IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani

Pitta, M. G. R.; Romano, Audrey; Cabantous, Stéphanie; Henri, Sandrine; Hammad, Awad; Kouriba, Bourèma; Argiro, Laurent; Kheir, Musa el; Bucheton, Bruno; Mary, Charles; El-Safi, Sayda; Dessein, Alain

doi:10.1172/jci38813

Cited by 168 publications

(235 citation statements)

References 46 publications

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“…In this circumstance, Th1 and Th17 cells act together to induce immune-mediated tissue damage. Furthermore, IL-17, in association with Th1 cytokines, plays a protective role in human visceral leishmaniasis, a lethal disease characterised by intense parasite proliferation [14]. Th17 cells also participate in the host defence against extracellular bacterial and fungal pathogens, such as …”

Section: Resultsmentioning

confidence: 99%

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

et al. 2010

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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...

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Section: Resultsmentioning

confidence: 99%

“…2F) and CD14 1 (Fig. 2I) [4][5][6][7][8][9][10][11][12][13][14][15][16]. The local detection of CD8 1 IL-17 1 cells is of particular interest since a noncytotoxic 17 (Tc17) CD27 1/À CD28 1 CD45RA À subset has recently been described in other inflammatory diseases [17].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2010

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“…IFN-γ activates macrophages, leading to inducible nitric oxide synthase activation and concomitant nitric oxide production, which promotes parasite death 26,27 . Recently, the pro-infl ammatory cytokine IL-17 was also reported to have a protective role in L. donovani-induced VL 28 and in experimental L. (L.) chagasi infections by acting synergistically with IFN-γ to eliminate the parasite 29 .…”

Section: Discussionmentioning

confidence: 99%

Severe visceral leishmaniasis in children: the relationship between cytokine patterns and clinical features

Gama

Gomes

Sílveira

et al. 2013

Rev. Soc. Bras. Med. Trop.

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Revista da Sociedade Brasileira de Medicina Tropical 46(6):741-745, Nov-Dec, 2013http://dx.doi.org/10.1590/0037-8682-0203-2013 INTRODUCTION ABSTRACT Introduction:The relationship between severe clinical manifestations of visceral leishmaniasis (VL) and immune response profi les has not yet been clarifi ed, despite numerous studies on the subject. This study aimed to investigate the relationship between cytokine profi les and the presence of immunological markers associated with clinical manifestations and, particularly, signs of severity, as defi ned in a protocol drafted by the Ministry of Health (Brazil). Methods: We conducted a prospective, descriptive study between May 2008 and December 2009. This study was based on an assessment of all pediatric patients with VL who were observed in a reference hospital in Maranhão. Results: Among 27 children, 55.5% presented with more than one sign of severity or warning sign. Patients without signs of severity or warning signs and patients with only one warning sign had the highest interferon-gamma (IFN-γ) levels, although their interleukin 10 (IL-10) levels were also elevated. In contrast, patients with the features of severe disease had the lowest IFN-γ levels. Three patients who presented with more than two signs of severe disease died; these patients had undetectable interleukin 2 (IL-2) and IFN-γ levels and low IL-10 levels, which varied between 0 and 36.8pg/mL. Conclusions: Our results showed that disease severity was associated with low IFN-γ levels and elevated IL-10 levels. However, further studies with larger samples are needed to better characterize the relationship between disease severity and cytokine levels, with the aim of identifying immunological markers of active-disease severity.

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“…Such a causal link would imply that restoration of splenic architecture should improve immunocompetence in infected mice. IFN-γ, TNF, and IL-10 are key cytokines regulating host resistance and immunedependent chemotherapy against L. donovani (39,42), with data from human VL suggesting that IL-17A may also play a beneficial role (43). Therefore, we first sought to determine whether these cytokines could be detected directly ex vivo from mice infected with L. donovani and treated or not with Sm.…”

Section: Preconditioning With Sm Partially Restores Immunocompetence mentioning

confidence: 99%

Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

Dalton¹,

Maroof²,

Owens³

et al. 2010

J. Clin. Invest.

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Receptor tyrosine kinases are involved in multiple cellular processes, and drugs that inhibit their action are used in the clinic to treat several types of cancer. However, the value of receptor tyrosine kinase inhibitors (RTKIs) for treating infectious disease has yet to be explored. Here, we have shown in mice that administration of the broad-spectrum RTKI sunitinib maleate (Sm) blocked the vascular remodeling and progressive splenomegaly associated with experimental visceral leishmaniasis. Furthermore, Sm treatment restored the integrity of the splenic microarchitecture. Although restoration of splenic architecture was accompanied by an increase in the frequency of IFN-γ + CD4 + T cells, Sm treatment alone was insufficient to cause a reduction in tissue parasite burden. However, preconditioning by short-term Sm treatment proved to be successful as an adjunct therapy, increasing the frequency of IFN-γ + and IFN-γ + TNF + CD4 + T cells, enhancing NO production by splenic macrophages, and providing dose-sparing effects when combined with a first-line immune-dependent anti-leishmanial drug. We propose, therefore, that RTKIs may prove clinically useful as agents to restore immune competence before the administration of chemo-or immunotherapeutic drugs in the treatment of visceral leishmaniasis or other diseases involving lymphoid tissue remodeling, including cancer.

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IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani

Cited by 168 publications

References 46 publications

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

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

Severe visceral leishmaniasis in children: the relationship between cytokine patterns and clinical features

Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

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