Analysis of localized immune responses reveals presence of Th17 and Treg cells in cutaneous leishmaniasis due to Leishmania tropica

BMC Immunology

Poonam Salotra¹  Ram Awatar Bumb²  Nasim Akhtar Ansari³  Himanshu Kaushal¹  Kumar Avishek¹  Rajesh Kumar⁴  Anand Raj⁶  Gajendra Kumar Katara⁵ 

[1] National Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi 110029, India;Department of Dermatology, STD and Leprosy, SP Medical College, Bikaner, Rajasthan, India;Present address: Medical Research Centre, Jazan University, Jazan, Saudi Arabia;Present address: Department of Tropical Medicine, Tulane University, School of Public Health, New Orleans, LA 70112, USA;Present address: Department of Microbiology & Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA;Present address: Laboratory of Erythropoietin, National Dope Testing laboratory (NDTL), JN Stadium Complex, New Delhi 110003, India

关键词: Treg cell;    Th17 cell;    Cytokines;    Cutaneous Leishmaniasis;    cDNA array;   

Others  :  1077741
DOI  :  10.1186/1471-2172-14-52

 received in 2013-08-30, accepted in 2013-11-13,  发布年份 2013

【 摘 要 】

Purpose

The interaction between the Leishmania parasite and the host cell involves complex, multifaceted processes. The disease severity in cutaneous leishmaniasis (CL) is largely dependent on the causative species. Most of the information on immune responses in human CL is available with respect to L. major infection and is lacking for L. tropica species. In this study, we employed cytokine/chemokine/receptor membrane cDNA array to capture comprehensive picture of immuno-determinants in localized human tissue during L. tropica infection. Expression of selected molecules was evaluated by real time PCR in dermal lesion tissues at pre- and post treatment stages. Plasma IL-17 level was estimated by sandwich ELISA.

Results

The cDNA array analysis identified several immuno-determinants in tissue lesions of Indian CL including cytokines (IFN-γ, TNF-α, IL-1β, IL-10, IL-13), chemokines (IL-8, CCL2, CCL3, CCL4) and apoptotic molecules (Fas, TRAIL, IRF-1). Elevated mRNA levels of Th17 (IL-17, IL-23 and RORγt) and Treg (CD25, CTLA-4 and Foxp3) markers were observed in lesion tissues of CL patients compared to the control group, which subsided post treatment. Plasma IL-17 levels were found to be significantly higher in CL samples compared to controls.

Conclusions

In addition to defining comprehensive immunological responses inside lesion tissues of CL patients, our study demonstrated the presence of Th17 and Treg cells in CL caused by L. tropica.

