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1.
F1000Res ; 92020.
Artículo en Inglés | MEDLINE | ID: mdl-32051758

RESUMEN

Chronic infection by the obligate intracellular pathogen Mycobacterium leprae may lead to the development of leprosy. Of note, in the lepromatous clinical form of the disease, failure of the immune system to constrain infection allows the pathogen to reproduce to very high numbers with minimal clinical signs, favoring transmission. The bacillus can modulate cellular metabolism to support its survival, and these changes directly influence immune responses, leading to host tolerance, permanent disease, and dissemination. Among the metabolic changes, upregulation of cholesterol, phospholipids, and fatty acid biosynthesis is particularly important, as it leads to lipid accumulation in the host cells (macrophages and Schwann cells) in the form of lipid droplets, which are sites of polyunsaturated fatty acid-derived lipid mediator biosynthesis that modulate the inflammatory and immune responses. In Schwann cells, energy metabolism is also subverted to support a lipogenic environment. Furthermore, effects on tryptophan and iron metabolisms favor pathogen survival with moderate tissue damage. This review discusses the implications of metabolic changes on the course of M. leprae infection and host immune response and emphasizes the induction of regulatory T cells, which may play a pivotal role in immune modulation in leprosy.

2.
Front Immunol ; 11: 23, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32038662

RESUMEN

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.

3.
Sci Rep ; 9(1): 17931, 2019 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-31784594

RESUMEN

Early diagnosis of leprosy is challenging, particularly its inflammatory reactions, the major cause of irreversible neuropathy in leprosy. Current diagnostics cannot identify which patients are at risk of developing reactions. This study assessed blood RNA expression levels as potential biomarkers for leprosy. Prospective cohorts of newly diagnosed leprosy patients, including reactions, and healthy controls were recruited in Bangladesh, Brazil, Ethiopia and Nepal. RNA expression in 1,090 whole blood samples was determined for 103 target genes for innate and adaptive immune profiling by dual color Reverse-Transcription Multiplex Ligation-dependent Probe Amplification (dcRT-MLPA) followed by cluster analysis. We identified transcriptomic biomarkers associated with leprosy disease, different leprosy phenotypes as well as high exposure to Mycobacterium leprae which respectively allow improved diagnosis and classification of leprosy patients and detection of infection. Importantly, a transcriptomic signature of risk for reversal reactions consisting of five genes (CCL2, CD8A, IL2, IL15 and MARCO) was identified based on cross-sectional comparison of RNA expression. In addition, intra-individual longitudinal analyses of leprosy patients before, during and after treatment of reversal reactions, indicated that several IFN-induced genes increased significantly at onset of reaction whereas IL15 decreased. This multi-site study, situated in four leprosy endemic areas, demonstrates the potential of host transcriptomic biomarkers as correlates of risk for leprosy. Importantly, a prospective five-gene signature for reversal reactions could predict reversal reactions at least 2 weeks before onset. Thus, transcriptomic biomarkers provide promise for early detection of these acute inflammatory episodes and thereby help prevent permanent neuropathy and disability in leprosy patients.

4.
Front Immunol ; 9: 1223, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29915584

RESUMEN

Leprosy reactions are responsible for incapacities in leprosy and represent the major cause of permanent neuropathy. The identification of biomarkers able to identify patients more prone to develop reaction could contribute to adequate clinical management and the prevention of disability. Reversal reaction may occur in unstable borderline patients and also in lepromatous patients. To identify biomarker signature profiles related with the reversal reaction onset, multibacillary patients were recruited and classified accordingly the occurrence or not of reversal reaction during or after multidrugtherapy. Analysis of skin lesion cells at diagnosis of multibacillary leprosy demonstrated that in the group that developed reaction (T1R) in the future there was a downregulation of autophagy associated with the overexpression of TLR2 and MLST8. The autophagy impairment in T1R group was associated with increased expression of NLRP3, caspase-1 (p10) and IL-1ß production. In addition, analysis of IL-1ß production in serum from multibacillary patients demonstrated that patients who developed reversal reaction have significantly increased concentrations of IL-1ß at diagnosis, suggesting that the pattern of innate immune responses could predict the reactional episode outcome. In vitro analysis demonstrated that the blockade of autophagy with 3-methyladenine (3-MA) in Mycobacterium leprae-stimulated human primary monocytes increased the assembly of NLRP3 specks assembly, and it was associated with an increase of IL-1ß and IL-6 production. Together, our data suggest an important role for autophagy in multibacillary leprosy patients to avoid exacerbated inflammasome activation and the onset of reversal reaction.


