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1.
Front Med (Lausanne) ; 8: 711623, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34692720

RESUMO

Erythema Nodosum Leprosum (ENL) is a recurrent acute inflammatory complication of leprosy affecting up to 50% of all Borderline Lepromatous and Lepromatous Leprosy (BL/LL) patients. Although ENL is described as an immune reaction mediated by neutrophils, studies demonstrating the direct role of neutrophils in ENL are still rare. One subpopulation of low-density neutrophils (LDNs), present within the fraction of peripheral blood mononuclear cells (PBMC), has been associated with the pathogenesis and severity of diseases like sepsis, lupus, and tuberculosis. We herein analyzed LDNs and high-density neutrophils (HDNs) in terms of frequency, phenotype, and morphology. Serum levels of MMP-9 (a neutrophilic degranulation marker) were evaluated by ELISA; and LDNs were generated in vitro by stimulating healthy-donor, whole-blood cultures. PBMC layers of ENL patients presented segmented/hypersegmented cells that were morphologically compatible with neutrophils. Immunofluorescence analyses identified LDNs in ENL. Flow cytometry confirmed the elevated frequency of circulating LDNs (CD14-CD15+) in ENL patients compared to healthy donors and nonreactional Borderline Tuberculoid (BT) patients. Moreover, flow cytometry analyses revealed that ENL LDNs had a neutrophilic-activated phenotype. ENL patients under thalidomide treatment presented similar frequency of LDNs as observed before treatment but its activation status was lower. In addition, Mycobacterium leprae induced in vitro generation of LDNs in whole blood in a dose-dependent fashion; and TGF-ß, an inhibitor of neutrophilic degranulation, prevented LDNs generation. MMP-9 serum levels of BL/LL patients with or without ENL correlated with LDNs frequency at the same time that ultrastructural observations of ENL LDNs showed suggestive signs of degranulation. Together, our data provide new insights into the knowledge and understanding of the pathogenesis of ENL while enriching the role of neutrophils in leprosy.

2.
PLoS Pathog ; 17(10): e1009972, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34695167

RESUMO

Transcriptional profiling is a powerful tool to investigate and detect human diseases. In this study, we used bulk RNA-sequencing (RNA-Seq) to compare the transcriptomes in skin lesions of leprosy patients or controls affected by other dermal conditions such as granuloma annulare, a confounder for paucibacillary leprosy. We identified five genes capable of accurately distinguishing multibacillary and paucibacillary leprosy from other skin conditions. Indoleamine 2,3-dioxygenase 1 (IDO1) expression alone was highly discriminatory, followed by TLR10, BLK, CD38, and SLAMF7, whereas the HS3ST2 and CD40LG mRNA separated multi- and paucibacillary leprosy. Finally, from the main differentially expressed genes (DEG) and enriched pathways, we conclude that paucibacillary disease is characterized by epithelioid transformation and granuloma formation, with an exacerbated cellular immune response, while multibacillary leprosy features epithelial-mesenchymal transition with phagocytic and lipid biogenesis patterns in the skin. These findings will help catalyze the development of better diagnostic tools and potential host-based therapeutic interventions. Finally, our data may help elucidate host-pathogen interplay driving disease clinical manifestations.


Assuntos
Marcadores Genéticos/genética , Hanseníase/diagnóstico , Hanseníase/genética , Transcriptoma , Perfilação da Expressão Gênica , Humanos , RNA Mensageiro/análise , RNA-Seq
3.
Cells ; 10(9)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34571865

RESUMO

Leprosy reactional episodes are acute inflammatory events that may occur during the clinical course of the disease. Type 1 reaction (T1R) is associated with an increase in neural damage, and the understanding of the molecular pathways related to T1R onset is pivotal for the development of strategies that may effectively control the reaction. Interferon-gamma (IFN-γ) is a key cytokine associated with T1R onset and is also associated with autophagy induction. Here, we evaluated the modulation of the autophagy pathway in Mycobacterium leprae-stimulated cells in the presence or absence of IFN-γ. We observed that IFN-γ treatment promoted autophagy activation and increased the expression of genes related to the formation of phagosomes, autophagy regulation and function, or lysosomal pathways in M. leprae-stimulated cells. IFN-γ increased interleukin (IL)-15 secretion in M. leprae-stimulated THP-1 cells in a process associated with autophagy activation. We also observed higher IL15 gene expression in multibacillary (MB) patients who later developed T1R during clinical follow-up when compared to MB patients who did not develop the episode. By overlapping gene expression patterns, we observed 13 common elements shared between T1R skin lesion cells and THP-1 cells stimulated with both M. leprae and IFN-γ. Among these genes, the autophagy regulator Translocated Promoter Region, Nuclear Basket Protein (TPR) was significantly increased in T1R cells when compared with non-reactional MB cells. Overall, our results indicate that IFN-γ may induce a TPR-mediated autophagy transcriptional program in M. leprae-stimulated cells similar to that observed in skin cells during T1R by a pathway that involves IL-15 production, suggesting the involvement of this cytokine in the pathogenesis of T1R.


