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2.
Am J Trop Med Hyg ; 100(2): 377-385, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30652669

RESUMEN

Type 2 reaction (T2R) or erythema nodosum leprosum (ENL), a sudden episode of acute inflammation predominantly affecting lepromatous leprosy patients (LL), characterized by a reduced cellular immune response. This possibly indicates a close relationship between the onset of T2R and the altered frequency, and functional activity of T lymphocytes, particularly of memory subsets. This study performed ex vivo and in vitro characterizations of T cell blood subpopulations from LL patients with or without T2R. In addition, the evaluation of activity of these subpopulations was performed by analyzing the frequency of these cells producing IFN-γ, TNF, and IL-10 by flow cytometry. Furthermore, the expression of transcription factors, for the differentiation of T cells, were analyzed by quantitative real-time polymerase chain reaction. Our results showed an increased frequency of CD8+/TNF+ effector memory T cells (TEM) among T2Rs. Moreover, there was evidence of a reduced frequency of CD4 and CD8+ IFN-γ-producing cells in T2R, and a reduced expression of STAT4 and TBX21. Finally, a significant and positive correlation between bacteriological index (BI) of T2R patients and CD4+/TNF+ and CD4+/IFN-γ+ T cells was observed. Thus, negative correlation between BI and the frequency of CD4+/IL-10+ T cells was noted. These results suggest that CD8+/TNF+ TEM are primarily responsible for the transient alteration in the immune response to Mycobacterium leprae in ENL patients. Thus, our study improves our understanding of pathogenic mechanisms and might suggest new therapeutic approaches for leprosy.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Eritema Nudoso/inmunología , Lepra Lepromatosa/inmunología , Mycobacterium leprae/patogenicidad , Factor de Necrosis Tumoral alfa/inmunología , Adolescente , Adulto , Anciano , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD8-positivos/microbiología , Estudios de Casos y Controles , Eritema Nudoso/genética , Eritema Nudoso/patología , Femenino , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Memoria Inmunológica , Inmunofenotipificación , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-10/genética , Interleucina-10/inmunología , Lepra Lepromatosa/genética , Lepra Lepromatosa/patología , Masculino , Persona de Mediana Edad , Mycobacterium leprae/crecimiento & desarrollo , Mycobacterium leprae/inmunología , Cultivo Primario de Células , Factor de Transcripción STAT4/genética , Factor de Transcripción STAT4/inmunología , Transducción de Señal , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunología , Factor de Necrosis Tumoral alfa/genética
3.
PLoS Negl Trop Dis ; 13(1): e0007089, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30689631

RESUMEN

BACKGROUND: Leprosy is a treatable infectious disease caused by Mycobacterium leprae. However, there is additional morbidity from leprosy-associated pathologic immune reactions, reversal reaction (RR) and erythema nodosum leprosum (ENL), which occur in 1 in 3 people with leprosy, even with effective treatment of M. leprae. There is currently no predictive marker in use to indicate which people with leprosy will develop these debilitating immune reactions. Our peripheral blood mononuclear cell (PBMC) transcriptome analysis revealed that activation of the classical complement pathway is common to both RR and ENL. Additionally, differential expression of immunoglobulin receptors and B cell receptors during RR and ENL support a role for the antibody-mediated immune response during both RR and ENL. In this study, we investigated B-cell immunophenotypes, total and M. leprae-specific antibodies, and complement levels in leprosy patients with and without RR or ENL. The objective was to determine the role of these immune mediators in pathogenesis and assess their potential as biomarkers of risk for immune reactions in people with leprosy. METHODOLOGY/FINDINGS: We followed newly diagnosed leprosy cases (n = 96) for two years for development of RR or ENL. They were compared with active RR (n = 35), active ENL (n = 29), and healthy household contacts (n = 14). People with leprosy who subsequently developed ENL had increased IgM, IgG1, and C3d-associated immune complexes with decreased complement 4 (C4) at leprosy diagnosis. People who developed RR also had decreased C4 at leprosy diagnosis. Additionally, elevated anti-M. leprae antibody levels were associated with subsequent RR or ENL. CONCLUSIONS: Differential co-receptor expression and immunoglobulin levels before and during immune reactions intimate a central role for humoral immunity in RR and ENL. Decreased C4 and elevated anti-M. leprae antibodies in people with new diagnosis of leprosy may be risk factors for subsequent development of leprosy immune reactions.


