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1.
Microb Pathog ; 118: 277-284, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29605649

RESUMEN

Mast cells (MCs) have important immunoregulatory roles in skin inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory protein that can be expressed by mast cells, neutrophils, eosinophils, monocytes, epithelial and T cells. This study investigated MCs heterogeneity and ANXA1 expression in human dermatoses with special emphasis in leprosy. Sixty one skin biopsies from 2 groups were investigated: 40 newly diagnosed untreated leprosy patients (18 reaction-free, 11 type 1 reaction/T1R, 11 type 2 reaction/T2R); 21 patients with other dermatoses. Tryptase/try+ and chymase/chy + phenotypic markers and toluidine blue stained intact/degranulated MC counts/mm2 were evaluated. Try+/chy+ MCs and ANXA1 were identified by streptavidin-biotin-peroxidase immunostaining and density was reported. In leprosy, degranulated MCs outnumbered intact ones regardless of the leprosy form (from tuberculoid/TT to lepromatous/LL), leprosy reactions (reactional/reaction-free) and type of reaction (T1R/T2R). Compared to other dermatoses, leprosy skin lesions showed lower numbers of degranulated and intact MCs. Try+ MCs outnumbered chy+ in leprosy lesions (reaction-free/reactional, particularly in T2R), but not in other dermatoses. Compared to other dermatoses, ANXA1 expression, which is also expressed in mast cells, was higher in the epidermis of leprosy skin lesions, independently of reactional episode. In leprosy, higher MC degranulation and differential expression of try+/chy+ subsets independent of leprosy type and reaction suggest that the Mycobacterium leprae infection itself dictates the inflammatory MCs activation in skin lesions. Higher expression of ANXA1 in leprosy suggests its potential anti-inflammatory role to maintain homeostasis preventing tissue and nerve damage.


Asunto(s)
Anexina A1/biosíntesis , Anexina A1/inmunología , Antiinflamatorios/inmunología , Antiinflamatorios/metabolismo , Lepra/inmunología , Lepra/metabolismo , Mastocitos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Brasil , Quimasas/metabolismo , Epidermis/inmunología , Epidermis/patología , Femenino , Humanos , Lepra/patología , Lepra Lepromatosa/metabolismo , Lepra Tuberculoide/metabolismo , Masculino , Mastocitos/patología , Persona de Mediana Edad , Mycobacterium leprae/inmunología , Mycobacterium leprae/patogenicidad , Piel/patología , Enfermedades de la Piel/metabolismo , Enfermedades de la Piel/patología , Triptasas/metabolismo , Adulto Joven
2.
PLoS Negl Trop Dis ; 11(6): e0005598, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28617800

RESUMEN

BACKGROUND: Since leprosy is both treated and controlled by multidrug therapy (MDT) it is important to monitor recurrent cases for drug resistance and to distinguish between relapse and reinfection as a means of assessing therapeutic efficacy. All three objectives can be reached with single nucleotide resolution using next generation sequencing and bioinformatics analysis of Mycobacterium leprae DNA present in human skin. METHODOLOGY: DNA was isolated by means of optimized extraction and enrichment methods from samples from three recurrent cases in leprosy patients participating in an open-label, randomized, controlled clinical trial of uniform MDT in Brazil (U-MDT/CT-BR). Genome-wide sequencing of M. leprae was performed and the resultant sequence assemblies analyzed in silico. PRINCIPAL FINDINGS: In all three cases, no mutations responsible for resistance to rifampicin, dapsone and ofloxacin were found, thus eliminating drug resistance as a possible cause of disease recurrence. However, sequence differences were detected between the strains from the first and second disease episodes in all three patients. In one case, clear evidence was obtained for reinfection with an unrelated strain whereas in the other two cases, relapse appeared more probable. CONCLUSIONS/SIGNIFICANCE: This is the first report of using M. leprae whole genome sequencing to reveal that treated and cured leprosy patients who remain in endemic areas can be reinfected by another strain. Next generation sequencing can be applied reliably to M. leprae DNA extracted from biopsies to discriminate between cases of relapse and reinfection, thereby providing a powerful tool for evaluating different outcomes of therapeutic regimens and for following disease transmission.