Assuntos
Autofagia/genética , Interleucina-15/genética , Hanseníase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Criança , Citocinas/genética , Feminino , Expressão Gênica/genética , Humanos , Interferon gama/genética , Hanseníase/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/patogenicidade , Pele/metabolismo , Pele/microbiologia , Células THP-1/metabolismo , Adulto Jovem
4.
BMC Infect Dis ; 21(1): 858, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425777

RESUMO

BACKGROUND: Diagnosing neuritis in leprosy patients with neuropathic pain or chronic neuropathy remains challenging since no specific laboratory or neurophysiological marker is available. METHODS: In a cross-sectional study developed at a leprosy outpatient clinic in Rio de Janeiro, RJ, Brazil, 54 individuals complaining of neural pain (single or multiple sites) were classified into two groups ("neuropathic pain" or "neuritis") by a neurological specialist in leprosy based on anamnesis together with clinical and electrophysiological examinations. A neurologist, blind to the pain diagnoses, interviewed and examined the participants using a standardized form that included clinical predictors, pain features, and neurological symptoms. The association between the clinical predictors and pain classifications was evaluated via the Pearson Chi-Square or Fisher's exact test (p < 0.05). RESULTS: Six clinical algorithms were generated to evaluate sensitivity and specificity, with 95% confidence intervals, for clinical predictors statistically associated with neuritis. The most conclusive clinical algorithm was: pain onset at any time during the previous 90 days, or in association with the initiation of neurological symptoms during the prior 30-day period, necessarily associated with the worsening of pain upon movement and nerve palpation, with 94% of specificity and 35% of sensitivity. CONCLUSION: This algorithm could help physicians confirm neuritis in leprosy patients with neural pain, particularly in primary health care units with no access to neurologists or electrophysiological tests.


Assuntos
Hanseníase , Neuralgia , Neurite (Inflamação) , Brasil , Regras de Decisão Clínica , Estudos Transversais , Humanos , Hanseníase/complicações , Hanseníase/diagnóstico , Neurite (Inflamação)/diagnóstico
5.
Front Immunol ; 12: 662307, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34354699

RESUMO

The treatment of multibacillary cases of leprosy with multidrug therapy (MDT) comprises 12 doses of a combination of rifampicin, dapsone and clofazimine. Previous studies have described the immunological phenotypic pattern in skin lesions in multibacillary patients. Here, we evaluated the effect of MDT on skin cell phenotype and on the Mycobacterium leprae-specific immune response. An analysis of skin cell phenotype demonstrated a significant decrease in MRS1 (SR-A), CXCL10 (IP-10) and IFNG (IFN-γ) gene and protein expression after MDT release. Patients were randomized according to whether they experienced a reduction in bacillary load after MDT. A reduction in CXCL10 (IP-10) in sera was associated with the absence of a reduction in the bacillary load at release. Although IFN-γ production in response to M. leprae was not affected by MDT, CXCL10 (IP-10) levels in response to M. leprae increased in cells from patients who experienced a reduction in bacillary load after treatment. Together, our results suggest that CXCL10 (IP-10) may be a good marker for monitoring treatment efficacy in multibacillary patients.