Asunto(s)
Anticuerpos Antibacterianos/sangre , Complemento C3d/análisis , Complemento C4/análisis , Eritema Nudoso/epidemiología , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Lepra Lepromatosa/epidemiología , Mycobacterium leprae/inmunología , Adulto , Anciano , Anticuerpos Antibacterianos/inmunología , Linfocitos B/inmunología , Complemento C3d/inmunología , Complemento C4/inmunología , Eritema Nudoso/sangre , Eritema Nudoso/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunidad Activa/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Lepra Lepromatosa/sangre , Lepra Lepromatosa/inmunología , Masculino , Persona de Mediana Edad , Factores de Riesgo
4.
PLoS Negl Trop Dis ; 12(12): e0007035, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30592714

RESUMEN

BACKGROUND: Erythema nodosum leprosum (ENL) is a systemic inflammatory complication occurring mainly in patients with lepromatous leprosy (LL) and borderline lepromatous leprosy (BL). Prednisolone is widely used for treatment of ENL reactions. However, it has been reported that prolonged treatment with prednisolone increases the risk for prednisolone-induced complications such as osteoporosis, diabetes, cataract and arteriosclerosis. It has been speculated that perhaps these complications result from lipid profile alterations by prednisolone. The effects of extended prednisolone treatment on lipid profiles in ENL patients have not been studied in leprosy patients with ENL reactions. Therefore, in this study we conducted a case-control study to investigate the changes in lipid profiles and serological responses in Ethiopian patients with ENL reaction after prednisolone treatment. METHODS: A prospective matched case-control study was employed to recruit 30 patients with ENL and 30 non-reactional LL patient controls at ALERT Hospital, Ethiopia. Blood samples were obtained from each patient with ENL reaction before and after prednisolone treatment as well as from LL controls. The serological host responses to PGL-1, LAM and Ag85 M. leprae antigens were measured by ELISA. Total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL) and low density lipoprotein (LDL) were measured by spectrophotometric method. RESULTS: The host antibody response to M. leprae PGL-1, LAM and Ag85 antigens were significantly reduced in patients with ENL reactions compared to LL controls after treatment. Comparison between patients with acute and chronic ENL showed that host-response to PGL-1 was significantly reduced in chronic ENL after prednisolone treatment. Untreated patients with ENL reactions had low lipid concentration compared to LL controls. However, after treatment, both groups had comparable lipid profiles except for LDL, which was significantly higher in patients with ENL reaction. Comparison within the ENL group before and after treatment showed that prednisolone significantly increased LDL and HDL levels in ENL patients and this was more prominent in chronic ENL than in acute patients with ENL. CONCLUSION: The significantly increased prednisolone-induced LDL and TG levels, particularly in patients with chronic ENL reactions, is a concern in the use of prednisolone for extended periods in ENL patients. The findings highlight the importance of monitoring lipid profiles during treatment of patients to minimize the long-term risk of prednisolone-induced complications.


Asunto(s)
Eritema Nudoso/sangre , Eritema Nudoso/tratamiento farmacológico , Lepra Lepromatosa/complicaciones , Prednisolona/administración & dosificación , Adolescente , Adulto , Estudios de Casos y Controles , Colesterol/sangre , Eritema Nudoso/etiología , Eritema Nudoso/inmunología , Femenino , Humanos , Lepra Lepromatosa/microbiología , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Masculino , Persona de Mediana Edad , Mycobacterium leprae/fisiología , Prednisolona/efectos adversos , Estudios Prospectivos , Triglicéridos/sangre , Adulto Joven
5.
Acta Trop ; 183: 134-141, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29474830

RESUMEN

Erythema Nodosum Leprosum (ENL) occurs due to the immunological complication of multibacillary leprosy and is characterized by painful nodules and systemic compromising. It is usually recurrent and/or chronic and has both physical and economic impact on the patient, being a very important cause of disability. In addition, ENL is a major health problem in countries where leprosy is endemic. Therefore, adequate control of this condition is important. The management of ENL aims to control acute inflammation and neuritis and prevent the onset of new episodes. However, all currently available treatment modalities have one or two drawbacks and are not effective for all patients. Corticosteroid is the anti-inflammatory of choice in ENL but may cause dependence, especially for chronic patients. Thalidomide has a rapid action but its use is limited due the teratogenicity and neurotoxicity. Clofazimine and pentoxifylline have slow action and have important adverse effects. Finally, there is no pattern or guidelines for treating these patients, becoming more difficult to evaluate and to control this condition. This review aims to show the main drugs used in the treatment of ENL and the challenges in the management of the reaction.