Asunto(s)
Genoma Bacteriano , Lepra/diagnóstico , Tipificación Molecular/métodos , Mycobacterium leprae/clasificación , Mycobacterium leprae/genética , Análisis de Secuencia de ADN/métodos , Adolescente , Adulto , Brasil , Biología Computacional/métodos , ADN Bacteriano/aislamiento & purificación , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Mycobacterium leprae/aislamiento & purificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Adulto Joven
4.
J Infect Dis ; 205(9): 1417-24, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22459738

RESUMEN

In leprosy, type 1 reaction (T1R) and type 2 reaction (T2R) are major causes of nerve injury and permanent disabilities. A previous study on plasma levels of 27 cytokines in patients with T1R or T2R and controls with nonreactional leprosy identified the gene for interleukin 6 (IL-6) as a candidate for genetic analysis. Two nested case-control studies were built from a cohort of 409 patients with leprosy from central Brazil, monitored for T1R and T2R. There was evidence for association between T2R and IL-6 tag single-nucleotide polymorphisms rs2069832 (P = .002), rs2069840 (P = .03), and rs2069845 (P = .04), with information on the entire IL-6 locus, as well as functional IL-6 variant rs1800795 (P = .005). Moreover, IL-6 plasma levels in patients with T2R correlated with IL-6 genotypes (P = .04). No association was found between IL-6 variants and T1R. Identifying genetic predictive factors for leprosy reactions may have a major impact on preventive strategies.


Asunto(s)
Predisposición Genética a la Enfermedad , Interleucina-6/genética , Lepra/genética , Adulto , Anciano , Brasil , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Sitios Genéticos , Marcadores Genéticos , Genotipo , Humanos , Lepra/diagnóstico , Lepra/inmunología , Lepra/fisiopatología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Selección Genética , Adulto Joven
5.
BMC Infect Dis ; 9: 75, 2009 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-19473542

RESUMEN

BACKGROUND: The clinical management of leprosy Type 1 (T1R) and Type 2 (T2R) reactions pose challenges mainly because they can cause severe nerve injury and disability. No laboratory test or marker is available for the diagnosis or prognosis of leprosy reactions. This study simultaneously screened plasma factors to identify circulating biomarkers associated with leprosy T1R and T2R among patients recruited in Goiania, Central Brazil. METHODS: A nested case-control study evaluated T1R (n = 10) and TR2 (n = 10) compared to leprosy patients without reactions (n = 29), matched by sex and age-group (+/- 5 years) and histopathological classification. Multiplex bead based technique provided profiles of 27 plasma factors including 16 pro inflammatory cytokines: tumor necrosis factor-alpha (TNF-alpha), Interferon-gamma (IFN-gamma), interleukin (IL)- IL12p70, IL2, IL17, IL1 beta, IL6, IL15, IL5, IL8, macrophage inflammatory protein (MIP)-1 alpha (MIP1alpha), 1 beta (MIP1beta), regulated upon activation normal T-cell expressed and secreted (RANTES), monocyte chemoattractrant protein 1 (MCP1), CC-chemokine 11 (CCL11/Eotaxin), CXC-chemokine 10 (CXCL10/IP10); 4 anti inflammatory interleukins: IL4, IL10, IL13, IL1Ralpha and 7 growth factors: IL7, IL9, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), platelet-derived growth factor BB (PDGF BB), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF). RESULTS: Elevations of plasma CXCL10 (P = 0.004) and IL6 (p = 0.013) were observed in T1R patients compared to controls without reaction. IL6 (p = 0.05), IL7 (p = 0.039), and PDGF-BB (p = 0.041) were elevated in T2R. RANTES and GMCSF were excluded due to values above and below detection limit respectively in all samples. CONCLUSION: Potential biomarkers of T1R identified were CXCL10 and IL6 whereas IL7, PDGF-BB and IL6, may be laboratory markers of TR2. Additional studies on these biomarkers may help understand the immunopathologic mechanisms of leprosy reactions and indicate their usefulness for the diagnosis and for the clinical management of these events.


Asunto(s)
Biomarcadores/sangre , Citocinas/sangre , Lepra/sangre , Adolescente , Adulto , Anciano , Brasil , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
6.
Am J Trop Med Hyg ; 77(5): 829-33, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17984336

RESUMEN

Leprosy affects skin and peripheral nerves, and acute inflammatory type 1 reactions (reversal reaction) can cause neurologic impairment and disabilities. Single skin lesion paucibacillary leprosy volunteers (N = 135) recruited in three Brazilian endemic regions, treated with single-dose rifampin, ofloxacin, and minocycline (ROM), were monitored for 3 years. Poor outcome was defined as type 1 reactions with or without neuritis. IgM anti-phenolic glycolipid I, histopathology, Mitsuda test, and Mycobacterium leprae DNA polymerase chain reaction (ML-PCR) were performed at baseline. chi(2) test, Kaplan-Meir curves, and Cox proportional hazards were applied. The majority of volunteers were adults with a mean age of 30.5 +/- 15.4 years; 44.4% were ML-PCR positive. During follow-up, 14.8% of the patients had a poor clinical outcome, classified as a type 1 reaction. Older age (> or = 40 years), ML-PCR positivity, and lesion size > 5 cm were associated with increased risk. In multivariate analysis, age (> or = 40 years) and ML-PCR positivity remained baseline predictors of type 1 reaction among monolesion leprosy patients.