Assuntos
Quimiocina CXCL10/sangue , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Pele/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carga Bacteriana/efeitos dos fármacos , Biomarcadores/sangue , Quimiocina CXCL10/imunologia , Quimioterapia Combinada , Feminino , Humanos , Hansenostáticos/administração & dosagem , Hanseníase/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Pele/microbiologia , Pele/patologia , Resultado do Tratamento , Adulto Jovem
6.
Front Med (Lausanne) ; 8: 698495, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447763

RESUMO

Leprosy remains endemic in several developing countries, such as India and Brazil, in part due to delayed diagnosis that facilitates ongoing transmission. Although immunoglobulins against several Mycobacterium leprae antigens have been indicated for the early diagnosis, and IgA participates in the early stages of leprosy and in subclinical infection, relatively little research has examined anti-M. leprae IgA responses. Here, we investigated serum IgA reactivity against NDO-HSA, LID-1 and NDO-LID, in paucibacillary (PB) and multibacillary (MB) patients and their household contacts, using enzyme-linked immunosorbent assay (ELISA). Diagnostic accuracy of each ELISA was evaluated by receiver operating characteristic (ROC) curve analysis. Our data reveal elevated IgA serum levels against the three M. leprae specific antigens in MB patients, whereas IgA reactivity in PB patients was increased only to NDO-HSA. Further, MB and PB household contacts displayed higher IgA reactivity to NDO-HSA than non-endemic controls. Our data suggest measurement of serum IgA against NDO-HSA as an additional tool in the diagnosis and classification of the disease, with potential utility for household contact follow-up.

8.
PLoS Negl Trop Dis ; 15(3): e0009214, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33690671

RESUMO

BACKGROUND: Leprosy continues to be a public health problem in Brazil. Furthermore, detection rates in elderly people have increased, particularly those of multibacillary (L-Lep) patients, who are responsible for transmitting M. leprae. Part of the decline in physiological function during aging is due to increased oxidative damage and change in T cell subpopulations, which are critical in defense against the disease. It is not still clear how age-related changes like those related to oxidation affect elderly people with leprosy. The aim of this work was to verify whether the elderly leprosy patients have higher ROS production and how it can impact the evolution of leprosy. METHODOLOGY/PRINCIPAL FINDINGS: 87 leprosy patients, grouped according to age range and clinical form of leprosy, and 25 healthy volunteers were analyzed. Gene expression analysis of antioxidant and oxidative burst enzymes were performed in whole blood using Biomark's microfluidic-based qPCR. The same genes were evaluated in skin lesion samples by RT-qPCR. The presence of oxidative damage markers (carbonylated proteins and 4-hydroxynonenal) was analyzed by a DNPH colorimetric assay and immunofluorescence. Carbonylated protein content was significantly higher in elderly compared to young patients. One year after multidrug therapy (MDT) discharge and M. leprae clearance, oxidative damage increased in young L-Lep patients but not in elderly ones. Both elderly T and L-Lep patients present higher 4-HNE in cutaneous lesions than the young, mainly surrounding memory CD8+ T cells. Furthermore, young L-Lep demonstrated greater ability to neutralize ROS compared to elderly L-Lep patients, who presented lower gene expression of antioxidant enzymes, mainly glutathione peroxidase. CONCLUSIONS/SIGNIFICANCE: We conclude that elderly patients present exacerbated oxidative damage both in blood and in skin lesions and that age-related changes can be an important factor in leprosy immunopathogenesis. Ultimately, elderly patients could benefit from co-supplementation of antioxidants concomitant to MDT, to avoid worsening of the disease.


Assuntos
Hansenostáticos/uso terapêutico , Hanseníase/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Aldeídos , Antioxidantes , Carga Bacteriana , Brasil , Estudos de Casos e Controles , Quimioterapia Combinada , Feminino , Humanos , Hansenostáticos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae , Estresse Oxidativo , Carbonilação Proteica , Pele/metabolismo , Pele/patologia
9.
Front Immunol ; 12: 647385, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777045