Asunto(s)
Antiinflamatorios/uso terapéutico , Eritema Nudoso/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Leprostáticos/uso terapéutico , Lepra Lepromatosa/tratamiento farmacológico , Pentoxifilina/uso terapéutico , Talidomida/uso terapéutico , Eritema Nudoso/inmunología , Humanos , Inflamación , Lepra Lepromatosa/inmunología , Enfermedades Desatendidas/tratamiento farmacológico , Recurrencia , Inducción de Remisión , Resultado del Tratamiento
7.
BMJ Case Rep ; 20182018 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-29301808

RESUMEN

Coeliac disease (CD) is an autoimmune disease, characterised by a permanent sensitivity to gluten. It is being progressively recognised as a multisystemic disease, with multiple extraintestinal manifestations. Skin conditions (eg, dermatitis herpetiformis) are an example of its manifestations; however, its underlying mechanisms are still not well understood. This article presents three cases of uncommon skin conditions in patients with a history of CD. Two of them concern linear IgA bullous dermatosis and erythema nodosum, which have been described in the literature as having potential associations with CD, though only a few cases were reported. The third case corresponds to pityriasis lichenoides-a rare lymphoproliferative disorder of unknown aetiology-, which has no correlation with CD in the literature reviewed. The authors aim to draw attention to the possibility of CD as a potential predisposing factor for the occurrence of these skin diseases.


Asunto(s)
Enfermedad Celíaca/complicaciones , Eritema Nudoso/inmunología , Dermatosis Bullosa IgA Lineal/inmunología , Pitiriasis Liquenoide/inmunología , Adolescente , Enfermedad Celíaca/inmunología , Niño , Preescolar , Femenino , Humanos , Masculino
8.
PLoS Negl Trop Dis ; 11(12): e0006121, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29253897

RESUMEN

B-cells, in addition to antibody secretion, have emerged increasingly as effector and immunoregulatory cells in several chronic inflammatory diseases. Although Erythema Nodosum Leprosum (ENL) is an inflammatory complication of leprosy, the role of B- cell subsets has never been studied in this patient group. Therefore, it would be interesting to examine the contribution of B-cells in the pathogenesis of ENL. A case-control study design was used to recruit 30 untreated patients with ENL and 30 non-reactional lepromatous leprosy (LL) patient controls at ALERT Hospital, Ethiopia. Peripheral blood samples were obtained before, during and after treatment from each patient. Peripheral blood mononuclear cells (PBMCs) were isolated and used for immunophenotyping of B- cell subsets by flow cytometry. The kinetics of B-cells in patients with ENL before, during and after Prednisolone treatment of ENL was compared with LL patient controls as well as within ENL group. Total B-cells, mature B-cells and resting memory B-cells were not significantly different between patients with ENL reactions and LL controls before treatment. Interestingly, while the percentage of naive B-cells was significantly lower in untreated ENL patients than in LL patient controls, the percentage of activated memory B-cells was significantly higher in these untreated ENL patients than in LL controls. On the other hand, the percentage of tissue-like memory B-cells was considerably low in untreated ENL patients compared to LL controls. It appears that the lower frequency of tissue-like memory B-cells in untreated ENL could promote the B-cell/T-cell interaction in these patients through downregulation of inhibitory molecules unlike in LL patients. Conversely, the increased production of activated memory B-cells in ENL patients could imply the scale up of immune activation through antigen presentation to T-cells. However, the generation and differential function of these memory B-cells need further investigation. The finding of increased percentage of activated memory B-cells in untreated patients with ENL reactions suggests the association of these cells with the ENL pathology. The mechanism by which inflammatory reactions like ENL affecting these memory cells and contributing to the disease pathology is an interesting area to be explored for and could lead to the development of novel and highly efficacious drug for ENL treatment.