Asunto(s)
Autofagia , Inflamasomas/metabolismo , Lepra Multibacilar/etiología , Lepra Multibacilar/metabolismo , Adulto , Anciano , Biomarcadores , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Interleucina-1beta/metabolismo , Lepra Multibacilar/patología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/microbiología , Mycobacterium leprae/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Transducción de Señal , Transcriptoma
5.
Trials ; 19(1): 244, 2018 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-29685164

RESUMEN

BACKGROUND: The annual new-case detection rate for leprosy, while generally stable over the last decade, shows that transmission rates have remained stagnant despite the successful worldwide administration of multidrug therapy since the 1980s. As such, novel control strategies are urgently needed. Focusing on managing leprosy patient contacts, the most susceptible to contracting the disease, has been seen as a potential strategy in limiting the spread of leprosy as shown by a number of recent epidemiological studies. Immunoprophylaxis with Bacillus Calmette-Guérin (BCG) has been seen as an effective preventive measure due to its ability to stimulate the development of cellular immunity which is essential in controlling the disease, especially in its multibacillary (MB) forms. The association of immunoprophylaxis with chemoprophylaxis in a single dose of rifampicin has been shown to be a promising preventive strategy, although a variety of studies have found instances of early case detection just a few months after BCG vaccination. METHODS/DESIGN: The present study is a phase IV chemoprophylactic clinical trial consisting of administration of a single dose of rifampicin in MB leprosy patient contacts under care at the Souza Araújo Outpatient Clinic/FIOCRUZ as part of a randomized (2:1), double-blind, placebo-controlled study. It is comprised of two groups: 1) rifampicin + BCG; and 2) placebo + BCG. DISCUSSION: The aim is to evaluate whether the use of chemoprophylaxis with a single dose of rifampicin in MB leprosy patient contacts prior to the BCG vaccine would be able to prevent the onset of leprosy in those cases that may occur just a few months after vaccination. Contact subclinical infections (polymerase chain reaction) and the immunological parameters (anti-PGL-1, anti-LID-1, and IFN-γ) will be evaluated and the results will be compared after 12 months of follow-up. TRIAL REGISTRATION: The Brazilian Registry of Clinical Trials (ReBEC), RBR-69QK5P . Retrospectively registered on 1 June 2017.


Asunto(s)
Vacuna BCG/administración & dosificación , Trazado de Contacto , Leprostáticos/administración & dosificación , Lepra Multibacilar/prevención & control , Rifampin/administración & dosificación , Adolescente , Adulto , Anciano , Vacuna BCG/efectos adversos , Brasil , Niño , Preescolar , Ensayos Clínicos Fase IV como Asunto , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Lactante , Leprostáticos/efectos adversos , Lepra Multibacilar/inmunología , Lepra Multibacilar/microbiología , Lepra Multibacilar/transmisión , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Rifampin/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Vacunación , Adulto Joven
6.
Front Immunol ; 9: 518, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29643852

RESUMEN

Leprosy is an infectious disease that may present different clinical forms depending on host immune response to Mycobacterium leprae. Several studies have clarified the role of various T cell populations in leprosy; however, recent evidences suggest that local innate immune mechanisms are key determinants in driving the disease to its different clinical manifestations. Leprosy is an ideal model to study the immunoregulatory role of innate immune molecules and its interaction with nervous system, which can affect homeostasis and contribute to the development of inflammatory episodes during the course of the disease. Macrophages, dendritic cells, neutrophils, and keratinocytes are the major cell populations studied and the comprehension of the complex networking created by cytokine release, lipid and iron metabolism, as well as antimicrobial effector pathways might provide data that will help in the development of new strategies for leprosy management.


Asunto(s)
Inmunidad Innata , Lepra/inmunología , Animales , Humanos , Lepra/patología , Lepra/transmisión , Mycobacterium leprae/fisiología
7.
Mem Inst Oswaldo Cruz ; 113(5): e170467, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29513821

RESUMEN

BACKGROUND Leprosy remains a health problem in many countries, with difficulties in diagnosis resulting in delayed treatment and more severe disabilities. Antibodies against several Mycobacterium leprae antigens have, however, shown value as diagnostic and/or prognostic markers. OBJECTIVES The objective of this study was to evaluate serum immunoglobulin (Ig) IgM and IgG subclass reactivity against three M. leprae specific antigens: NDO-HSA, a conjugate formed by natural octyl disaccharide bound to human serum albumin; LID-1, the fusion protein product of the ml0405 and ml2331 genes; and NDO-LID, a combination of LID-1 and NDO. METHODS Sera from healthy controls, paucibacillary (PB) and multibacillary (MB) leprosy patients, and their respective household contacts, were evaluated for the presence of antigen-specific IgM, IgG, and IgG subclass antibodies by enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity of each ELISA were evaluated by receiver operating characteristic (ROC) curve analysis. FINDINGS Our data confirm that serum IgM antibodies against NDO-HSA and IgG antibodies against LID-1, as well as IgG/M antibodies against NDO-LID, are markedly increased in MB patients. For the first time, our data reveal a selective increase in IgG1 and IgG3 antibodies against LID-1 and NDO-LID in MB patients, demonstrating that these antibody isotypes are suitable for differentiation between MB and PB patients. ROC curve analysis indicates an improved capacity for diagnosing MB leprosy patients using the detection of IgG antibodies, particularly the IgG1 isotype, specific to LID-1 and NDO-LID over the performance levels attained with NDO-HSA. CONCLUSIONS Our findings indicate that serological tests based on the detection of antigen-specific IgG1 antibodies are a useful tool to differentiate MB from PB patients, and indicate the enhanced performance of the LID-1 and NDO-LID antigens in the serodiagnosis of leprosy.


