th1/th2 immune responses are associated with active cutaneous leishmaniasis and clinical cure is associated with strong interferon-γ production. Hum Immunol. 2009;70(6):383-390.
10. Chen X, Bäumel M, Männel DN, Howard OZ, Oppenheim JJ. Interaction of tnf with tnf receptor type 2 promotes expansion and function of mouse cd4+ cd25+ t regulatory cells. J Immunol. 2007;179(1):154-161.
11. da Silva Santos C, Brodskyn CI. The role of cd4 and cd8 t cells in human cutaneous leishmaniasis. Front Public Health. 2014;2:165.
12. de Assis Souza M, de Castro MCB, de Oliveira AP,et al. Cytokines and no in american tegumentary leishmaniasis patients: Profiles in active disease, after therapy and in self-healed individuals. Microb Pathog. 2013;57:27-32.
13. de Hippólito DDC, Gomes AHS, Maia MM,et al. Gene expression profile of cytokines produced in biopsies from patients with american cutaneous leishmaniasis. Acta Trop. 2019;189:69-75.
14. Esboei BR, Mohebali M, Mousavi P, Fakhar M, Akhoundi B. Potent antileishmanial activity of chitosan against iranian strain of Leishmania major (mrho/ir/75/er): In vitro and in vivo assay. J Vector Borne Dis. 2018;55:111.
15. Fahimeh Firouzjaie-Karder, Behnaz Akhoundi, Mehdi Mohebali, et al. A comparative evaluation of regulatory t cells profile among acute and chronic cutaneous leishmaniasis using flow cytometry. Iran J Parasitol. 2019;14(2):190-196.
16. Fromm PD, Kling JC, Remke A, Bogdan C, Körner H. Fatal leishmaniasis in the absence of tnf despite a strong th1 response. Front Microbiol. 2015;6:1520.
17. Gómez PN, Hidalgo IC, Hidalgo MdlPC, Sánchez RÁ, Delgado AR, Cabeza-Barrera J. Cutaneous leishmaniasis associated with tnf-α blockers: A case report. Eur J Hosp Pharm. 2019;26:233-234.
18. Hijawi KJ, Hijjawi NS, Ibbini JH. Detection, genotyping, and phylogenetic analysis of Leishmania isolates collected from infected jordanian residents and syrian refugees who suffered from cutaneous leishmaniasis. Parasitol Res. 2019;118(3):793-805.
19. Hoseini SG, Javanmard SH, Hejazi SH,et al. Comparison of immune regulatory factors in acute and chronic lesions of cutaneous leishmaniasis due to Leishmania major. J Res Med Sci. 2014;19(Suppl 1):S36-S40.
20. Ibarra-Meneses AV, Mondal D, Alvar J, Moreno J, Carrillo E. Cytokines and chemokines measured in dried sla-stimulated whole blood spots for asymptomatic Leishmania infantum and Leishmania donovani infection. Sci rep. 2017;7:1-7.
21. Karimkhani C, Wanga V, Naghavi P, Dellavalle RP, Naghavi M. Global burden of cutaneous leishmaniasis. Lancet Infect Dis. 2017;17(3):264.
22. Körner H, McMorran B, Schlüter D, Fromm P. The role of tnf in parasitic diseases: Still more questions than answers. Int J Parasitol. 2010;40(8):879-888.
23. Louzir H, Melby PC, Ben Salah A,et al .Immunologic determinants of disease evolution in localized cutaneous leishmaniasis due to Leishmania major. J Infect Dis. 1998;177(6):1687-1695.
24. Mahdavi SA, Javadian B, Barzegari S, Rahimi Esboei B, Moosazadeh M. Epidemiological study and geographical distribution of cutaneous leishmaniasis in golestan province, 2014-2016. J. Maz Univ Med Sci. 2020;29:125-130.
25. Mansueto P, Vitale G, Di Lorenzo G, Rini G, Mansueto S, Cillari E. Immunopathology of leishmaniasis: An update. Int J Immunopathol Pharmacol. 2007;20(3):435-445.
26. Maspi N, Abdoli A, Ghaffarifar F. Pro-and anti-inflammatory cytokines in cutaneous leishmaniasis: A review. Pathog Glob Health. 2016;110(6):247-260.
27. Melby PC, Chandrasekar B, Zhao W, Coe JE. The hamster as a model of human visceral leishmaniasis: Progressive disease and impaired generation of nitric oxide in the face of a prominent th1-like cytokine response. J Immunol. 2001;166(3):1912-1920.
28. Moafi M, Rezvan H, Sherkat R,et al. Comparison of pro‐inflammatory cytokines of non‐healing and healing cutaneous leishmaniasis. Scand J Immunol. 2017; 85(4):291-299.