RESUMO

Leprosy is an infectious disease that remains endemic in approximately 100 developing countries, where about 200,000 new cases are diagnosed each year. Moreover, multibacillary leprosy, the most contagious form of the disease, has been detected at continuously higher rates among Brazilian elderly people. Due to the so-called immunosenescence, characterized by several alterations in the quality of the immune response during aging, this group is more susceptible to infectious diseases. In view of such data, the purpose of our work was to investigate if age-related alterations in the immune response could influence the pathogenesis of leprosy. As such, we studied 87 individuals, 62 newly diagnosed and untreated leprosy patients distributed according to the age range and to the clinical forms of the disease and 25 healthy volunteers, who were studied as controls. The frequency of senescent and memory CD8+ leukocytes was assessed by immunofluorescence of biopsies from cutaneous lesions, while the serum levels of IgG anti-CMV antibodies were analyzed by chemiluminescence and the gene expression of T cell receptors' inhibitors by RT-qPCR. We noted an accumulation of memory CD8+ T lymphocytes, as well as reduced CD8+CD28+ cell expression in skin lesions from elderly patients, when compared to younger people. Alterations in LAG3 and PDCD1 gene expression in cutaneous lesions of young MB patients were also observed, when compared to elderly patients. Such data suggest that the age-related alterations of T lymphocyte subsets can facilitate the onset of leprosy in elderly patients, not to mention other chronic inflammatory diseases.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Senescência Celular/imunologia , Memória Imunológica , Imunossenescência/imunologia , Hanseníase/imunologia , Mycobacterium leprae , Dermatopatias/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Antígenos CD/genética , Estudos de Casos e Controles , Citomegalovirus/imunologia , Feminino , Expressão Gênica , Humanos , Imunoglobulina G/sangue , Hanseníase/sangue , Hanseníase/microbiologia , Hanseníase/patologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Pele/imunologia , Pele/patologia , Dermatopatias/sangue , Dermatopatias/microbiologia , Dermatopatias/patologia , Adulto Jovem
10.
Sci Rep ; 11(1): 1947, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479421

RESUMO

Reduction in incidence has been associated with the introduction of novel approaches, like chemo/immune-prophylaxis. Incidence determined through follow-up cohort studies can evaluate the implementation of these innovative policies towards control and prevention. We have assessed the incidence in our contacts cohort over past 33 years, considering the effect of demographic and clinical variables. Survival analysis was used to estimate the risk of leprosy. A total of 9024 contacts were evaluated, of which 192 developed leprosy, resulting in an overall incidence of 1.4/1000 person-years. The multivariate analysis showed that the major risk factors were (i) contact from MB index cases and (ii) consanguinity (iii) intra household contact. Lower risk was detected for contacts with BCG scar who were revaccinated. There was a significant decrease in accumulated risk between the 2011-2019 period compared with 1987, probably linked to the improvement in laboratory tools to monitor contacts, thereby providing early diagnosis of contacts at intake and reduction of transmission. Our findings suggest that a combination of contact surveillance and tracing, adequate neurodermatological examination, and availability of molecular tools is highly effective in supporting early diagnosis, while a second dose of the BCG vaccination can exert extra protection.


Assuntos
Hanseníase/epidemiologia , Adolescente , Adulto , Vacina BCG/administração & dosagem , Criança , Estudos de Coortes , Busca de Comunicante , Feminino , Humanos , Incidência , Hanseníase/prevenção & controle , Hanseníase/transmissão , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Análise de Sobrevida , Adulto Jovem
11.
Muscle Nerve ; 63(4): 593-599, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33347629

RESUMO

BACKGROUND: The present study assesses the contributions of axonal degeneration and demyelination in leprosy nerve damage. New clinical strategies can emerge from an in-depth understanding of the pathogenesis of neural leprosy (NL). METHODS: Morphometric analysis of myelinated nerve fibers was performed on 44 nerve biopsy samples collected from leprosy patients. Measures of density, diameter distribution, g-ratios, and the counting of axonal ovoids on the myelinated fibers were taken and compared to those in the control group. RESULTS: The proportion of small myelinated fibers increased in the leprosy group while large fiber frequency decreased. Indicative of axonal atrophy, the g-ratio was lower in the leprosy group. The frequency of axonal ovoids was identical to that found in the non-leprosy neuropathies. CONCLUSIONS: Axonal atrophy, Wallerian degeneration, and demyelination coexist in NL. Axonal degeneration predominates over demyelination in the chronic course of the disease; however, this may change during leprosy reactive episodes. This study regards demyelination and axon degeneration as concurrent mechanisms of damage to nerve fibers in leprosy. It also calls into question the view that demyelination is the primary and predominant mechanism in the complex pathogeny of NL.