Asunto(s)
Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Lepra Multibacilar/diagnóstico , Lepra Paucibacilar/diagnóstico , Estudios de Casos y Controles , Trazado de Contacto , Ensayo de Inmunoadsorción Enzimática , Humanos , Lepra Multibacilar/inmunología , Lepra Paucibacilar/inmunología , Mycobacterium leprae/inmunología , Curva ROC , Sensibilidad y Especificidad
8.
Mem. Inst. Oswaldo Cruz ; 113(5): e170467, 2018. tab, graf
Artículo en Inglés | LILACS | ID: biblio-894925

RESUMEN

BACKGROUND Leprosy remains a health problem in many countries, with difficulties in diagnosis resulting in delayed treatment and more severe disabilities. Antibodies against several Mycobacterium leprae antigens have, however, shown value as diagnostic and/or prognostic markers. OBJECTIVES The objective of this study was to evaluate serum immunoglobulin (Ig) IgM and IgG subclass reactivity against three M. leprae specific antigens: NDO-HSA, a conjugate formed by natural octyl disaccharide bound to human serum albumin; LID-1, the fusion protein product of the ml0405 and ml2331 genes; and NDO-LID, a combination of LID-1 and NDO. METHODS Sera from healthy controls, paucibacillary (PB) and multibacillary (MB) leprosy patients, and their respective household contacts, were evaluated for the presence of antigen-specific IgM, IgG, and IgG subclass antibodies by enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity of each ELISA were evaluated by receiver operating characteristic (ROC) curve analysis. FINDINGS Our data confirm that serum IgM antibodies against NDO-HSA and IgG antibodies against LID-1, as well as IgG/M antibodies against NDO-LID, are markedly increased in MB patients. For the first time, our data reveal a selective increase in IgG1 and IgG3 antibodies against LID-1 and NDO-LID in MB patients, demonstrating that these antibody isotypes are suitable for differentiation between MB and PB patients. ROC curve analysis indicates an improved capacity for diagnosing MB leprosy patients using the detection of IgG antibodies, particularly the IgG1 isotype, specific to LID-1 and NDO-LID over the performance levels attained with NDO-HSA. CONCLUSIONS Our findings indicate that serological tests based on the detection of antigen-specific IgG1 antibodies are a useful tool to differentiate MB from PB patients, and indicate the enhanced performance of the LID-1 and NDO-LID antigens in the serodiagnosis of leprosy.


Asunto(s)
Inmunoglobulina G/sangre , Lepra Multibacilar/diagnóstico , Lepra Paucibacilar/diagnóstico , Mycobacterium leprae/inmunología , Curva ROC , Sensibilidad y Especificidad
9.
J Infect Dis ; 216(12): 1635-1643, 2017 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-29272525

RESUMEN

Background: Leprosy, the leading infectious cause of disability worldwide, remains a major public health challenge in the most severely affected countries despite the sharp decline in new cases in recent years. The search for biomarkers is essential to achieve a better understanding of the molecular and cellular mechanisms underlying the disease. Methods: Pentraxin-3 (PTX3) analyses of sera from 87 leprosy patients with or without reactions were conducted via enzyme-linked immunosorbent assay. In situ identification of PTX3 in skin lesion was confirmed by quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, and immunofluorescence assays. Results: We found that PTX3 serum levels were higher in multibacillary patients when evaluated before the onset of acute erythema nodosum leprosum (ENL) and persistently elevated during reaction. Thalidomide treatment reduced PTX3 in the serum 7 days after starting treatment. In situ analyses have also demonstrated enhancement of PTX3 in ENL lesions and showed that treatment with thalidomide reduced its expression and the prominent neutrophilic infiltrate, a hallmark of the disease. Conclusions: In summary, our study provides in vivo evidence that PTX3 is enhanced during ENL but not in reversal reaction and provides a new molecular target in ENL pathogenesis.


