Interleukin 17 (IL-17) plays a critical role in inflammation and autoimmunity. Very little is known about IL-17 in protozoa infection. Here we show that lymphocytes from mucosal leishmaniasis (ML) and cutaneous leishmaniasis (CL) produce higher levels of IL-17 than uninfected controls (UC) (p<0.01). There was a tendency for higher number of cells in tissue expressing IL-17 in ML than in CL and a direct correlation between number of cells expressing IL-17 and cellular inflammation at the lesion site (r2 = 0.86, p = 0.0001). This data gives support for the role of IL-17 in the pathogenesis of the inflammatory reaction in leishmaniasis.

dCutaneous leishmaniasis (CL) caused by Leishmania braziliensis is characterized by a strong Th1 response that leads to skin lesion development. In areas where L. braziliensis transmission is endemic, up to 15% of healthy subjects have tested positive for delayed-type hypersensitivity to soluble leishmania antigen (SLA) and are considered to have subclinical (SC) infection. SC subjects produce less gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) than do CL patients, but they are able to control the infection. ؉ T cells was higher in CL than in SC cells. While the use of a granzyme B inhibitor decreased the number of apoptotic cells in the CL group, the use of z-VAD-FMK had no effect on the frequency of these cells. These results suggest that CL CD8 ؉ T cells are more cytotoxic and may be involved in pathology. L eishmaniasis is caused by infection with parasites of the genusLeishmania. Leishmaniasis is a neglected tropical disease; 214,000 new cases of cutaneous leishmaniasis (CL) are reported annually worldwide, and the estimated incidence of leishmaniasis is 690,000 to 1,200,000 cases. Approximately 67,000 cases are reported in South America, Central America, and the Caribbean (1). In mice, the majority of Leishmania-specific CD4 ϩ T cells differentiate into T-helper 1 (Th1) cells that secrete gamma interferon (IFN-␥) and contribute to the elimination of the parasite through the activation of macrophages (2, 3). Although protective immunity has predominantly been related to IFN-␥-producing CD4 ϩ T cells, infection with Leishmania also results in the activation and expansion of parasite-specific CD8 ϩ T cells (4, 5). Human CL caused by Leishmania braziliensis is characterized by a strong Th1 response with the production of high levels of IFN-␥ and tumor necrosis factor alpha (TNF-␣) (6, 7). This exaggerated Th1 response is associated with the development of lesions and the severity of the disease (6, 8-10). In patients with CL caused by L. braziliensis, there are more CD4 ϩ than CD8 ϩ T cells, but this ratio reaches an equilibrium due to the increase in CD8 ϩ T cells that occurs during the healing process (11). The enrichment of Leishmania-reactive CD8 ϩ T cells in older lesions suggests that these cells may play a role in the healing process (12). In contrast, other studies have associated CD8ϩ T cell functions with pathology. For example, the cytotoxicity mediated by CD8 ϩ T cells is greater in mucosal leishmaniasis (ML), a more severe form of L. braziliensis infection, than in CL (13,14). More recently, it was shown that the frequency with which CD8 ϩ T cells express granzyme in the lesions of CL patients is greater than that in patients in the early phase of CL (i.e., before the ulcer has developed) and that the frequency with which CD8 ϩ T cells express granzyme is directly associated with the intensity of the inflammatory reaction observed in CL ulcers (15,16). This controversy regarding the role of cytotoxicity in the pathogenesis of human leishmaniasis indicates that the functions of CD...

Cutaneous leishmaniasis (CL) is characterized by high production of pro-inflammatory cytokines and development of pathology. Individuals with subclinical L. braziliensis infection (SC) have a positive skin test to leishmania but do not develop disease. We evaluated if the downregulation of inflammatory response in SC is mediated by IL-10 and IL-27 and if IL-17 is associated with control of infection. Participants include SC individuals, CL patients and healthy subjects. Cytokines protein and mRNA were detected by ELISA and real-time PCR. IFN-γ and TNF-α levels were higher in CL than in SC group. The IL-10 levels and mRNA for IL-10 were similar in both SC and CL. mRNA for IL-27 was increased in cells from SC after stimulation with L. braziliensis antigen. There was a tendency for increased levels of IL-17 in SC compared to CL. The weak type 1 immune response observed in SC L. braziliensis infection is not due to the regulatory effects of IL-10 and IL-27. The control of Leishmania infection may be mediated by innate immune response with participation of IL-17. The results from this pilot study warrant further larger studies to investigate the potential contributions of IL-17 and IL-27 to the control of L. braziliensis infection.

This study extends previous reports of an association between psoriasis and obesity and shows a direct correlation between obesity as measured according to different parameters and psoriasis severity.