Assuntos
Axônios/patologia , Hanseníase Tuberculoide/patologia , Bainha de Mielina/patologia , Fibras Nervosas Mielinizadas/patologia , Doenças do Sistema Nervoso Periférico/patologia , Doenças Desmielinizantes/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Walleriana/patologia , Adulto Jovem
12.
Infect Dis Poverty ; 9(1): 167, 2020 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-33341111

RESUMO

BACKGROUND: Leprosy is a chronic infectious disease classified into two subgroups for therapeutic purposes: paucibacillary (PB) and multibacillary (MB), closely related to the host immune responses. In this context it is noteworthy looking for immunological biomarkers applicable as complementary diagnostic tools as well as a laboratorial strategy to follow-up leprosy household contacts. METHODS: The cross-sectional study enrolled 49 participants, including 19 patients and 30 healthy controls. Peripheral blood mononuclear cells (PBMC) were isolated and incubated in the presence of Mycobacterium leprae bacilli. The cells were prepared for surface (CD4+ and CD8+) and intracytoplasmic cytokine staining (IFN-γ, IL-4 and IL-10). Multiple comparisons amongst groups were carried out by ANOVA, Kruskal-Wallis, Student T or Mann-Whitney test. Comparative analysis of categorical variables was performed by Chi-square. Functional biomarker signature analysis was conducted using the global median values for each biomarker index as the cut-off edge to identify the proportion of subjects with high biomarker levels. RESULTS: The cytokine signature analysis demonstrated that leprosy patients presented a polyfunctional profile of T-cells subsets, with increased frequency of IFN-γ+ T-cell subsets along with IL-10+ and IL-4+ from CD4+ T-cells, as compared to health Controls (Venn diagram report). Moreover, statistical analysis was carried out using parametric or non-parametric variance analysis followed by pairwise multiple comparisons, according to the data normality distribution. L(PB) displayed a polyfunctional profile characterized by enhanced percentage of IFN-γ+, IL-10+ and IL-4+ produced by most T-cell subsets, as compared to L(MB) that presented a more restricted cytokine functional profile mediated by IL-10+ and IL-4+ T-cells with minor contribution of IFN-γ produced by CD4+ T-cells. Noteworthy was that HHC(MB) exhibited enhanced frequency of IFN-γ+ T-cells, contrasting with HHC(PB) that presented a cytokine profile limited to IL-10 and IL-4. CONCLUSIONS: Our data demonstrated that L(PB) displayed enhanced percentage of IFN-γ+, IL-10+ and IL-4+ as compared to L(MB) that presented functional profile mediated by IL-10+ and IL-4+ T-cells and HHC(MB) exhibited enhanced frequency of IFN-γ+ T-cells, contrasting with HHC(PB). Together, our findings provide additional immunological features associated with leprosy and household contacts. These data provide evidence that biomarkers of immune response can be useful complementary diagnostic/prognostic tools as well as insights that household contacts should be monitored to access putative subclinical infection.


Assuntos
Biomarcadores/sangue , Hanseníase/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Células Cultivadas , Criança , Busca de Comunicante , Estudos Transversais , Citocinas/imunologia , Saúde da Família , Feminino , Humanos , Hanseníase/classificação , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium lepraemurium/imunologia , Adulto Jovem
13.
Front Immunol ; 11: 1493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849508

RESUMO

In HIV-infected individuals, a paradoxical clinical deterioration may occur in preexisting leprosy when highly active antiretroviral therapy (HAART)-associated reversal reaction (RR) develops. Leprosy-HIV co-infected patients during HAART may present a more severe form of the disease (RR/HIV), but the immune mechanisms related to the pathogenesis of leprosy-HIV co-infection remain unknown. Although the adaptive immune responses have been extensively studied in leprosy-HIV co-infected individuals, recent studies have described that innate immune cells may drive the overall immune responses to mycobacterial antigens. Monocytes are critical to the innate immune system and play an important role in several inflammatory conditions associated with chronic infections. In leprosy, different tissue macrophage phenotypes have been associated with the different clinical forms of the disease, but it is not clear how HIV infection modulates the phenotype of innate immune cells (monocytes or macrophages) during leprosy. In the present study, we investigated the phenotype of monocytes and macrophages in leprosy-HIV co-infected individuals, with or without RR. We did not observe differences between the monocyte profiles in the studied groups; however, analysis of gene expression within the skin lesion cells revealed that the RR/HIV group presents a higher expression of macrophage scavenger receptor 1 (MRS1), CD209 molecule (CD209), vascular endothelial growth factor (VEGF), arginase 2 (ARG2), and peroxisome proliferator-activated receptor gamma (PPARG) when compared with the RR group. Our data suggest that different phenotypes of tissue macrophages found in the skin from RR and RR/HIV patients could differentially contribute to the progression of leprosy.


Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/imunologia , HIV-1/fisiologia , Hanseníase/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Mycobacterium leprae/fisiologia , Adulto , Idoso , Diferenciação Celular , Coinfecção , Progressão da Doença , Feminino , Infecções por HIV/complicações , Infecções por HIV/terapia , Humanos , Hanseníase/complicações , Hanseníase/terapia , Masculino , Pessoa de Meia-Idade , Receptores Depuradores Classe A/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-32340990

RESUMO

A case of Mycobacterium leprae rifampin resistance after irregular antileprosy treatments since 1971 is reported. Whole-genome sequencing from four longitudinal samples indicated relapse due to acquired rifampin resistance and not to reinfection with another strain. A putative compensatory mutation in rpoC was also detected. Clinical improvement was achieved using an alternative therapy.


Assuntos
Hanseníase , Mycobacterium leprae , Humanos , Hanseníase/tratamento farmacológico , Mutação , Mycobacterium leprae/genética , Recidiva , Rifampina/farmacologia
15.
Front Immunol ; 11: 23, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32038662

RESUMO

Pain is a frequent symptom in leprosy patients. It may be predominantly nociceptive, as in neuritis, or neuropathic, due to injury or nerve dysfunction. The differential diagnosis of these two forms of pain is a challenge in clinical practice, especially because it is quite common for a patient to suffer from both types of pain. A better understanding of cytokine profile may serve as a tool in assessing patients and also help to comprehend pathophysiology of leprosy pain. Patients with leprosy and neural pain (n = 22), neuropathic pain (n = 18), neuritis (nociceptive pain) (n = 4), or no pain (n = 17), further to those with diabetic neuropathy and neuropathic pain (n = 17) were recruited at Souza Araujo Out-Patient Unit (Fiocruz, Rio de Janeiro, RJ, Brazil). Serum levels of IL1ß, IL-6, IL-10, IL-17, TNF, CCL-2/MCP-1, IFN-γ, CXCL-10/IP-10, and TGF-ß were evaluated in the different Groups. Impairment in thermal or pain sensitivity was the most frequent clinical finding (95.5%) in leprosy neuropathy patients with and without pain, but less frequent in Diabetic Group (88.2%). Previous reactional episodes have occurred in patients in the leprosy and Pain Group (p = 0.027) more often. Analysis of cytokine levels have demonstrated that the concentrations of IL-1ß, TNF, TGF-ß, and IL-17 in serum samples of patients having leprosy neuropathy in combination with neuropathic or nociceptive pain were higher when compared to the samples of leprosy neuropathy patients without pain. In addition, these cytokine levels were significantly augmented in leprosy patients with neuropathic pain in relation to those with neuropathic pain due to diabetes. IL-1ß levels are an independent variable associated with both types of pain in patients with leprosy neuropathy. IL-6 concentration was increased in both groups with pain. Moreover, CCL-2/MCP-1 and CXCL-10/IP-10 levels were higher in patients with diabetic neuropathy over those with leprosy neuropathy. In brief, IL-1ß is an independent variable related to neuropathic and nociceptive pain in patients with leprosy, and could be an important biomarker for patient follow-up. IL-6 was higher in both groups with pain (leprosy and diabetic patients), and could be a therapeutic target in pain control.


Assuntos
Neuropatias Diabéticas/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Hanseníase/sangue , Neuralgia/sangue , Neurite (Inflamação)/sangue , Idoso , Biomarcadores/sangue , Brasil/epidemiologia , Estudos Transversais , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/epidemiologia , Diagnóstico Diferencial , Feminino , Humanos , Hanseníase/diagnóstico , Hanseníase/epidemiologia , Masculino , Pessoa de Meia-Idade , Neuralgia/diagnóstico , Neuralgia/epidemiologia , Neurite (Inflamação)/diagnóstico , Neurite (Inflamação)/epidemiologia , Estudos Retrospectivos
16.
Immunohorizons ; 4(2): 47-56, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034084