Asunto(s)
Biomarcadores/análisis , Proteína C-Reactiva/análisis , Eritema Nudoso/diagnóstico , Eritema Nudoso/patología , Lepra Lepromatosa/diagnóstico , Lepra Lepromatosa/patología , Componente Amiloide P Sérico/análisis , Adolescente , Adulto , Anciano , Proteína C-Reactiva/genética , Estudios de Casos y Controles , Niño , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Leprostáticos/administración & dosificación , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Componente Amiloide P Sérico/genética , Piel/patología , Talidomida/administración & dosificación , Adulto Joven
10.
Microbes Infect ; 19(11): 505-514, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28684130

RESUMEN

Our previous study has demonstrated that IL-10 may modulate both indoleamine 2,3-dioxygenase (IDO) and CD163 expression in lepromatous leprosy (LL) cells, favoring Mycobacterium leprae persistence through induction of regulatory pathways and iron storage. Here, we observed that in LL lesion cells there is an increase in the expression of proteins involved in iron metabolism such as hemoglobin (Hb), haptoglobin, heme oxygenase 1 and transferrin receptor 1 (TfR1) when compared to tuberculoid leprosy (BT) cells. We also found increased iron deposits and diminished expression of the iron exporter ferroportin 1 in LL lesion cells. Hemin, but not FeSO4 stimulation, was able to enhance M. leprae viability by a mechanism that involves IDO. Analysis of cell phenotype in lesions demonstrated a predominance of M2 markers in LL when compared with BT lesion cells. A positive correlation between CD163 and PPARG with the bacillary index (BI) was observed. In contrast, TNF, STAT1 and CSF2 presented a negative correlation with the BI. In summary, this study demonstrates that iron may regulate IDO expression by a mechanism that involves IL-10, which may contribute for the predominance of M2-like phenotype in LL lesions that favors the phagocytosis and maintenance of M. leprae in host cells.


Asunto(s)
Indolamina-Pirrol 2,3,-Dioxigenasa/fisiología , Hierro/fisiología , Mycobacterium leprae/fisiología , Adulto , Femenino , Humanos , Immunoblotting , Técnicas para Inmunoenzimas , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Hierro/metabolismo , Lepra Lepromatosa/metabolismo , Lepra Lepromatosa/microbiología , Masculino , Persona de Mediana Edad , Mycobacterium leprae/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
11.
PLoS Negl Trop Dis ; 11(7): e0005754, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28715406

RESUMEN

The pathways that trigger exacerbated immune reactions in leprosy could be determined by genetic variations. Here, in a prospective approach, both genetic and non-genetic variables influencing the amount of time before the development of reactional episodes were studied using Kaplan-Meier survival curves, and the genetic effect was estimated by the Cox proportional-hazards regression model. In a sample including 447 leprosy patients, we confirmed that gender (male), and high bacillary clinical forms are risk factors for leprosy reactions. From the 15 single nucleotide polymorphisms (SNPs) at the 8 candidate genes genotyped (TNF/LTA, IFNG, IL10, TLR1, NOD2, SOD2, and IL6) we observed statistically different survival curves for rs751271 at the NOD2 and rs2069845 at the IL6 genes (log-rank p-values = 0.002 and 0.023, respectively), suggesting an influence on the amount of time before developing leprosy reactions. Cox models showed associations between the SNPs rs751271 at NOD2 and rs2069845 at IL6 with leprosy reactions (HRGT = 0.45, p = 0.002; HRAG = 1.88, p = 0.0008, respectively). Finally, IL-6 and IFN-γ levels were confirmed as high, while IL-10 titers were low in the sera of reactional patients. Rs751271-GT genotype-bearing individuals correlated (p = 0.05) with lower levels of IL-6 in sera samples, corroborating the genetic results. Although the experimental size may be considered a limitation of the study, the findings confirm the association of classical variables such as sex and clinical forms with leprosy, demonstrating the consistency of the results. From the results, we conclude that SNPs at the NOD2 and IL6 genes are associated with leprosy reactions as an outcome. NOD2 also has a clear functional pro-inflammatory link that is coherent with the exacerbated responses observed in these patients.


Asunto(s)
Predisposición Genética a la Enfermedad , Inflamación/patología , Interleucina-6/genética , Lepra/patología , Proteína Adaptadora de Señalización NOD2/genética , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Cohortes , Femenino , Humanos , Inflamación/genética , Lepra/genética , Masculino , Persona de Mediana Edad , Factores de Riesgo
12.
Nutr J ; 16(1): 36, 2017 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-28599665