Asunto(s)
Anticuerpos Antibacterianos/inmunología , Linfocitos B/inmunología , Eritema Nudoso/inmunología , Eritema Nudoso/patología , Lepra/patología , Mycobacterium leprae/inmunología , Antiinflamatorios/uso terapéutico , Estudios de Casos y Controles , Eritema Nudoso/tratamiento farmacológico , Etiopía , Humanos , Memoria Inmunológica/inmunología , Lepra/inmunología , Lepra/microbiología , Recuento de Linfocitos , Prednisolona/uso terapéutico , Linfocitos T/inmunología
9.
PLoS Negl Trop Dis ; 11(10): e0006001, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28991896

RESUMEN

Leprosy is a disease caused by Mycobacterium leprae where the clinical spectrum correlates with the patient immune response. Erythema Nodosum Leprosum (ENL) is an immune-mediated inflammatory complication, which causes significant morbidity in affected leprosy patients. The underlying cause of ENL is not conclusively known. However, immune-complexes and cell-mediated immunity have been suggested in the pathogenesis of ENL. The aim of this study was to investigate the regulatory T-cells in patients with ENL. Forty-six untreated patients with ENL and 31 non-reactional lepromatous leprosy (LL) patient controls visiting ALERT Hospital, Ethiopia were enrolled to the study. Blood samples were obtained before, during and after prednisolone treatment of ENL cases. Peripheral blood mononuclear cells (PBMCs) were isolated and used for immunophenotyping of regulatory T-cells by flow cytometry. Five markers: CD3, CD4 or CD8, CD25, CD27 and FoxP3 were used to define CD4+ and CD8+ regulatory T-cells. Clinical and histopathological data were obtained as supplementary information. All patients had been followed for 28 weeks. Patients with ENL reactions had a lower percentage of CD4+ regulatory T-cells (1.7%) than LL patient controls (3.8%) at diagnosis of ENL before treatment. After treatment, the percentage of CD4+regulatory T-cells was not significantly different between the two groups. The percentage of CD8+ regulatory T-cells was not significantly different in ENL and LL controls before and after treatment. Furthermore, patients with ENL had higher percentage of CD4+ T-ells and CD4+/CD8+ T-cells ratio than LL patient controls before treatment. The expression of CD25 on CD4+ and CD8+ T-cells was not significantly different in ENL and LL controls suggesting that CD25 expression is not associated with ENL reactions while FoxP3 expression on CD4+ T-cells was significantly lower in patients with ENL than in LL controls. We also found that prednisolone treatment of patients with ENL reactions suppresses CD4+ T-cell but not CD8+ T-cell frequencies. Hence, ENL is associated with lower levels of T regulatory cells and higher CD4+/CD8+ T-cell ratio. We suggest that this loss of regulation is one of the causes of ENL.


Asunto(s)
Eritema Nudoso/etiología , Eritema Nudoso/inmunología , Lepra/complicaciones , Linfocitos T/fisiología , Adolescente , Adulto , Antiinflamatorios/uso terapéutico , Estudios de Casos y Controles , Eritema Nudoso/tratamiento farmacológico , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Lepra/inmunología , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Linfocitos T/clasificación , Adulto Joven
11.
J Eur Acad Dermatol Venereol ; 31(4): 705-711, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27859670