Psoriasis is an autoimmune disease associated with the production of pro-inflammatory cytokines. The identification of these molecules in the pathogenesis of psoriasis facilitated the use of monoclonal antibodies to block their actions as a treatment for severe psoriasis. An increased inflammatory response has been documented in patients with obesity, a condition that is associated with the occurrence and severity of psoriasis. Osteopontin (OPN), TNF and CXCL9 levels are enhanced in patients with psoriasis, although OPN has been documented in the adipose tissue of obese patients without psoriasis. The prevalence of obesity is much higher in psoriasis patients compared with the general population. Thus, we aimed to evaluate the relationship between cytokine levels and psoriasis in the context of obesity. We compared OPN and CXCL9 plasma levels among 117 psoriasis patients and 27 healthy body mass index-matched subjects using ELISA. We also analyzed the TNF, CCL2 and CCL5 levels in a smaller subgroup of patients and matched controls. Median OPN, CCL5 and CXCL9 levels were significantly higher in psoriasis patients compared with the controls, independent of obesity. There was no difference between the median CCL2 levels in the psoriasis patients and the controls (P<0.05), although the CCL2 levels were elevated in obese patients compared with non-obese psoriasis patients (P<0.001). Facial involvement and the psoriasis area severity index (PASI) score were not associated (P<0.05) with OPN levels or elevated levels of chemokines. There was no significant correlation between the OPN and CXCL9 levels or the OPN and TNF levels in psoriasis patients. This work confirms that OPN, CCL5 and CXCL9 plasma levels are higher in psoriasis patients and provides evidence that their higher levels are not a consequence of obesity. Furthermore, the results demonstrate that OPN production is independent of TNF-α and CXCL9.

CD4(+)CD25(+)FOXP3(+) regulatory T cells have long been shown to mediate susceptibility to Leishmania infection, mainly via interleukin 10 production. In this work, we showed that the main sources of interleukin 10 in peripheral blood mononuclear cells (PBMCs) from patients with cutaneous leishmaniasis due to Leishmania braziliensis are CD4(+)CD25(-)CD127(-/low)FOXP3(-) cells. Compared with uninfected controls, patients with CL had increased frequencies of circulating interleukin 10-producing CD4(+)CD25(-)CD127(-/low) cells, which efficiently suppressed tumor necrosis factor α production by the total PBMC population. Also, in CL lesions, interleukin 10 was mainly produced by CD4(+)CD25(-) cells, and interleukin 10 messenger RNA expression was associated with interleukin 27, interleukin 21, and interferon γ expression, rather than with FOXP3 or transforming growth factor β expressions. Active production of both interleukin 27 and interleukin 21, together with production of interferon γ and interleukin 10, was also detected in the lesions. Since these cytokines are associated with the differentiation and activity of Tr-1 cells, our results suggest that this cell population may play an important role in the immunomodulation of CL. Therefore, development of treatments that interfere with this pathway may lead to faster parasite elimination.

Th1 immune responses are crucial for eliminating Leishmania parasites. However, despite strong Th1 responses, cutaneous leishmaniasis (CL) patients infected with L. braziliensis develop the disease, while milder Th1 responses are found in sub-clinical (SC) infections. Therefore, CL patients may experience impaired regulatory T cell (Treg) function, causing excessive Th1 responses and tissue damage. To address this hypothesis, we characterized the function of circulating Tregs in L. braziliensis infected CL patients and compared them to Tregs from uninfected controls (UC) and SC subjects. The frequency of circulating Tregs was similar in CL patients, UC and SC subjects. Moreover, CL patients Tregs suppressed lymphocyte proliferation and PBMC pro-inflammatory cytokine production more efficiently than UC Tregs, and also produced higher levels of IL-10 than UC and SC Tregs. Furthermore, PBMC and mononuclear cells from lesions of CL patients responded normally to Treg-induced suppression. Therefore, the lesion development in CL patients infected with L. braziliensis is not associated with impairment in Treg function or failure of cells to respond to immunomodulation. Rather, the increased Treg activation in CL patients may impair parasite elimination, resulting in establishment of chronic infection. Thus, immunological strategies that interfere with this response may improve leishmaniasis treatment.

Summary Aims The polymorphism observed in Leishmania braziliensis is associated with different clinical forms of leishmaniasis. Neutrophils ( PMN s) participate in the pathogenesis of leishmania infection, and here, we evaluate neutrophil function after infection with isolates of L. braziliensis from cutaneous leishmaniasis ( CL ) or disseminated leishmaniasis ( DL ) patients. Methods and results Neutrophils from 30 healthy subjects ( HS ) were infected with isolates of L . ( V .) braziliensis obtained from three CL and three DL patients. They were infected at the ratio of 3:1 parasites per neutrophil, and leishmania uptake was evaluated by microscopy. The neutrophil activation markers and oxidative burst by expression of dihidrorhodamine ( DHR ) were evaluated by flow cytometry and cytokine production by ELISA . The frequency of infected cells and the number of amastigotes were higher in neutrophils infected with CL isolates compared to DL isolates ( P < 0.05). The DHR and CD 66b expression after infection with DL isolate was lower than with CL isolates. There was no difference regarding chemokine production. Conclusion The L. (V.) braziliensis isolates of DL induced lower respiratory burst and neutrophils activation markers compared with CL isolates which may contribute to parasite survival and dissemination in DL patients.