RESUMEN

BACKGROUND: Several studies have been focusing on the effect of omega-3 polyunsaturated fatty acids on modulation of inflammatory markers in several cardiopathies. Although immunoregulatory dysfunction has been associated to the chronic cardiac involvement in Chagas disease, there is no study examining the effects of omega-3 supplementation in these patients. We investigated the effects of omega-3 PUFAs on markers of inflammation and lipid profile in chronic Chagas cardiomyopathy patients. METHODS: The present study was a single-center double-blind clinical trial including patients with chronic Chagas cardiomyopathy. Patients were randomly assigned to receive omega-3 PUFAs capsules (1.8g EPA and 1.2g DHA) or placebo (corn oil) during an 8-week period. Cytokines, fasting glucose, lipid, and anthropometric profiles were evaluated. RESULTS: Forty-two patients (23 women and 19 men) were included in the study and there were only two losses to follow-up during the 8-week period. Most of sociodemographic and clinical characteristics were similar between the groups at baseline, except for the cytokines IL-1ß, IL-6, IL-8, IL-10, IL-17α, and IFNγ. The omega-3 PUFAs group demonstrated greater improvements in serum triglycerides (-21.1 vs. -4.1; p = 0.05) and IL-10 levels (-10.6 vs. -35.7; p = 0.01) in comparison to controls after 8 weeks of intervention. No further differences were observed between groups. CONCLUSION: Omega-3 PUFAs supplementation may favorably affect lipid and inflammatory profile in chronic Chagas cardiomyopathy patients, demonstrated by a decrease in triglycerides and improvements on IL-10 concentration. Further studies examining the clinical effects of omega-3 fatty acids supplementation in chronic Chagas cardiomyopathy are necessary. TRIAL REGISTRATION: NCT01863576.


Asunto(s)
Biomarcadores/sangre , Cardiomiopatía Chagásica/sangre , Cardiomiopatía Chagásica/tratamiento farmacológico , Ácidos Grasos Omega-3/administración & dosificación , Anciano , Glucemia/metabolismo , Proteína C-Reactiva/metabolismo , Cardiomiopatías/sangre , Cardiomiopatías/tratamiento farmacológico , Colesterol/sangre , Enfermedad Crónica , Citocinas/sangre , Dieta , Suplementos Dietéticos , Método Doble Ciego , Ácidos Grasos Omega-3/sangre , Femenino , Estudios de Seguimiento , Humanos , Inflamación/sangre , Masculino , Persona de Mediana Edad , Triglicéridos/sangre
13.
PLoS Negl Trop Dis ; 11(5): e0005560, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28467415

RESUMEN

Household contacts of multibacillary leprosy patients (HCMB) constitute the group of individuals at the highest risk of developing leprosy. Early diagnosis and treatment of their index cases combined with Bacille Calmette-Guerin (BCG) immunization remain important strategies adopted in Brazil to prevent HCMB from evolving into active disease. In the present study, we assessed the impact of these measures on the immune response to Mycobacterium leprae in HCMB. Peripheral blood mononuclear cells (PBMC) from HCMB (n = 16) were obtained at the beginning of leprosy index case treatment (T0). At this time point, contacts were vaccinated (n = 13) or not (n = 3) in accordance with their infancy history of BCG vaccination and PBMCs were recollected at least 6 months later (T1). As expected, a significant increase in memory CD4 and CD8 T cell frequencies responsive to M. leprae whole-cell sonicate was observed in most contacts. Of note, higher frequencies of CD4+ T cells that recognize M. leprae specific epitopes were also detected. Moreover, increased production of the inflammatory mediators IL1-ß, IL-6, IL-17, TNF, IFN-γ, MIP1-ß, and MCP-1 was found at T1. Interestingly, the increment in these parameters was observed even in those contacts that were not BCG vaccinated at T0. This result reinforces the hypothesis that the continuous exposure of HCMB to live M. leprae down regulates the specific cellular immune response against the pathogen. Moreover, our data suggest that BCG vaccination of HCMB induces activation of T cell clones, likely through "trained immunity", that recognize M. leprae specific antigens not shared with BCG as an additional protective mechanism besides the expected boost in cell-mediated immunity by BCG homologues of M. leprae antigens.


Asunto(s)
Antígenos Bacterianos/inmunología , Vacuna BCG/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Inmunidad Celular , Lepra Multibacilar/inmunología , Adulto , Anticuerpos Antibacterianos/sangre , Brasil , Linfocitos T CD8-positivos/inmunología , Citocinas/metabolismo , Epítopos de Linfocito T/inmunología , Composición Familiar , Femenino , Humanos , Inmunoglobulina M/sangre , Lepra Multibacilar/prevención & control , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Mycobacterium leprae , Estudios Prospectivos , Adulto Joven
14.
PLoS Pathog ; 13(1): e1006103, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-28056107