Asunto(s)
ADN Bacteriano/aislamiento & purificación , Eritema Nudoso/epidemiología , Lepra/tratamiento farmacológico , Lepra/microbiología , Minociclina/uso terapéutico , Mycobacterium leprae/aislamiento & purificación , Ofloxacino/uso terapéutico , Rifampin/uso terapéutico , Adolescente , Adulto , Envejecimiento , Estudios de Cohortes , Eritema Nudoso/sangre , Eritema Nudoso/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Factores de Riesgo , Factores de Tiempo
7.
Rev Inst Med Trop Sao Paulo ; 47(1): 55-7, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15729475

RESUMEN

We report a case of phaeohyphomycosis caused by Exophiala jeanselmei in a cardiac transplant recipient maintained on immunosuppressive therapy with mycophenolate mofetil tacrolimus and prednisone. The lesion began after trauma on the right leg that evolved to multiple lesions with nodules and ulcers. Diagnosis was performed by histological examination and culture of pus from skin lesions. Treatment consisted of itraconazole (200 mg/day) for three months with no improvement and subsequently with amphotericin B (0.5 mg/Kg per day to a total of 3.8 g intravenously). After four months of treatment, the lesions showed marked improvement with reduction in the swelling and healing of sinuses and residual scarring.


Asunto(s)
Dermatomicosis/microbiología , Exophiala , Trasplante de Corazón , Huésped Inmunocomprometido , Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/patología , Humanos , Inmunosupresores/uso terapéutico , Itraconazol/uso terapéutico , Masculino , Persona de Mediana Edad , Tejido Subcutáneo/microbiología
8.
Rev. Inst. Med. Trop. Säo Paulo ; 47(1): 55-57, jan.-fev. 2005. ilus
Artículo en Inglés | LILACS | ID: lil-393344

RESUMEN

Este trabalho relata um caso de feohifomicose subcutânea causado por Exophiala jeanselmei em um paciente que havia recebido transplante de coração e mantinha terapia com micofenolato mofetil, tracolimus e prednisone. As lesões tiveram início após trauma na perna inferior direita que evoluíram produzindo múltiplos nódulos e úlceras. Diagnóstico foi realizado através de avaliação histológica e de características macroscópicas e microscópicas da cultura das lesões da pele. O paciente fez uso de itraconazol em concentração de 200 mg/dia durante três meses, não se observando no entanto, melhora das lesões. Após este período, o paciente foi tratado com anfotericina B a uma concentração de 0,5 mg/Kg/dia totalizando 3,8 g. Após quatro meses de tratamento as lesões mostraram melhora evidente, verificando-se fechamento das fístulas e cicatrização das lesões.


Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Dermatomicosis/microbiología , Exophiala , Trasplante de Corazón , Huésped Inmunocomprometido , Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/patología , Inmunosupresores/uso terapéutico , Itraconazol/uso terapéutico , Tejido Subcutáneo/microbiología
9.
Int. J. Lepr ; 69(3): 177-186, Sept., 2001. ilus, tab, graf
Artículo en Inglés | Hanseníase | ID: han-26734

RESUMEN

This paper aims to describe the histomorphologic features of skin biopsies of single lesion leprosy patients recruited at outpatient clinics in four Brazilian states in the Northeast (Amazonas and Rondonia), Southeast (Rio de Janeiro) and Center-West (Goiás) between October 1997 and December 1998. Patients clinically diagnosed as single skin lesion paucibacillary (SSL-PB) leprosy had a standard 4-mm punch biopsy taken from the lesion before rifampin, ofloxacin, minocycline (ROM) therapy. The features of the cellular inflammatory infiltrates, the presence of nerve involvement and acid-fast bacilli (AFB) were used to categorize SSL-PB biopsies into different histopathological groups. Two-hundred-seventy-eight (93.0%) out of 299 patients had a skin biopsy available. Seven single lesion patients were diagnosed as BL or LL leprosy types (MB) by the histopathological exams and 12 cases were excluded due to other skin diseases. Therefore, 259 patients had skin lesions with histomorphological features compatible with PB leprosy categorized as follows: 33.6% (N = 87) of the biopsies represented well-circumscribed epithelioid cell granuloma (Group 1); 21.6% (N = 56) less-circumscribed epithelioid cell granuloma (Group 2); 12.0% (N = 31) were described as mononuclear inflammatory infiltrate permeated with epithelioid cells (Group 3), and 29.7% (N = 77) had perivascular/periadnexal mononuclear inflammatory infiltrate (Group 4). Minimal/no morphological alteration in the skin was detected in only 8 (3.1%) SSL-PB patients categorized as Group 5, who were considered to have leprosy by clinical parameters. SSL-PB leprosy patients recruited in a multicentric study presented histomorphology readings comprising the whole PB leprosy spectrum but also a few MB cases. These results indicate heterogeneity among SSL-PB patients, with a predominance of well-circumscribed and less-circumscribed epithelioid cell granulomas (Groups 1 and 2) in the sites studied and the heterogeneity of local cellular immune response. (AU)


