RESUMO
The diagnosis of pure neural leprosy is more challenging because patients share characteristics with other common pathologies, such as ulnar compression, which should be taken into consideration for differential diagnosis. In this study, we identify ulnar nerve conduction characteristics to aid in the differential diagnosis of ulnar neuropathy (UN) in leprosy and that of non-leprosy etiology. In addition, we include putative markers to better understand the inflammatory process that may occur in the nerve. Data were extracted from a database of people affected by leprosy (leprosy group) diagnosed with UN at leprosy diagnosis. A non-leprosy group of patients diagnosed with mechanical neuropathy (compressive, traumatic) was also included. Both groups were submitted to clinical, neurological, neurophysiological and immunological studies. Nerve enlargement and sensory impairment were significantly higher in leprosy patients than in patients with compressive UN. Bilateral impairment was significantly higher in the leprosy group than in the non-leprosy group. Leprosy reactions were associated to focal demyelinating lesions at the elbow and to temporal dispersion (TD). Clinical signs such as sensory impairment, nerve enlargement and bilateral ulnar nerve injury associated with eletrodiagnostic criteria such as demyelinating finds, specifically temporal dispersion, could be tools to help us decided on the best conduct in patients with elbow ulnar neuropathy and specifically decide if we should perform a nerve biopsy for diagnosis of pure neural leprosy.
Assuntos
Hanseníase/diagnóstico , Hanseníase/metabolismo , Neuropatias Ulnares/diagnóstico , Adolescente , Adulto , Idoso , Biomarcadores , Brasil/epidemiologia , Estudos Transversais , Gerenciamento de Dados , Bases de Dados Factuais , Diagnóstico Diferencial , Articulação do Cotovelo , Feminino , Humanos , Hanseníase Tuberculoide , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Nervo Ulnar/metabolismo , Neuropatias Ulnares/fisiopatologiaRESUMO
The respiratory tract is considered the main port of entry of Mycobacterium leprae, the causative agent of leprosy. However, the great majority of individuals exposed to the leprosy bacillus will never manifest the disease due to their capacity to develop protective immunity. Besides acting as a physical barrier, airway epithelium cells are recognized as key players by initiating a local innate immune response that orchestrates subsequent adaptive immunity to control airborne infections. However, to date, studies exploring the interaction of M. leprae with the respiratory epithelium have been scarce. In this work, the capacity of M. leprae to immune activate human alveolar epithelial cells was investigated, demonstrating that M. leprae-infected A549 cells secrete significantly increased IL-8 that is dependent on NF-κB activation. M. leprae was also able to induce IL-8 production in human primary nasal epithelial cells. M. leprae-treated A549 cells also showed higher expression levels of human ß-defensin-2 (hßD-2), MCP-1, MHC-II and the co-stimulatory molecule CD80. Furthermore, the TLR-9 antagonist inhibited both the secretion of IL-8 and NF-κB activation in response to M. leprae, indicating that bacterial DNA sensing by this Toll-like receptor constitutes an important innate immune pathway activated by the pathogen. Finally, evidence is presented suggesting that extracellular DNA molecules anchored to Hlp, a histone-like protein present on the M. leprae surface, constitute major TLR-9 ligands triggering this pathway. The ability of M. leprae to immune activate respiratory epithelial cells herein demonstrated may represent a very early event during infection that could possibly be essential to the generation of a protective response.
Assuntos
Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/metabolismo , Imunidade Inata , Hanseníase/imunologia , Hanseníase/metabolismo , Mycobacterium leprae/imunologia , Receptor Toll-Like 9/metabolismo , Células A549 , Biomarcadores , Células Cultivadas , Histonas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação , Hanseníase/microbiologia , NF-kappa B/metabolismoRESUMO
The enzyme IDO-1 is involved in the first stage of tryptophan catabolism and has been described in both microbicidal and tolerogenic microenvironments. Previous data from our group have shown that IDO-1 is differentially regulated in the distinctive clinical forms of leprosy. The present study aims to investigate the mechanisms associated with IDO-1 expression and activity in human monocyte-derived dendritic cells (mDCs) after stimulation with irradiated Mycobacterium leprae and its fractions. M. leprae and its fractions induced the expression and activity of IDO-1 in human mDCs. Among the stimuli studied, irradiated M. leprae and its membrane fraction (MLMA) induced the production of proinflammatory cytokines TNF and IL-6 whereas irradiated M. leprae and its cytosol fraction (MLSA) induced an increase in IL-10. We investigated if TLR2 activation was necessary for IDO-1 induction in mDCs. We observed that in cultures treated with a neutralizing anti-TLR2 antibody, there was a decrease in IDO-1 activity and expression induced by M. leprae and MLMA. The same effect was observed when we used a MyD88 inhibitor. Our data demonstrate that coculture of mDCs with autologous lymphocytes induced an increase in regulatory T (Treg) cell frequency in MLSA-stimulated cultures, showing that M. leprae constituents may play opposite roles that may possibly be related to the dubious effect of IDO-1 in the different clinical forms of disease. Our data show that M. leprae and its fractions are able to differentially modulate the activity and functionality of IDO-1 in mDCs by a pathway that involves TLR2, suggesting that this enzyme may play an important role in leprosy immunopathogenesis.
Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Tolerância Imunológica , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Hanseníase/etiologia , Hanseníase/metabolismo , Mycobacterium leprae/imunologia , Receptor 2 Toll-Like/metabolismo , Biomarcadores , Citometria de Fluxo , Humanos , Hanseníase/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The respiratory tract is considered the main port of entry of Mycobacterium leprae, the causative agent of leprosy. However, the great majority of individuals exposed to the leprosy bacillus will never manifest the disease due to their capacity to develop protective immunity. Besides acting as a physical barrier, airway epithelium cells are recognized as key players by initiating a local innate immune response that orchestrates subsequent adaptive immunity to control airborne infections. However, to date, studies exploring the interaction of M. leprae with the respiratory epithelium have been scarce. In this work, the capacity of M. leprae to immune activate human alveolar epithelial cells was investigated, demonstrating that M. leprae-infected A549 cells secrete significantly increased IL-8 that is dependent on NF-kB activation. M. leprae was also able to induce IL-8 production in human primary nasal epithelial cells. M. leprae-treated A549 cells also showed higher expression levels of human b-defensin-2 (hbD-2), MCP-1, MHC-II and the co-stimulatory molecule CD80. Furthermore, the TLR-9 antagonist inhibited both the secretion of IL-8 and NF-kB activation in response to M. leprae, indicating that bacterial DNA sensing by this Toll-like receptor constitutes an important innate immune pathway activated by the pathogen. Finally, evidence is presented suggesting that extracellular DNA molecules anchored to Hlp, a histone-like protein present on the M. leprae surface, constitute major TLR-9 ligands triggering this pathway. The ability of M. leprae to immune activate respiratory epithelial cells herein demonstrated may represent a very early event during infection that could possibly be essential to the generation of a protective response.(AU)
Assuntos
Humanos , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/metabolismo , Hanseníase/imunologia , Hanseníase/metabolismo , Mycobacterium leprae/imunologia , Receptores Toll-Like/metabolismo , Imunidade InataAssuntos
Hanseníase/tratamento farmacológico , Lipoproteínas HDL/metabolismo , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Colesterol/metabolismo , Humanos , Hanseníase/metabolismo , Metabolismo dos Lipídeos , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/metabolismo , Mycobacterium leprae/patogenicidadeRESUMO
The aim of this study was to evaluate the expression of human leukocyte antigen G (HLA-G) in leprosy. Biopsy and serum samples were collected from 18 patients presenting with leprosy and from healthy controls. Samples were analyzed using immunohistochemistry and ELISA techniques. HLA-G expression was observed in biopsy samples of all patients. The healthy control samples were consistently negative for HLA-G expression. Control plasma samples displayed significantly higher HLA-G expression than those from the patients (p < 0.01). These results are the first demonstration of the expression of HLA-G in leprosy.
Assuntos
Antígenos HLA-G/metabolismo , Hanseníase/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Feminino , Humanos , Hanseníase/classificação , Masculino , Pessoa de Meia-Idade , Pele/metabolismo , Adulto JovemRESUMO
Introduction: Leprosy is an infectious disease caused by Mycobacterium leprae, a debilitating disease that affects the skin and peripheral nerves. It is possible that tissue changes during infection with leprosy are related to alterations in the activity of the Notch signaling pathway, an innate signaling pathway in the physiology of the skin and peripheral nerves. Methods: This is a descriptive observational study. Thirty skin biopsies from leprosy patients and 15 from individuals with no history of this disease were evaluated. In these samples, gene expressions of cellular components associated with the Notch signaling pathway, Hes-1, Hey-1, Runx-1 Jagged-1, Notch-1, and Numb, were evaluated using q-PCR, and protein expression was evaluated using immunohistochemistry of Runx-1 and Hes-1. Results: Changes were observed in the transcription of Notch signaling pathway components; Hes-1 was downregulated and Runx-1 upregulated in the skin of infected patients. These results were confirmed by immunohistochemistry, where reduction of Hes-1 expression was found in the epidermis, eccrine glands, and hair follicles. Increased expression of Runx-1 was found in inflammatory cells in the dermis of infected patients; however, it is not related to tissue changes. With these results, a multivariate analysis was performed to determine the causes of transcription factor Hes-1 reduction. It was concluded that tissue inflammation was the main cause. Conclusions: The tissue changes found in the skin of infected patients could be associated with a reduction in the expression of Hes-1, a situation that would promote the survival and proliferation of M. leprae in this tissue.