RESUMEN

Leprosy is a chronic infectious disease that may present different clinical forms according to the immune response of the host. Levels of IFN-γ are significantly raised in paucibacillary tuberculoid (T-lep) when compared with multibacillary lepromatous (L-lep) patients. IFN-γ primes macrophages for inflammatory activation and induces the autophagy antimicrobial mechanism. The involvement of autophagy in the immune response against Mycobacterium leprae remains unexplored. Here, we demonstrated by different autophagic assays that LC3-positive autophagosomes were predominantly observed in T-lep when compared with L-lep lesions and skin-derived macrophages. Accumulation of the autophagic receptors SQSTM1/p62 and NBR1, expression of lysosomal antimicrobial peptides and colocalization analysis of autolysosomes revealed an impairment of the autophagic flux in L-lep cells, which was restored by IFN-γ or rapamycin treatment. Autophagy PCR array gene-expression analysis revealed a significantly upregulation of autophagy genes (BECN1, GPSM3, ATG14, APOL1, and TPR) in T-lep cells. Furthermore, an upregulation of autophagy genes (TPR, GFI1B and GNAI3) as well as LC3 levels was observed in cells of L-lep patients that developed type 1 reaction (T1R) episodes, an acute inflammatory condition associated with increased IFN-γ levels. Finally, we observed increased BCL2 expression in L-lep cells that could be responsible for the blockage of BECN1-mediated autophagy. In addition, in vitro studies demonstrated that dead, but not live M. leprae can induce autophagy in primary and lineage human monocytes, and that live mycobacteria can reduce the autophagy activation triggered by dead mycobacteria, suggesting that M. leprae may hamper the autophagic machinery as an immune escape mechanism. Together, these results indicate that autophagy is an important innate mechanism associated with the M. leprae control in skin macrophages.


Asunto(s)
Autofagia/fisiología , Lepra/inmunología , Piel/microbiología , Adulto , Anciano , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Interferón gamma/inmunología , Lepra/patología , Macrófagos/inmunología , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Mycobacterium leprae/inmunología , Reacción en Cadena de la Polimerasa , Piel/inmunología , Piel/patología , Transcriptoma , Adulto Joven
15.
J Infect Dis ; 215(3): 431-439, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-27932613

RESUMEN

Background: Type 1 reaction (T1R) is an acute T-helper type 1 (Th1) inflammatory episode in patients with leprosy. While immunological responses associated with T1R have been investigated, the corresponding metabolic responses that could contribute to T1R pathology have received little attention. Methods: Metabolomics-based analyses of sera from 7 patients with and 9 without T1R were conducted via liquid chromatography-mass spectrometry. Serum metabolites present at levels that significantly differed (P < .05) with a log2 fold change of ≥ 1.0 between patient groups were interrogated against known metabolic pathways. The structural identification of targeted metabolites was confirmed and abundance changes validated by mass spectrometry and enzyme-linked immunoassay. Results: Forty metabolic pathways were perturbed in patients with T1R, with 71 dysregulated metabolites mapping to pathways for lipid mediators of inflammation. Of note was an increase in the abundance of the proinflammatory leukotriene B4 (LTB4) and a corresponding decrease in the level of proresolving resolvin D1 (RvD1). Also, levels of prostaglandin D2 (PGD2) and lipoxin A4 (LXA4) in patients with T1R were significantly increased, while the level of prostaglandin E2 (PGE2) was decreased. Conclusions: The dysregulation of metabolic pathways leading to abundance shifts between proinflammatory and proresolving lipid mediators provides a link between metabolic and cellular immune responses that result in the Th1-mediated pathology of T1R.


Asunto(s)
Mediadores de Inflamación/metabolismo , Lepra/inmunología , Lípidos/inmunología , Células TH1/inmunología , Adulto , Anciano , Antígenos Bacterianos/inmunología , Cromatografía Liquida , Ácidos Grasos Insaturados/inmunología , Femenino , Glucolípidos/inmunología , Humanos , Lepra/metabolismo , Masculino , Espectrometría de Masas , Redes y Vías Metabólicas , Metabolómica , Persona de Mediana Edad , Mycobacterium leprae/inmunología
16.
s.l; Elsevier; 2017. 10 p. tab, graf.
No convencional en Inglés | Sec. Est. Saúde SP, HANSEN, SESSP-ILSLPROD, Sec. Est. Saúde SP, SESSP-ILSLACERVO, Sec. Est. Saúde SP | ID: biblio-1052567

RESUMEN

Our previous study has demonstrated that IL-10 may modulate both indoleamine 2,3-dioxygenase (IDO) and CD163 expression in lepromatous leprosy (LL) cells, favoring Mycobacterium leprae persistence through induction of regulatory pathways and iron storage. Here, we observed that in LL lesion cells there is an increase in the expression of proteins involved in iron metabolism such as hemoglobin (Hb), haptoglobin, heme oxygenase 1 and transferrin receptor 1 (TfR1) when compared to tuberculoid leprosy (BT) cells. We also found increased iron deposits and diminished expression of the iron exporter ferroportin 1 in LL lesion cells. Hemin, but not FeSO stimulation, was able to enhance M. leprae viability by a mechanism that involves IDO. Analysis of cell phenotype in lesions demonstrated a predominance of M2 markers in LL when compared with BT lesion cells. A positive correlation between CD163 and PPARG with the bacillary index (BI) was observed. In contrast, TNF, STAT1 and CSF2 presented a negative correlation with the BI. In summary, this study demonstrates that iron may regulate IDO expression by a mechanism that involves IL-10, which may contribute for the predominance of M2-like phenotype in LL lesions that favors the phagocytosis and maintenance of M. leprae in host cells.


Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Immunoblotting , Lepra Lepromatosa/metabolismo , Lepra Lepromatosa/microbiología , Técnicas para Inmunoenzimas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Indolamina-Pirrol 2,3,-Dioxigenasa/fisiología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Hierro/fisiología , Hierro/metabolismo , Mycobacterium leprae/fisiología , Mycobacterium leprae/metabolismo
17.
Trials ; 17(1): 433, 2016 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-27590681

RESUMEN

BACKGROUND: The effects of exercise training on Chagas heart disease are still unclear. This study aimed to evaluate the effect of exercise training over functional capacity, cardiac function, quality of life, and biomarkers in Chagas heart disease. METHODS: The PEACH study is a superiority randomized clinical trial which will include subjects who meet the following criteria: Chagas heart disease with a left ventricular ejection fraction below 45 % with or without heart failure symptoms; clinical stability in the last 3 months; adherence to clinical treatment; and age above 18 years. The exclusion criteria are: pregnancy; neuromuscular limitations; smoking; evidence of non-chagasic heart disease; systemic conditions that limit exercise practice or cardiopulmonary exercise test; unavailability to attend the center three times a week during the intervention period; and practitioners of regular exercise. The intervention group will perform an exercise training intervention three times per week during 6 months and will be compared to the control group without exercise. Both groups will undergo the same monthly pharmaceutical and nutritional counseling as well as standard medical treatment according to the Brazilian consensus on Chagas disease. The primary outcome is functional capacity based on peak exercise oxygen consumption during cardiopulmonary exercise testing. Secondary outcomes are: cardiac function; body composition; muscle respiratory strength; microvascular reactivity; cardiac rhythm abnormalities; autonomic function; biochemical; oxidative stress and inflammatory biomarkers; and quality of life. Subjects will be evaluated at baseline, and at 3 and 6 months after randomization. Thirty patients will be randomly assigned into exercise or control groups at a ratio of 1:1. DISCUSSION: Findings of the present study will be useful to determine if physical exercise programs should be included as an important additional therapy in the treatment of patients with Chagas heart disease. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02517632 (registered on 6 August 2015).


Asunto(s)
Rehabilitación Cardiaca/métodos , Cardiomiopatía Chagásica/rehabilitación , Terapia por Ejercicio/métodos , Biomarcadores/sangre , Brasil , Rehabilitación Cardiaca/efectos adversos , Cardiomiopatía Chagásica/diagnóstico , Cardiomiopatía Chagásica/fisiopatología , Protocolos Clínicos , Prueba de Esfuerzo , Terapia por Ejercicio/efectos adversos , Tolerancia al Ejercicio , Humanos , Calidad de Vida , Recuperación de la Función , Proyectos de Investigación , Volumen Sistólico , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Función Ventricular Izquierda
18.
PLoS Negl Trop Dis ; 10(8): e0004955, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27556927

RESUMEN

Erythema Nodosum Leprosum (ENL) is an immune reaction in leprosy that aggravates the patient´s clinical condition. ENL presents systemic symptoms of an acute infectious syndrome with high leukocytosis and intense malaise clinically similar to sepsis. The treatment of ENL patients requires immunosuppression and thus needs to be early and efficient to prevent both disabilities and permanent nerve damage. Some patients experience multiple episodes of ENL and prolonged use of immunosuppressive drugs may lead to serious adverse effects. Thalidomide treatment is extremely effective at ameliorating ENL symptoms. Several mechanisms have been proposed to explain the efficacy of thalidomide in ENL, including the inhibition of TNF production. Given its teratogenicity, thalidomide is prohibitive for women of childbearing age. A rational search for molecular targets during ENL episodes is essential to better understand the disease mechanisms involved, which may also lead to the discovery of new drugs and diagnostic tests. Previous studies have demonstrated that IFN-γ and GM-CSF, involved in the induction of CD64 expression, increase during ENL. The aim of the present study was to investigate CD64 expression during ENL and whether thalidomide treatment modulated its expression. Leprosy patients were allocated to one of five groups: (1) Lepromatous leprosy, (2) Borderline leprosy, (3) Reversal reaction, (4) ENL, and (5) ENL 7 days after thalidomide treatment. The present study demonstrated that CD64 mRNA and protein were expressed in ENL lesions and that thalidomide treatment reduced CD64 expression and neutrophil infiltrates-a hallmark of ENL. We also showed that ENL blood neutrophils exclusively expressed CD64 on the cell surface and that thalidomide diminished overall expression. Patient classification based on clinical symptoms found that severe ENL presented high levels of neutrophil CD64. Collectively, these data revealed that ENL neutrophils express CD64, presumably contributing to the immunopathogenesis of the disease.