RESUMO

Erythema nodosum leprosum (ENL) is an inflammatory complication in leprosy. Yet, the involvement of ENL neutrophils in the inflammatory response against Mycobacterium leprae remains poorly explored. Our primary aim was to investigate the utility of the surface expression of neutrophil IL-10R1 as an ENL biomarker and, secondarily, to evaluate whether leprosy or healthy M. leprae-stimulated neutrophils produce cytokines and are able to respond to IL-10. We, in this study, describe a subpopulation of circulating neutrophils of ENL patients that exclusively expressed IL-10R1, providing evidence that IL-10R1+ neutrophils are present in ENL lesions. It was also found that ENL neutrophils, but not those of nonreactional leprosy controls, were able to secret detectable levels of TNF ex vivo and the addition of IL-10 blocked TNF release. It was likewise observed that M. leprae-stimulated, healthy neutrophils expressed IL-10R1 in vitro, and ENL-linked cytokines were released by M. leprae-cultured neutrophils in vitro. Moreover, consistent with the presence of a fully functional IL-10R, the addition of IL-10 prevented the release of M. leprae-induced cytokines. Most importantly, dead M. leprae revealed its superior capacity to induce CCL4 and IL-8 in primary neutrophils over live Mycobacterium, suggesting that M. leprae may hamper the inflammatory machinery as an immune escape mechanism.


Assuntos
Eritema Nodoso/imunologia , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Interleucina-10/farmacologia , Hanseníase Virchowiana/imunologia , Neutrófilos/metabolismo , Pele/imunologia , Adulto , Células Cultivadas , Citocinas/metabolismo , Eritema Nodoso/tratamento farmacológico , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Hanseníase Virchowiana/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/microbiologia , Talidomida/uso terapêutico , Adulto Jovem
17.
Cell Microbiol ; 22(1): e13128, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31652371

RESUMO

Leprosy neuropathy is a chronic degenerative infectious disorder of the peripheral nerve caused by the intracellular obligate pathogen Mycobacterium leprae (M. leprae). Among all nonneuronal cells that constitute the nerve, Schwann cells are remarkable in supporting M. leprae persistence intracellularly. Notably, the success of leprosy infection has been attributed to its ability in inducing the demyelination phenotype after contacting myelinated fibres. However, the exact role M. leprae plays during the ongoing process of myelin breakdown is entirely unknown. Here, we provided evidence showing an unexpected predilection of leprosy pathogen for degenerating myelin ovoids inside Schwann cells. In addition, M. leprae infection accelerated the rate of myelin breakdown and clearance leading to increased formation of lipid droplets, by modulating a set of regulatory genes involved in myelin maintenance, autophagy, and lipid storage. Remarkably, the blockage of myelin breakdown significantly reduced M. leprae content, demonstrating a new unpredictable role of myelin dismantling favouring M. leprae physiology. Collectively, our study provides novel evidence that may explain the demyelination phenotype as an evolutionarily conserved mechanism used by leprosy pathogen to persist longer in the peripheral nerve.


Assuntos
Mycobacterium leprae/fisiologia , Bainha de Mielina/metabolismo , Células de Schwann/microbiologia , Animais , Células Cultivadas , Humanos , Hanseníase/complicações , Hanseníase/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium leprae/patogenicidade , Bainha de Mielina/microbiologia
18.
s.l; s.n; 2020. 8 p. graf.
Não convencional em Inglês | SES-SP, HANSEN, SESSP-ILSLPROD, SES-SP, SESSP-ILSLACERVO, SES-SP | ID: biblio-1102410

RESUMO

Leprosy neuropathy is a chronic degenerative infectious disorder of the peripheral nerve caused by the intracellular obligate pathogen Mycobacterium leprae (M. leprae). Among all nonneuronal cells that constitute the nerve, Schwann cells are remarkable in supporting M. leprae persistence intracellularly. Notably, the success of leprosy infection has been attributed to its ability in inducing the demyelination phenotype after contacting myelinated fibres. However, the exact role M. leprae plays during the ongoing process of myelin breakdown is entirely unknown. Here, we provided evidence showing an unexpected predilection of leprosy pathogen for degenerating myelin ovoids inside Schwann cells. In addition, M. leprae infection accelerated the rate of myelin breakdown and clearance leading to increased formation of lipid droplets, by modulating a set of regulatory genes involved in myelin maintenance, autophagy, and lipid storage. Remarkably, the blockage of myelin breakdown significantly reduced M. leprae content, demonstrating a new unpredictable role of myelin dismantling favouring M. leprae physiology. Collectively, our study provides novel evidence that may explain the demyelination phenotype as an evolutionarily conserved mechanism used by leprosy pathogen to persist longer in the peripheral nerve.