RESUMEN

BACKGROUND: Leprosy reactions are immunologically mediated conditions and a major cause of disability before, during and after multidrug therapy (MDT). Little data have been published on the epidemiology of leprosy reactions in Bangladesh. OBJECTIVES: To describe the pattern and prevalence of leprosy reactions in the postelimination stage. METHODS: A descriptive retrospective cross-sectional study was carried out in Chittagong Medical College Hospital using the registered records of patients in the period between 2004 and 2013. RESULTS: Of the 670 patients with leprosy, 488 (73.38%) were males and 182 (27.37%) were females. The prevalence of reaction was in 300 (44.78%) patients with a male:female ratio of 3.55 : 1. The age-specific cumulative reaction cases at >40 years were 115 (38.33%) among all age groups. The prevalence of reaction was found to be in 166 (55.33%) patients for the reversal reaction, 49 (16.57%) for the erythema nodosum leprosum (ENL) and 85 (28.33%) for the neuritis. Borderline tuberculoid was most common (106, 35.33%)in the reversal reaction group, while lepromatous leprosy was most common (37, 12.33%) in ENL group. More than half of the patients (169, 56.33%) had reactions at the time of presentations, while 85 (28.33%) and 46 (15.33%) patients developed reaction during and after MDT, respectively. The reversal reaction group presented with ≥six skin lesions in 96 (57.83%) patients and ≥two nerve function impairments (NFIs) in 107 (64.46%) patients. The ENL was present chiefly as papulo-nodular lesions in 45 (91.84%) patients followed by pustule-necrotic lesions in four (8.16%), neuritis in 33 (67.35%), fever in 24 (48.98%), lymphadenitis in six (12.24%), arthritis in five (10.20%) and iritis in two (4.08%). Bacterial index ≥3 had been demonstrated in 34 (60.71%) patients in ENL group. CONCLUSION: The incidence of leprosy reaction seemed to be more than three times common in borderline tuberculoid (52.33%) group than in lepromatous leprosy (14%) group. Reactions with NFI and disability still occur among multibacillary patients during and after MDT. Early detection and management of leprosy reaction are very important in preventing disability and deformity, and patients should be educated to undergo regular follow-up examinations. Developing reinforced new therapies to curb leprosy reactions is crucial for improving leprosy healthcare services.


Asunto(s)
Eritema Nudoso/inmunología , Hipersensibilidad Retardada/complicaciones , Hipersensibilidad Retardada/epidemiología , Lepra/tratamiento farmacológico , Linfadenitis/inmunología , Neuritis/inmunología , Adolescente , Adulto , Antígenos Bacterianos/inmunología , Artritis/epidemiología , Artritis/inmunología , Bangladesh/epidemiología , Niño , Preescolar , Eritema Nudoso/epidemiología , Femenino , Humanos , Lactante , Iritis/epidemiología , Iritis/inmunología , Leprostáticos/uso terapéutico , Lepra Dimorfa/tratamiento farmacológico , Lepra Lepromatosa/tratamiento farmacológico , Lepra Tuberculoide/tratamiento farmacológico , Linfadenitis/epidemiología , Masculino , Neuritis/epidemiología , Prevalencia , Estudios Retrospectivos , Adulto Joven
14.
JCI Insight ; 1(15): e88843, 2016 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-27699251

RESUMEN

Transcriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with MMP12 as part of a tissue remodeling network that contributes to granuloma formation. In lesions from lepromatous leprosy patients, those with disseminated disease, macrophages were linked with a gene network that programs phagocytosis. In erythema nodosum leprosum, neutrophil and endothelial cell gene networks were identified as part of the vasculitis that results in tissue injury. The present integrated computational approach provides a systems approach toward identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease.


Asunto(s)
Redes Reguladoras de Genes , Lepra/genética , Lepra/inmunología , Adolescente , Adulto , Eritema Nudoso/genética , Eritema Nudoso/inmunología , Femenino , Humanos , Lepra Lepromatosa/genética , Lepra Lepromatosa/inmunología , Lepra Tuberculoide/genética , Lepra Tuberculoide/inmunología , Masculino , Persona de Mediana Edad , Transcriptoma , Adulto Joven
15.
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
16.
J Immunol ; 197(5): 1905-13, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27474073

RESUMEN

The chronic course of lepromatous leprosy may be interrupted by acute inflammatory episodes known as erythema nodosum leprosum (ENL). Despite its being a major cause of peripheral nerve damage in leprosy patients, the immunopathogenesis of ENL remains ill-defined. Recognized by distinct families of germline-encoded pattern recognition receptors, endogenous and pathogen-derived nucleic acids are highly immunostimulatory molecules that play a major role in the host defense against infections, autoimmunity, and autoinflammation. The aim of this work was to investigate whether DNA sensing via TLR-9 constitutes a major inflammatory pathway during ENL. Flow cytometry and immunohistochemistry analysis showed significantly higher TLR-9 expression in ENL when compared with nonreactional lepromatous patients, both locally in the skin lesions and in circulating mononuclear cells. The levels of endogenous and pathogen-derived TLR-9 ligands in the circulation of ENL patients were also higher. Furthermore, PBMCs isolated from the ENL patients secreted higher levels of TNF, IL-6, and IL-1ß in response to a TLR-9 agonist than those of the nonreactional patients and healthy individuals. Finally, E6446, a TLR-9 synthetic antagonist, was able to significantly inhibit the secretion of proinflammatory cytokines by ENL PBMCs in response to Mycobacterium leprae lysate. Our data strongly indicate that DNA sensing via TLR-9 constitutes a major innate immunity pathway involved in the pathogenesis and evolution of ENL. Thus, the use of TLR-9 antagonists emerges as a potential alternative to more effectively treat ENL aiming to prevent the development of nerve injuries and deformities in leprosy.


