Human mucosal leishmaniasis: Neutrophils infiltrate areas of tissue damage that express high levels of Th17‐related cytokines

Abstract

Mucosal leishmaniasis (ML) is characterised by severe tissue destruction. Herein, we evaluated the involvement of the IL-17-type response in the inflammatory infiltrate of biopsy specimens from 17 ML patients. IL-17 and IL-17-inducing cytokines (IL-1b, IL-23, IL-6 and TGF-b) were detected by immunohistochemistry in ML patients. IL-17 1 cells exhibited CD4 1 , CD8 1 or CD14 1 phenotypes, and numerous IL-17 1 cells co-expressed the CC chemokine receptor 6 (CCR6). Neutrophils, a hallmark of Th17-mediated inflammation, were regularly detected in necrotic and perinecrotic areas and stained positive for neutrophil elastase, myeloperoxidase and MMP-9. Taken together, these observations demonstrate the existence of Th17 cells in ML lesions associated with neutrophils in areas of tissue injury and suggest that IL-17 is involved in ML pathogenesis.Key words: Human . Mucosal leishmaniasis . Neutrophils . Th17 IntroductionMucosal leishmaniasis (ML), a severe chronic disease caused by leishmania protozoa, remains a serious health problem in several parts of the world, including Brazil [1]. ML is at the hyperresponsive end of the spectrum of clinical diseases caused by Leishmania braziliensis [1]. Uncontrolled immune responses have been implicated in ML pathogenesis because T lymphocytes from ML patients initiate intense responses (characterised by lymphoproliferation and cytokine production) despite the low number of parasites in mucosal lesions [2][3][4]. In addition to Th1 cytokines, TGF-b and IL-6 are also produced in ML lesions, but the significance of this finding is poorly understood [5].Th17 cells participate in inflammatory responses to several human infectious agents [6,7]. IL-17, the Th17 signature cytokine, induces tissue damage mediated by neutrophil attraction and proteinase release. Neutrophil recruitment mediated by IL-17 1 cells contributes to disease progression in susceptible mouse strains infected with L. major [8]. Although the cytokine combination that leads to human Th17 differentiation and maintenance remains controversial, TGF-b and IL-6, along with IL-23 and IL-1b, have been implicated in this phenomenon [9,10].Recently in human ML, IL-17 expression has been detected determined. In this study, we expand on the observations reported by Bacellar et al. [11] by demonstrating that in addition to Th17 cells, CD8 1 and CD14 1 cells express IL-17. We also detected the presence of neutrophils expressing proteinases in tissue-damaged areas, suggesting a potential function for Th17 cells in ML lesions. Results and discussionExpression of IL-17, Th17-inducing cytokines and retinoic acid-related orphan receptor ct (RORrt) IL-17 expression was consistently higher in ML lesions (n 5 12) than in normal mucosal samples (n 5 4), as shown in Fig. 1A and B. Marked expression was detected in mononuclear cells, endothelial cells and perivascular fusiform cells. No reactivity was detected using an isotype control antibody (Fig. 1G). As for cytokines involved in IL-17 production, ML lesions presented an intense expressio...

American tegumentary leishmaniasis: mRNA expression for Th1 and Treg mediators are predominant in patients with recent active disease

“…The latter subtype, initially related to autoimmune disorders and allergen-specific responses, is being studied in Leishmania infections (Pitta and others, 2009;Bacellar and others, 2009;Boaventura and others, 2010). Interestingly, our results seem to confirm such reciprocity, once RORC (the human orthologue of RORγt), needed for Th17 activation, was found to be down-regulated in patients.…”

“…Herein, the expression of the cytokine in response to AgIns was slightly up-regulated in patients, without statistical difference in relation to the control. This may be due the presence of IL-10 in the microenvironment, which is capable of impairing IL-17 expression (Boaventura and others, 2010). Previous study of our laboratory verified secreted levels IL-17 in PBMC from ATL patients stimulated by both antigens, but at the same time, IL-10 was produced ( AgSol.…”

The Role of Inflammatory, Anti-Inflammatory, and Regulatory Cytokines in Patients Infected with Cutaneous Leishmaniasis in Amazonas State, Brazil

“…Bacellar et al [40] observed that IL-17 is produced during infection with L. braziliensis and lymphocytes obtained from patients with MCL and CL yielded higher concentrations of IL-17 compared to lymphocytes obtained from uninfected individuals. The presence of T H 17 cells in lesions of CL/MCL was associated with neutrophils and tissue destruction [40, 42]. Our data point to higher levels of T H 17 in the sera of patients infected with L. guyanensis when compared to the other two species identified ( L .…”

IL-17A–Producing γδ T Cells Suppress Early Control of Parasite Growth by Monocytes in the Liver

“…In contrast, IL-17 promoted the progression of cutaneous leishmaniasis in susceptible mice infected with L. major (24), whereas in IL-10-deficient mice infected with L. major, IL-17 was responsible for increased Th1 cell-mediated pathology (25). In humans, a negative association with parasite-induced IL-17 production by PBMCs from patients with cutaneous leishmaniasis and muco-cutaneous leishmaniasis infected with L. braziliensis has been reported (26,27). Thus, these findings indicate subtle and complex roles for IL-17 in leishmaniasis that depends on the parasite species and/or sites of disease and immune cell activation.…”