29. Mohammadi AM, Javadi A, Firooz A, Khamesipour A. Comparison of cytokine profile of ifn-γ, il-5 and il-10 in cutaneous leishmaniasis using pbmc vs. Whole blood. Iran J Microbiol. 2019;11(5):431-439.
30. Mohebali M. Visceral leishmaniasis in iran: Review of the epidemiological and clinical features. Iran J Parasitol. 2013;8(3):348-358.
31. Novais FO, Carvalho LP, Graff JW,et al. Cytotoxic t cells mediate pathology and metastasis in cutaneous leishmaniasis. PLoS Pathog. 2013;9(7):e1003504.
32. Novais FO, Wong AC, Villareal DO, Beiting DP, Scott P. Cd8+ t cells lack local signals to produce ifn-γ in the skin during Leishmania infection. J Immunol. 2018;200(5):1737-1745.
33. Organization WHO. Who bi-regional consultation on the status of leishmaniasis control and surveillance in east africa. 2018
34. Rezaei R, TAPPEH KH, Seyyedi S, Mikaili P. The anti-leishmanial efficacy of Artemisia dracunculus ethanolic extract in vitro and its effects on ifn-γ and il-4 response. Iran J Parasitol. 2017;12(3):398-407.
35. Salhi A, Rodrigues V, Santoro F,et al. Immunological and genetic evidence for a crucial role of il-10 in cutaneous lesions in humans infected with Leishmania braziliensis. J Immunol. 2008;180(9):6139-6148.
36. Santos B, Luize M, Nico D,et al. Leishmania donovani nucleoside hydrolase (nh36) domains induce t-cell cytokine responses in human visceral leishmaniasis. Front Immunol. 2017;8:227.
37. Schaut RG, Lamb IM, Toepp AJ, et al .Regulatory igdhi b cells suppress T cell function via il-10 and pd-l1 during progressive visceral leishmaniasis. J Immunol. 2016;196(10):4100-4109.
38. Solano-Gallego L, Montserrat-Sangrà S, Ordeix L, Martínez-Orellana P. Leishmania infantum-specific production of ifn-γ and il-10 in stimulated blood from dogs with clinical leishmaniosis. Parasit Vectors. 2016;9:317.
39. Torres-Guerrero E, Quintanilla-Cedillo MR, Ruiz-Esmenjaud J, Arenas R. Leishmaniasis: A review. F1000 Res. 2017;6:750.
40. Uzonna JE, Joyce KL, Scott P. Low dose Leishmania major promotes a transient t helper cell type 2 response that is down-regulated by interferon γ–producing cd8+ t cells. J Exp Med. 2004;199(11):1559-1566.
41. Venturin GL, Bragato JP, Melo LM,et al. Regulatory effect of pge2 on microbicidal activity and inflammatory cytokines in canine leishmaniasis. Parasite Immunol. 2020; 42(6):e12713.
42. Viettri M, Herrera L, Aguilar C,et al. Molecular characterization of Trypanosoma cruzi and Leishmania spp. Coinfection in mammals of venezuelan coendemic areas. J Vector Borne Dis. 2019;56(3):252-262.
43. Wilhelm P, Ritter U, Labbow S, Donhauser N, Röllinghoff M, Bogdan C, Körner H. Rapidly fatal leishmaniasis in resistant c57BL/6 mice lacking TNF. J Immunol. 2001;166(6):4012-4019.
2. Akhoundi M, Kuhls K, Cannet A,et al . A historical overview of the classification, evolution, and dispersion of Leishmania parasites and sandflies. PLoS Negl Trop Dis. 2016;10(3):e0004349.
3. Alexander J, Bryson K. T helper (h) 1/th2 and Leishmania: Paradox rather than paradigm. Immunol Lett. 2005;99(1):17-23.
4. Antonelli LR, Dutra WO, Almeida RP, Bacellar O, Carvalho EM, Gollob KJ. Activated inflammatory t cells correlate with lesion size in human cutaneous leishmaniasis. Immunol Lett. 2005;101(2):226-230.
5. Bacellar M, Polari L, Carneiro PP, et al. Leishmania braziliensis infection enhances toll-like receptors 2 and 4 expression and triggers tnf-α and il-10 production in human cutaneous leishmaniasis. Front Cell Infect Microbiol. 2019;9:120.
6. Barbosa Júnior WL, Justo AM, Aguiar dos Santos AM, et al. Higher levels of tnf and il‐4 cytokines and low mir‐182 expression in visceral leishmaniasis‐hiv co‐infected patients. Parasite Immunol. 2020; 42(4):e12701.