Asunto(s)
ADN/metabolismo , Eritema Nudoso/inmunología , Inmunidad Innata , Lepra Lepromatosa/inmunología , Transducción de Señal , Receptor Toll-Like 9/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Eritema Nudoso/microbiología , Femenino , Citometría de Flujo , Humanos , Lepra Lepromatosa/microbiología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/microbiología , Masculino , Persona de Mediana Edad , Mycobacterium leprae/química , Mycobacterium leprae/inmunología , Receptor Toll-Like 9/inmunología , Adulto Joven
17.
Int J Dermatol ; 55(5): e289-94, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26917228

RESUMEN

BACKGROUND: The pathogenesis of erythema nodosum (EN) is still poorly understood, and studies evaluating the involvement of a cytokine network are very scarce. OBJECTIVES: To investigate clinical and pathological features, the cytokine profiles, and the balance of T-regulatory (Treg) and T-helper (Th)17 cells in serum and lesional skin of patients with EN. METHODS: Patients with a diagnosis of EN were consecutively enrolled, and their clinical and histopathological features were recorded. A panel of cytokines was evaluated in both serum and lesional skin using enzyme-linked immunosorbent assay. Real-time polymerase chain reaction was performed to evaluate the Treg/Th17 cell balance. RESULTS: Histopathological examination of skin biopsy specimens from all patients (four women and one man) showed classical features of EN. The most widely expressed cytokines were innate immunity cytokines (mainly tumor necrosis factor alpha, interleukin-8 and -6) and growth factors (mainly granulocyte colony-stimulating factor and monocyte chemoattractant protein-1). The Treg/Th17 balance was highly different between patients. CONCLUSIONS: The present study emphasizes the crucial role of neutrophils in the pathogenesis of EN, as high levels of cytokines and growth factors mainly involved in neutrophil recruitment and activation were detected.


Asunto(s)
Citocinas/metabolismo , Eritema Nudoso/inmunología , Eritema Nudoso/patología , Linfocitos T Reguladores , Células Th17 , Adulto , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Quimiocina CCL2/metabolismo , Citocinas/sangre , Eritema Nudoso/metabolismo , Femenino , Factor Estimulante de Colonias de Granulocitos/metabolismo , Humanos , Interleucina-6/sangre , Interleucina-8/sangre , Recuento de Linfocitos , Masculino , Neutrófilos , Factor de Necrosis Tumoral alfa/sangre , Adulto Joven
18.
Indian J Lepr ; 87(4): 255-257, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29762955

RESUMEN

Erythema Nodosum Leprosum (ENL) is characterized by evanescent, erythematous, painful raised nodules which fade within 48-72 hours. Necrotic and ulcerative forms are rare presentations of severe ENL. A 27 year old male patient presented with multiple erythematous nodules on trunk and extremities associated with high grade fever, joint pain and pedal edema. Patient developed ulceration of nodules associated with pain and burning sensation over another 3 days. Slit smear showed clumps of granular bacilli. Biopsy showed superficial dermis showing edema with dense focal perivascular infiltrate of lymphocytes, macrophages and few scattered neutrophils. Fite-Faraco stain was negative. Patient was diagnosed as a case of erythema necroticans and started on oral steroids and thalidomide. The histological findings illustrate the need to consider leprosy diagnosis in necrotizing vasculitis even when Virchow's cells are not found in the infiltrate. Thalidomide is the drug of choice in such cases. This patient showed a marked response to the drug with healing of all ulcers within 2 weeks of starting thalidomide.


