In situ characterization of the granulomatous immune response with time in nonhealing lesional skin of Leishmania braziliensis-infected rhesus macaques (Macaca mulatta)

Souza-Lemos, C; de-Campos, Simone Neves; Têva, Antônio; Porrozzi, Renato; Grimaldi, Gabriel

doi:10.1016/j.vetimm.2011.05.002

Cited by 20 publications

(12 citation statements)

References 33 publications

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“…Additionally, FOXP3 expression was upregulated at skin sites of challenge with leishmanin antigen only in CDL patients. These results are consistent with several examples of chronic disease in which Foxp3 is upregulated in T cells [43]–[46] and previous reports of infiltration of dermal lesions caused by L. guyanensis and L. brazilienisis by Foxp3 + cells [15], [16], [47] and upregulation of FOXP3 in lesions from post Kala Azar DL [48]. Foxp3 may therefore constitute a marker for chronic DL caused by L. (Viannia) species.…”

Section: Discussionsupporting

confidence: 92%

Regulatory T Cells in the Pathogenesis and Healing of Chronic Human Dermal Leishmaniasis Caused by Leishmania (Viannia) Species

et al. 2012

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BackgroundThe inflammatory response is prominent in the pathogenesis of dermal leishmaniasis. We hypothesized that regulatory T cells (Tregs) may be diminished in chronic dermal leishmaniasis (CDL) and contribute to healing during treatment.Methodology/Principal FindingsThe frequency and functional capacity of Tregs were evaluated at diagnosis and following treatment of CDL patients having lesions of ≥6 months duration and asymptomatically infected residents of endemic foci. The frequency of CD4+CD25hi cells expressing Foxp3 or GITR or lacking expression of CD127 in peripheral blood was determined by flow cytometry. The capacity of CD4+CD25+ cells to inhibit Leishmania-specific responses was determined by co-culture with effector CD4+CD25− cells. The expression of FOXP3, IFNG, IL10 and IDO was determined in lesion and leishmanin skin test site biopsies by qRT-PCR. Although CDL patients presented higher frequency of CD4+CD25hiFoxp3+ cells in peripheral blood and higher expression of FOXP3 at leishmanin skin test sites, their CD4+CD25+ cells were significantly less capable of suppressing antigen specific-IFN-γ secretion by effector cells compared with asymptomatically infected individuals. At the end of treatment, both the frequency of CD4+CD25hiCD127− cells and their capacity to inhibit proliferation and IFN-γ secretion increased and coincided with healing of cutaneous lesions. IDO was downregulated during healing of lesions and its expression was positively correlated with IFNG but not FOXP3.Conclusions/SignificanceThe disparity between CD25hiFoxp3+ CD4 T cell frequency in peripheral blood, Foxp3 expression at the site of cutaneous responses to leishmanin, and suppressive capacity provides evidence of impaired Treg function in the pathogenesis of CDL. Moreover, the concurrence of increased Leishmania-specific suppressive capacity with induction of a CD25hiCD127− subset of CD4 T cells during healing supports the participation of Tregs in the resolution of chronic dermal lesions. Treg subsets may therefore be relevant in designing immunotherapeutic strategies for recalcitrant dermal leishmaniasis caused by Leishmania (Viannia) species.

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Section: Discussionsupporting

confidence: 92%

Regulatory T Cells in the Pathogenesis and Healing of Chronic Human Dermal Leishmaniasis Caused by Leishmania (Viannia) Species

et al. 2012

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“…Nevertheless, in our in vitro model, the blocking of IL-10 in the Mtb-derived conditioned media seems to be sufficient to impair STAT3 activation and the establishment of M2-like phenotype. This is in line with the fact that IL-10 is considered to be an important clinical biomarker of disease progression [54], increased levels for this cytokine are reported in both the blood [31,55] and in the bronchoalveolar lavage of active TB patients [56], and in the tuberculous granuloma context in NHP model [57]. The fact that we observed elevated levels of activated STAT3 in monocyte-macrophages in both TB patients and in the NHP tuberculous granuloma context, suggests that overactive production of IL-10 may be responsible.…”

Section: Discussionsupporting

confidence: 68%

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

et al. 2015

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The human CD14 + monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16 + monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti-inflammatory (M2-like) macrophage activation program characterized by the CD16 + CD163 + MerTK + pSTAT3 + phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16 + CD163 + MerTK + pSTAT3 + cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16 + C-D163 + MerTK + pSTAT3 + monocyte-to-macrophage differentiation program and its potential as a target for TB therapy, and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoring of treatment efficacy.

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“…In the present work, patients with lupoid CL disease had a significantly higher frequency of Foxp3+ in their peripheral blood than infected individuals who did not develop lupoid CL disease. These findings are consistent with previous reports of infiltration of dermal lesions caused by Leishmania guyanensis and Leishmania brazilienisis by Foxp3+ cells as well as several published studies on chronic disease that found Foxp3 upregulation in T cells and in lesions from post‐kala‐Azar dermal leishmaniasis . Rodriguez et al classified FOXP3 as a marker for chronic dermal leishmaniasis caused by Leishmania Viannia species .…”

Section: Discussionsupporting

confidence: 92%

Increased Th17 functions are accompanied by Tregs activities in lupoid leishmaniasis

Nabavi

Pezeshkpoor

Valizadeh

et al. 2017

Parasite Immunology

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The immunopathogenesis of lupoid leishmaniasis is challenging. Although an appropriate immune response is critical for controlling these parasites, inappropriate inflammatory reactions can also promote increased pathology. The role of immune modulatory effect of the main transcription factors and cytokines of T regulatory and Th17 cells in pathogenesis of leishmaniasis chronicity was investigated in this study. The gene expression of interleukin-10 (IL-10), transforming growth factor-β (TGF-β1), forkhead box P3 (Foxp3), interleukin-17(IL-17A) and retinoic acid-related orphan receptor gamma t (ROrC) was assessed in peripheral blood mononuclear cells of eighty blood samples from cutaneous leishmaniasis (CL) patients with usual lesions (n = 31), lupoid lesions (n = 29) and healthy volunteers (n = 20). Quantitative relative real-time PCR (qRT-PCR) was performed using the Taqman and Sybergreen methods for expression of target genes. Expression of Foxp3 (P = .013), IL-10 (P < .001) and IL-17A (P < .001) was significantly higher in lupoid patient compare to the nonlupoid group. Expression of Foxp3 (P < .001), IL-10 (P < .001) and IL-17A (P = .033) was significantly more in nonlupoid subjects than in healthy volunteers, except for RORγt. These findings suggest that Foxp3 cells, IL-10 and IL-17 play important roles in the immunopathogenesis of CL and that these roles differ depending on the causal leishmania species and different body compartments.

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In situ characterization of the granulomatous immune response with time in nonhealing lesional skin of Leishmania braziliensis-infected rhesus macaques (Macaca mulatta)

Cited by 20 publications

References 33 publications

Regulatory T Cells in the Pathogenesis and Healing of Chronic Human Dermal Leishmaniasis Caused by Leishmania (Viannia) Species

Regulatory T Cells in the Pathogenesis and Healing of Chronic Human Dermal Leishmaniasis Caused by Leishmania (Viannia) Species

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

Increased Th17 functions are accompanied by Tregs activities in lupoid leishmaniasis

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