Asunto(s)
Humanos , Lepra/etnología , Lepra/fisiopatología
10.
Int. J. Lepr ; 68(3): 247-257, Sept., 2000. tab, graf, mapa
Artículo en Inglés | Hanseníase | ID: han-26830

RESUMEN

In Brazil, there is little information about the clinical and epidemiological characteristics of paucibacillary, single skin lesion leprosy patients (SSL-PB). Only recently has the official notification system distinguished leprosy patients with a single lesion as a clinical entity, for whom the single-dose ROM (rifampin, ofloxacin and minocycline) regimen has been recommended. In this paper, we describe the baseline clinical features and the immunological background of a multicenter cohort of SSL-PB leprosy cases enrolled between December 1997-1998. Patients were recruited at health centers located in the following regions: Southeast = Rio de Janeiro; North = Amazon and Rondônia states and Center-West = Goiás state. Eligible cases were newly detected, untreated single-lesion leprosy patients without thickened nerve involvement, and were assessed by clinical, bacilloscopic and histopathological exams. The Mitsuda skin test and anti-PGL-I serology (ELISA) were also performed. Of the 299 SSL-PB leprosy patients, 259 (86.6%) fulfilled the criteria for single-dose ROM intervention. Our results showed that patients recruited from different sites had similar features, considering the clinical and immunological profiles. There was a predominance of adults (mean age 32.4; S.D. = 16.0), and a BCG scar was detected in 76.7% of the children (< or = 15 years old). Only 7 cases were diagnosed as the multibacillary type, representing less than 3% of the patients being misclassified. Our data indicate that in Brazil SSL-PB case ascertainment based on clinical and bacilloscopic criteria can be accurately defined under a routine control program; 75.0% of SSL-PB cases were Mitsuda positive (> or = 5 mm) and seropositivity for anti-PGL-I was detected in 17.3% of the patients. These data are compatible with effective cell-mediated immunity and low bacillary load, suggesting favorable clinical outcomes for most SSL-PB participants of this cohort. (AU)


Asunto(s)
Lepra Dimorfa/fisiopatología , Lepra Lepromatosa/fisiopatología , Lepra Tuberculoide/fisiopatología , Lepra/fisiopatología
11.
Int. J. Lepr ; 66(3): 356-364, Sept. 1998. tab, graf
Artículo en Inglés | Hanseníase | ID: han-27237

RESUMEN

The anti-phenolic glycolipid-I (PGL-I) assay as currently applied for leprosy is conceived as an early marker of asymptomatic infection, early disease diagnosis and cure monitoring. Its use as a prognostic marker of reaction is still a matter of controversy. We conducted a case-control study to investigate whether IgM and IgG anti-PGL-I antibodies could discriminate patients at increased risk of developing reactions. Eligible cases were untreated leprosy patients at the onset of type 1 and type 2 reactions recruited from among 600 concurrent, newly detected, untreated leprosy patients attending an outpatient clinic in central Brazil. For the patients with reaction, approximately the same number of leprosy cases without reaction matched as to bacterial index (BI), age and gender were randomly selected. Individuals without clinical leprosy were evaluated as healthy controls. Sera from type 1 reaction (N = 43) and type 2 reaction (N = 26) patients were tested by an ELISA using PGL-I synthetic disaccharide-BSA antigen and 1:300 sera dilution (cut-off point > or = 0.2 OD). Antibody profiles were evaluated by exploratory data analysis and reverse cumulative distribution curves. The IgG anti-PGL-I response did not have a defined pattern, being detected only at low levels. Our results indicate that leprosy patients, independently of their reactional status, produce high levels of IgM anti-PGL-I, demonstrating a strong correlation between the magnitude of antibody response and the BI. Patients with a higher BI were at least 3.4 times more prone to produce an antibody response compared to healthy controls. (AU)


Asunto(s)
Lepra/tratamiento farmacológico , Lepra/inmunología , Ensayo de Inmunoadsorción Enzimática/instrumentación , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre
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