Asunto(s)
Eritema Nudoso/diagnóstico , Lepra Lepromatosa/diagnóstico , Adulto , Eritema Nudoso/tratamiento farmacológico , Eritema Nudoso/inmunología , Humanos , Lepra Lepromatosa/tratamiento farmacológico , Lepra Lepromatosa/inmunología , Masculino , Neutrófilos/inmunología , Talidomida/administración & dosificación
19.
Indian J Lepr ; 87(1): 23-6, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26591847

RESUMEN

Lepra reactions are acute episodes occurring during the disease process of leprosy and are of 2 types: type 1 or reversal reaction and type 2 reaction or erythema odosumleprosum (ENL). In the episodes of lepra reaction several parts are affected including face and extremities like oral cavity. In the present case report we reported a rare case of lepromatous leprosy with necrotic ENL involving scalp apart from the usual sites. A 58 year old married male presented to us with complaints of spontaneous onset, recurrent eruption of multiple reddish raised painful lesions. Biopsy from the infiltrated skin over the back showed atrophic epidermis, free Grenz zone, diffuse and periadnexal macrophage granulomas with predominant mononuclear infiltrate, appandageal atrophy, fibrosis around the neural structures and leukocytoclastic vasculitis. Fites stain showed strong positivity for M. leprae. His routine blood investigations showed anemia (Hb = 7.8 gm%), neutrophil leukocytosis (TLC = 17,600, DLC = P66L28M4E2) and raised ESR (80 mm in the first hour). These bullous and necrotic lesions in leprosy may be a manifestation of severe type II reactions in patients with very high bacillary load.


Asunto(s)
Eritema Nudoso/etiología , Lepra Lepromatosa/complicaciones , Eritema Nudoso/inmunología , Eritema Nudoso/microbiología , Eritema Nudoso/patología , Humanos , Lepra Lepromatosa/microbiología , Masculino , Persona de Mediana Edad , Mycobacterium leprae/aislamiento & purificación , Mycobacterium leprae/fisiología , Necrosis , Cuero Cabelludo/microbiología , Cuero Cabelludo/patología
20.
Clin Rev Allergy Immunol ; 49(1): 19-35, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25791751

RESUMEN

Sarcoidosis is a systemic inflammatory disorder characterised by tissue infiltration by mononuclear phagocytes and lymphocytes with associated non-caseating granuloma formation. Originally described as a disorder of the skin, sarcoidosis can involve any organ with wide-ranging clinical manifestations and disease course. Recent studies have provided new insights into the mechanisms involved in disease pathobiology, and we now know that sarcoidosis has a clear genetic basis largely involving human leukocyte antigen (HLA) genes. In contrast to Mendelian-monogenic disorders--which are generally due to specific and relatively rare mutations often leading to a single amino acid change in an encoded protein--sarcoidosis results from genetic variations relatively common in the general population and involving multiple genes, each contributing an effect of varying magnitude. However, an individual may have the necessary genetic profile and yet the disease will not develop unless an environmental or infectious factor is encountered. Genetics appears also to contribute to the huge variability in clinical phenotype and disease behaviour. Moreover, it has been established that sarcoidosis granulomatous inflammation is a highly polarized T helper 1 immune response that starts with an antigenic stimulus followed by T cell activation via a classic HLA class II-mediated pathway. A complex network of lymphocytes, macrophages, and cytokines is pivotal in the orchestration and evolution of the granulomatous process. Despite these advances, the aetiology of sarcoidosis remains elusive and its pathogenesis incompletely understood. As such, there is an urgent need for a better understanding of disease pathogenesis, which hopefully will translate into the development of truly effective therapies.


Asunto(s)
Granuloma/patología , Antígenos de Histocompatibilidad Clase II/inmunología , Macrófagos/patología , Sarcoidosis/patología , Células TH1/patología , Citocinas/genética , Citocinas/inmunología , Eritema Nudoso/genética , Eritema Nudoso/inmunología , Eritema Nudoso/patología , Regulación de la Expresión Génica , Granuloma/genética , Granuloma/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Inflamación , Enfermedades Linfáticas/genética , Enfermedades Linfáticas/inmunología , Enfermedades Linfáticas/patología , Macrófagos/inmunología , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Fenotipo , Propionibacterium acnes/inmunología , Propionibacterium acnes/patogenicidad , Receptores de Quimiocina/genética , Receptores de Quimiocina/inmunología , Sarcoidosis/genética , Sarcoidosis/inmunología , Transducción de Señal , Células TH1/inmunología
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