【 授权许可】

   
2013 Katara et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]World Health Organization: Control of the Leishmaniases. World Health Organ Tech Rep Ser 2010, 949:91-106.
• [2]Kumar R, Bumb RA, Ansari NA, Mehta RD, Salotra P: Cutaneous leishmaniasis caused by Leishmania tropica in Bikaner, India: Parasite identification and characterization using molecular and immunological tools. Am J Trop Med Hyg 2007, 76:896-901.
• [3]Dogra J, Aneja N, Lal BB, Mishra SN: Cutaneous leishmaniasis in India. Clinical experience with itraconazole. Int J Dermatol 1990, 29:661-662.
• [4]Soni P, Prasad N, Khandelwal K, Ghiya BC, Mehta RD, Bumb RA, Salotra P: Unresponsive cutaneous leishmaniasis and HIV co-infection: report of three cases. Indian J Dermatol Venereol Leprol 2011, 77:251.
• [5]Prasad N, Ghiya BC, Bumb RA, Kaushal H, Saboskar AA, Lezama-Davila CM, Salotra P, Satoskar AR: Heat, Oriental sore, and HIV. Lancet 2011, 377:610.
• [6]Bastien P, Killick-Kendrick R: Leishmania tropica infection in hamsters and a review of the animal pathogenicity of this species. Exp Parasitol 1992, 75:433-441.
• [7]Kumar R, Bumb RA, Salotra P: Evaluation of localized and systemic immune responses in cutaneous leishmaniasis caused by Leishmania tropica: interleukin-8, monocyte chemotactic protein-1 and nitric oxide are major regulatory factors. Immunology 2010, 130:193-201.
• [8]Kumar R, Bumb RA, Salotra P: Correlation of parasitic load with interleukin-4 response in patients with cutaneous leishmaniasis due to Leishmania tropica. FEMS Immunol Med Microbiol 2009, 57:239-246.
• [9]Khader SA, Gopal R: IL-17 in protective immunity to intracellular pathogens. Virulence 2010, 1:423-427.
• [10]Pitta MG, Romano A, Cabantous S, Henri S, Hammad A, Kouriba B, Argiro L, el Kheir M, Bucheton B, Mary C, et al.: IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani. J Clin Invest 2009, 119:2379-2387.
• [11]Bacellar O, Faria D, Nascimento M, Cardoso TM, Gollob KJ, Dutra WO, Scott P, Carvalho EM: Interleukin 17 production among patients with American cutaneous leishmaniasis. J Infect Dis 2009, 200:75-78.
• [12]Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL: CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 2002, 420:502-507.
• [13]Campanelli AP, Roselino AM, Cavassani KA, Pereira MS, Mortara RA, Brodskyn CI, Goncalves HS, Belkaid Y, Barral-Netto M, Barral A, et al.: CD4+CD25+ T cells in skin lesions of patients with cutaneous leishmaniasis exhibit phenotypic and functional characteristics of natural regulatory T cells. J Infect Dis 2006, 193:1313-1322.
• [14]Bourreau E, Ronet C, Darsissac E, Lise MC, Marie DS, Clity E, Tacchini-Cottier F, Couppie P, Launois P: In leishmaniasis due to Leishmania guyanensis infection, distinct intralesional interleukin-10 and Foxp3 mRNA expression are associated with unresponsiveness to treatment. J Infect Dis 2009, 199:576-579.
• [15]Katara GK, Ansari NA, Verma S, Ramesh V, Salotra P: Foxp3 and IL −10 expression correlates with parasite burden in lesional tissues of post kala azar dermal leishmaniasis (PKDL) patients. PLoS Neg Trop Dis 2011, 5:e1171.
• [16]Buates S, Matlashewski G: General suppression of macrophage gene expression during Leishmania donovani infection. J Immunol 2001, 166:3416-3422.
• [17]Chaussabel D, Semnani RT, McDowell MA, Sacks D, Sher A, Nutman TB: Unique gene expression profiles of human macrophages and dendritic cells to phylogenetically distinct parasites. Blood 2003, 102:672-681.
• [18]Rodriguez NE, Chang HK, Wilson ME: Novel program of macrophage gene expression induced by phagocytosis of Leishmania chagasi. Infect Immun 2004, 72:2111-2122.
• [19]Eckmann L, Smith JR, Housley MP, Dwinell MB, Kagnoff MF: Analysis by high density cDNA arrays of altered gene expression in human intestinal epithelial cells in response to infection with the invasive enteric bacteria Salmonella. J Biol Chem 2000, 275:14084-14094.
• [20]Coombes BK, Mahony JB: cDNA array analysis of altered gene expression in human endothelial cells in response to Chlamydia pneumoniae infection. Infect Immun 2001, 69:1420-1427.
• [21]Bogdan C, Gessner A, Solbach W, Röllinghoff M: Invasion, control and persistence of Leishmania parasites. Curr Opin Immunol 1996, 4:517-525.
• [22]Ansari NA, Ramesh V, Salotra P: Interferon (IFN)-gamma, tumor necrosis factor-alpha, interleukin-6, and IFN-gamma receptor 1 are the major immunological determinants associated with post-kala azar dermal leishmaniasis. J Infect Dis 2006, 194:958-965.
• [23]Katara GK, Ansari NA, Singh A, Ramesh V, Salotra P: Evidence for involvement of Th17 type responses in post kala azar dermal leishmaniasis (PKDL). PLoS Negl Trop Dis 2012, 6:e1703.
• [24]Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, Soumelis V: A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 2008, 9:650-657.
• [25]Ansari NA, Kumar R, Gautam S, Nylén S, Singh OP, Sundar S, Sacks D: IL-27 and IL-21 are associated with T cell IL-10 responses in human visceral leishmaniasis. J Immunol 2011, 186:3977-3985.
• [26]Anderson CF, Stumhofer JS, Hunter CA, Sacks D: IL-27 regulates IL-10 and IL-17 from CD4+ cells in nonhealing Leishmania major infection. J Immunol 2009, 183:4619-4627.
• [27]Boaventura VS, Santos CS, Cardoso CR, de Andrade J, dos Santos WL, Clarêncio J, Silva JS, Borges VM, Barral-Netto M, Brodskyn CI, et al.: Human mucosal leishmaniasis: neutrophils infiltrate areas of tissue damage that express high levels of Th17-related cytokines. Eur J Immunol 2010, 40:2830-2836.
• [28]Kobets T, Havelková H, Grekov I, Volkova V, Vojtíšková J, Slapničková M, Kurey I, Sohrabi Y, Svobodová M, Demant P, et al.: Genetics of host response to Leishmania tropica in mice - different control of skin pathology, chemokine reaction, and invasion into spleen and liver. PLoS Negl Trop Dis 2012, 6:e1667.
• [29]Marin ND, París SC, Vélez VM, Rojas CA, Rojas M, García LF: Regulatory T cell frequency and modulation of IFN-gamma and IL-17 in active and latent tuberculosis. Tuberculosis 2010, 90:252-261.
• [30]Wang Q, Zheng Y, Huang Z, Tian Y, Zhou J, Mao Q, Wu Y, Ni B: Activated IL-23/IL-17 pathway closely correlates with increased Foxp3 expression in livers of chronic hepatitis B patients. BMC Immunol 2011, 12:25. BioMed Central Full Text
• [31]Zhang L, Yang XQ, Cheng J, Hui RS, Gao TW: Increased Th17 cells are accompanied by FoxP3 (+) Treg cell accumulation and correlated with psoriasis disease severity. Clin Immunol 2010, 135:108-117.