Asunto(s)
Eritema Nudoso/inmunología , Leprostáticos/uso terapéutico , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Receptores de IgG/genética , Talidomida/uso terapéutico , Adolescente , Adulto , Anciano , Biopsia , Eritema Nudoso/diagnóstico , Eritema Nudoso/tratamiento farmacológico , Eritema Nudoso/microbiología , Femenino , Humanos , Lepra Dimorfa/tratamiento farmacológico , Lepra Dimorfa/inmunología , Lepra Dimorfa/microbiología , Lepra Lepromatosa/tratamiento farmacológico , Lepra Lepromatosa/inmunología , Lepra Lepromatosa/microbiología , Masculino , Persona de Mediana Edad , Receptores de IgG/inmunología , Piel/microbiología , Piel/patología , Adulto Joven
19.
J Infect Dis ; 214(2): 311-20, 2016 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-27190175

RESUMEN

Cytosolic detection of nucleic acids elicits a type I interferon (IFN) response and plays a critical role in host defense against intracellular pathogens. Herein, a global gene expression profile of Mycobacterium leprae-infected primary human Schwann cells identified the genes differentially expressed in the type I IFN pathway. Among them, the gene encoding 2'-5' oligoadenylate synthetase-like (OASL) underwent the greatest upregulation and was also shown to be upregulated in M. leprae-infected human macrophage cell lineages, primary monocytes, and skin lesion specimens from patients with a disseminated form of leprosy. OASL knock down was associated with decreased viability of M. leprae that was concomitant with upregulation of either antimicrobial peptide expression or autophagy levels. Downregulation of MCP-1/CCL2 release was also observed during OASL knock down. M. leprae-mediated OASL expression was dependent on cytosolic DNA sensing mediated by stimulator of IFN genes signaling. The addition of M. leprae DNA enhanced nonpathogenic Mycobacterium bovis bacillus Calmette-Guerin intracellular survival, downregulated antimicrobial peptide expression, and increased MCP-1/CCL2 secretion. Thus, our data uncover a promycobacterial role for OASL during M. leprae infection that directs the host immune response toward a niche that permits survival of the pathogen.


Asunto(s)
2',5'-Oligoadenilato Sintetasa/metabolismo , Interacciones Huésped-Patógeno , Proteínas de la Membrana/metabolismo , Viabilidad Microbiana , Mycobacterium leprae/fisiología , Células de Schwann/microbiología , Células Cultivadas , Células Epiteliales/microbiología , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Lepra/microbiología , Lepra/patología , Macrófagos/microbiología , Mycobacterium bovis/fisiología
20.
J Neuropathol Exp Neurol ; 75(3): 272-83, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26888306

RESUMEN

Mycobacterium leprae (ML) infection causes nerve damage that often leads to permanent loss of cutaneous sensitivity and limb deformities, but understanding of the pathogenesis of leprous neuropathy that would lead to more effective treatments is incomplete. We studied reactional leprosy patients with (n = 9) and without (n = 8) acute neuritis. Nerve conduction studies over the course of the reactional episode showed the findings of demyelination in all patients with neuritis. Evaluation of patient sera revealed no correlation of the presence of antibodies against gangliosides and the clinical demyelination. In nerve biopsies of 3 patients with neuritis, we identified tumor necrosis factor (TNF), TNF receptors, and TNF-converting enzyme in Schwann cells (SCs) using immunofluorescence. To elucidate immunopathogenetic mechanisms, we performed experiments using a human SC line. ML induced transmembrane TNF and TNF receptor 1 expression in the SCs; TNF also induced interleukin (IL)- 6 and IL-8 production by the SCs; and ML induced IL-23 secretion, indicating involvement of this previously unrecognized factor in leprosy nerve damage. These data suggest that ML may contribute to TNF-mediated inflammation and focal demyelination by rendering SCs more sensitive to TNF within the nerves of patients with leprous neuropathy.


Asunto(s)
Citocinas/metabolismo , Enfermedades Desmielinizantes/complicaciones , Enfermedades Desmielinizantes/metabolismo , Lepra/complicaciones , Neuritis/complicaciones , Adulto , Anciano , Línea Celular Transformada , Citocinas/genética , Enfermedades Desmielinizantes/patología , Estimulación Eléctrica , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/fisiología , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium leprae/fisiología , Proteínas del Tejido Nervioso/metabolismo , Conducción Nerviosa/fisiología , Examen Neurológico , Tiempo de Reacción , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Adulto Joven
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