7. Bunn PT, de Oca MM, de Labastida Rivera F,et al. Distinct roles for cd4+ foxp3+ regulatory t cells and il-10–mediated immunoregulatory mechanisms during experimental visceral leishmaniasis caused by Leishmania donovani. J Immunol. 2018;201(11):3362-3372.
8. Carneiro PP, Conceição J, Macedo M, Magalhães V, Carvalho EM, Bacellar O. The role of nitric oxide and reactive oxygen species in the killing of Leishmania braziliensis by monocytes from patients with cutaneous leishmaniasis. PLoS one. 2016;11(2):e0148084.
9. Castellano LR, Correia Filho D, Argiro L, et al. Th1/th2 immune responses are associated with active cutaneous leishmaniasis and clinical cure is associated with strong interferon-γ production. Hum Immunol. 2009;70(6):383-390.
10. Chen X, Bäumel M, Männel DN, Howard OZ, Oppenheim JJ. Interaction of tnf with tnf receptor type 2 promotes expansion and function of mouse cd4+ cd25+ t regulatory cells. J Immunol. 2007;179(1):154-161.
11. da Silva Santos C, Brodskyn CI. The role of cd4 and cd8 t cells in human cutaneous leishmaniasis. Front Public Health. 2014;2:165.
12. de Assis Souza M, de Castro MCB, de Oliveira AP,et al. Cytokines and no in american tegumentary leishmaniasis patients: Profiles in active disease, after therapy and in self-healed individuals. Microb Pathog. 2013;57:27-32.
13. de Hippólito DDC, Gomes AHS, Maia MM,et al. Gene expression profile of cytokines produced in biopsies from patients with american cutaneous leishmaniasis. Acta Trop. 2019;189:69-75.
14. Esboei BR, Mohebali M, Mousavi P, Fakhar M, Akhoundi B. Potent antileishmanial activity of chitosan against iranian strain of Leishmania major (mrho/ir/75/er): In vitro and in vivo assay. J Vector Borne Dis. 2018;55:111.
15. Fahimeh Firouzjaie-Karder, Behnaz Akhoundi, Mehdi Mohebali, et al. A comparative evaluation of regulatory t cells profile among acute and chronic cutaneous leishmaniasis using flow cytometry. Iran J Parasitol. 2019;14(2):190-196.
16. Fromm PD, Kling JC, Remke A, Bogdan C, Körner H. Fatal leishmaniasis in the absence of tnf despite a strong th1 response. Front Microbiol. 2015;6:1520.
17. Gómez PN, Hidalgo IC, Hidalgo MdlPC, Sánchez RÁ, Delgado AR, Cabeza-Barrera J. Cutaneous leishmaniasis associated with tnf-α blockers: A case report. Eur J Hosp Pharm. 2019;26:233-234.
18. Hijawi KJ, Hijjawi NS, Ibbini JH. Detection, genotyping, and phylogenetic analysis of Leishmania isolates collected from infected jordanian residents and syrian refugees who suffered from cutaneous leishmaniasis. Parasitol Res. 2019;118(3):793-805.
19. Hoseini SG, Javanmard SH, Hejazi SH,et al. Comparison of immune regulatory factors in acute and chronic lesions of cutaneous leishmaniasis due to Leishmania major. J Res Med Sci. 2014;19(Suppl 1):S36-S40.
20. Ibarra-Meneses AV, Mondal D, Alvar J, Moreno J, Carrillo E. Cytokines and chemokines measured in dried sla-stimulated whole blood spots for asymptomatic Leishmania infantum and Leishmania donovani infection. Sci rep. 2017;7:1-7.
21. Karimkhani C, Wanga V, Naghavi P, Dellavalle RP, Naghavi M. Global burden of cutaneous leishmaniasis. Lancet Infect Dis. 2017;17(3):264.
22. Körner H, McMorran B, Schlüter D, Fromm P. The role of tnf in parasitic diseases: Still more questions than answers. Int J Parasitol. 2010;40(8):879-888.
23. Louzir H, Melby PC, Ben Salah A,et al .Immunologic determinants of disease evolution in localized cutaneous leishmaniasis due to Leishmania major. J Infect Dis. 1998;177(6):1687-1695.
24. Mahdavi SA, Javadian B, Barzegari S, Rahimi Esboei B, Moosazadeh M. Epidemiological study and geographical distribution of cutaneous leishmaniasis in golestan province, 2014-2016. J. Maz Univ Med Sci. 2020;29:125-130.
25. Mansueto P, Vitale G, Di Lorenzo G, Rini G, Mansueto S, Cillari E. Immunopathology of leishmaniasis: An update. Int J Immunopathol Pharmacol. 2007;20(3):435-445.