Assuntos
Células de Schwann/microbiologia , Doenças do Sistema Nervoso Periférico/metabolismo , Mycobacterium leprae/patogenicidade , Bainha de Mielina/microbiologia , Doenças Desmielinizantes/microbiologia , Hanseníase/complicações
19.
PLoS Negl Trop Dis ; 13(9): e0007368, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31504035

RESUMO

Up to 50% of patients with the multibacillary form of leprosy are expected to develop acute systemic inflammatory episodes known as type 2 reactions (T2R), thus aggravating their clinical status. Thalidomide rapidly improves T2R symptoms. But, due to its restricted use worldwide, novel alternative therapies are urgently needed. The T2R triggering mechanisms and immune-inflammatory pathways involved in its pathology remain ill defined. In a recent report, we defined the recognition of nucleic acids by TLR9 as a major innate immunity pathway that is activated during T2R. DNA recognition has been described as a major inflammatory pathway in several autoimmune diseases, and neutrophil DNA extracellular traps (NETs) have been shown to be a prime source of endogenous DNA. Considering that neutrophil abundance is a marked characteristic of T2R lesions, the objective of this study was to investigate NETs production in T2R patients based on the hypothesis that the excessive NETs formation would play a major role in T2R pathogenesis. Abundant NETs were found in T2R skin lesions, and increased spontaneous NETs formation was observed in T2R peripheral neutrophils. Both the M. leprae whole-cell sonicate and the CpG-Hlp complex, mimicking a mycobacterial TLR9 ligand, were able to induce NETs production in vitro. Moreover, TLR9 expression was shown to be higher in T2R neutrophils, suggesting that DNA recognition via TLR9 may be one of the pathways triggering this process during T2R. Finally, treatment of T2R patients with thalidomide for 7 consecutive days resulted in a decrease in all of the evaluated in vivo and ex vivo NETosis parameters. Altogether, our findings shed light on the pathogenesis of T2R, which, it is hoped, will contribute to the emergence of novel alternative therapies and the identification of prognostic reactional markers in the near future.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata , Hanseníase/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/imunologia , Doenças Autoimunes/microbiologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Hanseníase/tratamento farmacológico , Hanseníase/patologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Mycobacterium leprae/patogenicidade , Neutrófilos/patologia , Talidomida/administração & dosagem , Talidomida/uso terapêutico
20.
Mem Inst Oswaldo Cruz ; 114: e190056, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389520

RESUMO

BACKGROUND: Fibrosis in the peripheral nerve is the end stage of leprous neuropathy and the cause of the resulting permanent neural function impairments. Preventive measures to avoid this irreversible pathological state are a relief strategy for leprosy sufferers. OBJECTIVES: The present study describes the frequency of fibrosis along with its characterisation and pathogenic development. METHODS: Six-hundred-and-thirteen nerve samples were sorted from 278 neural leprosy (NL) and 335 non-leprosy neuropathy patients (ON). The total number of samples was histologically examined by routine staining methods (haematoxylin-eosin, Wade staining and Gomori's trichrome) and fibrosis was evaluated via semi-quantitative estimation. FINDINGS: Fibrosis was most frequent in the NL group (33% against 0.4% in ON) while fibrosis in association with endoneurial microfasciculation was found in 38 (41.3%) of the NL samples in the examination of semithin sections. Pericytic activation in the perivascular environment was confirmed to be the source of the fibroblasts and perineurial cells delimiting microfascicles. End-stage fibrosis in leprosy displays an arrangement of microfascicles devoid of neural components (i.e., Schwann cells and axons) lined by an intermediate phenotype of fibroblastic-perineurial cells filled with bundles of collagen fibres. MAIN CONCLUSIONS: The present study underscores that fibrosis is frequently the severe end stage of neural leprosy NL pathogeny after analysing the notably distinct development of fibrosis within the neural environment.


Assuntos
Fibrose/patologia , Hanseníase Tuberculoide/patologia , Nervos Periféricos/patologia , Biópsia , Humanos , Imuno-Histoquímica , Doenças do Sistema Nervoso Periférico/patologia , Células de Schwann/patologia
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