26. Maspi N, Abdoli A, Ghaffarifar F. Pro-and anti-inflammatory cytokines in cutaneous leishmaniasis: A review. Pathog Glob Health. 2016;110(6):247-260.
27. Melby PC, Chandrasekar B, Zhao W, Coe JE. The hamster as a model of human visceral leishmaniasis: Progressive disease and impaired generation of nitric oxide in the face of a prominent th1-like cytokine response. J Immunol. 2001;166(3):1912-1920.
28. Moafi M, Rezvan H, Sherkat R,et al. Comparison of pro‐inflammatory cytokines of non‐healing and healing cutaneous leishmaniasis. Scand J Immunol. 2017; 85(4):291-299.
29. Mohammadi AM, Javadi A, Firooz A, Khamesipour A. Comparison of cytokine profile of ifn-γ, il-5 and il-10 in cutaneous leishmaniasis using pbmc vs. Whole blood. Iran J Microbiol. 2019;11(5):431-439.
30. Mohebali M. Visceral leishmaniasis in iran: Review of the epidemiological and clinical features. Iran J Parasitol. 2013;8(3):348-358.
31. Novais FO, Carvalho LP, Graff JW,et al. Cytotoxic t cells mediate pathology and metastasis in cutaneous leishmaniasis. PLoS Pathog. 2013;9(7):e1003504.
32. Novais FO, Wong AC, Villareal DO, Beiting DP, Scott P. Cd8+ t cells lack local signals to produce ifn-γ in the skin during Leishmania infection. J Immunol. 2018;200(5):1737-1745.
33. Organization WHO. Who bi-regional consultation on the status of leishmaniasis control and surveillance in east africa. 2018
34. Rezaei R, TAPPEH KH, Seyyedi S, Mikaili P. The anti-leishmanial efficacy of Artemisia dracunculus ethanolic extract in vitro and its effects on ifn-γ and il-4 response. Iran J Parasitol. 2017;12(3):398-407.
35. Salhi A, Rodrigues V, Santoro F,et al. Immunological and genetic evidence for a crucial role of il-10 in cutaneous lesions in humans infected with Leishmania braziliensis. J Immunol. 2008;180(9):6139-6148.
36. Santos B, Luize M, Nico D,et al. Leishmania donovani nucleoside hydrolase (nh36) domains induce t-cell cytokine responses in human visceral leishmaniasis. Front Immunol. 2017;8:227.
37. Schaut RG, Lamb IM, Toepp AJ, et al .Regulatory igdhi b cells suppress T cell function via il-10 and pd-l1 during progressive visceral leishmaniasis. J Immunol. 2016;196(10):4100-4109.
38. Solano-Gallego L, Montserrat-Sangrà S, Ordeix L, Martínez-Orellana P. Leishmania infantum-specific production of ifn-γ and il-10 in stimulated blood from dogs with clinical leishmaniosis. Parasit Vectors. 2016;9:317.
39. Torres-Guerrero E, Quintanilla-Cedillo MR, Ruiz-Esmenjaud J, Arenas R. Leishmaniasis: A review. F1000 Res. 2017;6:750.
40. Uzonna JE, Joyce KL, Scott P. Low dose Leishmania major promotes a transient t helper cell type 2 response that is down-regulated by interferon γ–producing cd8+ t cells. J Exp Med. 2004;199(11):1559-1566.
41. Venturin GL, Bragato JP, Melo LM,et al. Regulatory effect of pge2 on microbicidal activity and inflammatory cytokines in canine leishmaniasis. Parasite Immunol. 2020; 42(6):e12713.
42. Viettri M, Herrera L, Aguilar C,et al. Molecular characterization of Trypanosoma cruzi and Leishmania spp. Coinfection in mammals of venezuelan coendemic areas. J Vector Borne Dis. 2019;56(3):252-262.
43. Wilhelm P, Ritter U, Labbow S, Donhauser N, Röllinghoff M, Bogdan C, Körner H. Rapidly fatal leishmaniasis in resistant c57BL/6 mice lacking TNF. J Immunol. 2001;166(6):4012-4019.
| Files | ||
| Issue | Vol 16 No 3 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijpa.v16i3.7103 | |
| Keywords | ||
| Cutaneous leishmaniasis IFN-gamma TNF-alpha Iinterlokin-10 Immunological response | ||
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How to Cite
1.
Taraghian M, Hanif H, Mousavi P, Baharlooeyan cheshmeh Z, Samei A, Abdollahi A, Vazini H. The Comparison of the IFN-ɤ, TNF-α and IL-10 Cytokines in Healing and Non-healing Cutaneous Leishmaniasis. Iran J Parasitol. 2021;16(3):490-498.