Assuntos
Hanseníase/metabolismo , Fibras Nervosas/patologia , Receptores Notch/fisiologia , Pele/metabolismo , Adulto , Idoso , Subunidade alfa 2 de Fator de Ligação ao Core/análise , Ciclina D1/análise , Feminino , Humanos , Imuno-Histoquímica , Hanseníase/patologia , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/química , Transdução de Sinais/fisiologia , Pele/patologia , Fatores de Transcrição HES-1/análiseRESUMO
BACKGROUND: Leprosy is an infectious-contagious disease caused by Mycobacterium leprae that remain endemic in 105 countries. This neglected disease has a wide range of clinical and histopathological manifestations that are related to the host inflammatory and immune responses. More recently, the inflammasome has assumed a relevant role in the inflammatory response against microbiological agents. However, the involvement of inflammasome in leprosy remains poorly understood. OBJECTIVES: The aim is to associate biomarkers of inflammasome with the different immunopathological forms of leprosy. METHODS: We performed an observational, cross-sectional, and comparative study of the immunophenotypic expression of inflammasome-associated proteins in immunopathological forms of leprosy of 99 skin lesion samples by immunohistochemistry. The intensity and percentage of NLRP3, Caspase-1, Caspases-4/5, interleukin-1ß and interleukin-18 immunoreactivities in the inflammatory infiltrate of skin biopsies were evaluated. FINDINGS: Strong expression of NLRP3 and inflammatory Caspases-4/5 were observed in lepromatous leprosy (lepromatous pole). In addition, were observed low expression of caspase-1, interleukin-1ß, and interleukin-18 in tuberculoid and lepromatous leprosy. The interpolar or borderline form showed immunophenotype predominantly similar to the lepromatous pole. MAIN CONCLUSIONS: Our results demonstrate that the NLRP3 inflammasome is inactive in leprosy, suggesting immune evasion of M. leprae.
Assuntos
Evasão da Resposta Imune/imunologia , Inflamassomos/metabolismo , Hanseníase/imunologia , Hanseníase/metabolismo , Mycobacterium leprae/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estudos Transversais , Humanos , Imuno-Histoquímica , Hanseníase/patologiaRESUMO
BACKGROUND Leprosy is an infectious-contagious disease caused by Mycobacterium leprae that remain endemic in 105 countries. This neglected disease has a wide range of clinical and histopathological manifestations that are related to the host inflammatory and immune responses. More recently, the inflammasome has assumed a relevant role in the inflammatory response against microbiological agents. However, the involvement of inflammasome in leprosy remains poorly understood. OBJECTIVES The aim is to associate biomarkers of inflammasome with the different immunopathological forms of leprosy. METHODS We performed an observational, cross-sectional, and comparative study of the immunophenotypic expression of inflammasome-associated proteins in immunopathological forms of leprosy of 99 skin lesion samples by immunohistochemistry. The intensity and percentage of NLRP3, Caspase-1, Caspases-4/5, interleukin-1β and interleukin-18 immunoreactivities in the inflammatory infiltrate of skin biopsies were evaluated. FINDINGS Strong expression of NLRP3 and inflammatory Caspases-4/5 were observed in lepromatous leprosy (lepromatous pole). In addition, were observed low expression of caspase-1, interleukin-1β, and interleukin-18 in tuberculoid and lepromatous leprosy. The interpolar or borderline form showed immunophenotype predominantly similar to the lepromatous pole. MAIN CONCLUSIONS Our results demonstrate that the NLRP3 inflammasome is inactive in leprosy, suggesting immune evasion of M. leprae.
Assuntos
Humanos , Evasão da Resposta Imune/imunologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hanseníase/imunologia , Hanseníase/metabolismo , Mycobacterium leprae/imunologia , Imuno-Histoquímica , Estudos Transversais , Hanseníase/patologiaRESUMO
The changes in host lipid metabolism during leprosy have been correlated to fatty acid alterations in serum and with high-density lipoprotein (HDL) dysfunctionality. This is most evident in multibacillary leprosy patients (Mb), who present an accumulation of host lipids in Schwann cells and macrophages. This accumulation in host peripheral tissues should be withdrawn by HDL, but it is unclear why this lipoprotein from Mb patients loses this function. To investigate HDL metabolism changes during the course of leprosy, HDL composition and functionality of Mb, Pb patients (paucibacillary) pre- or post-multidrug therapy (MDT) and HC (healthy controls) were analyzed. Mb pre-MDT patients presented lower levels of HDL-cholesterol compared to HC. Moreover, Ultra Performance Liquid Chromatography-Mass Spectrometry lipidomics of HDL showed an altered lipid profile of Mb pre-MDT compared to HC and Pb patients. In functional tests, HDL from Mb pre-MDT patients showed impaired anti-inflammatory and anti-oxidative stress activities and a lower cholesterol acceptor capacity compared to other groups. Mb pre-MDT showed lower concentrations of ApoA-I (apolipoprotein A-I), the major HDL protein, when compared to HC, with a post-MDT recovery. Changes in ApoA-I expression could also be observed in M. leprae-infected hepatic cells. The presence of bacilli in the liver of a Mb patient, along with cell damage, indicated hepatic involvement during leprosy, which may reflect on ApoA-I expression. Together, altered compositional and functional profiles observed on HDL of Mb patients can explain metabolic and physiological changes observed in Mb leprosy, contributing to a better understanding of its pathogenesis. AUTHOR SUMMARY: Leprosy is a chronic disease caused by Mycobacterium leprae, which causes lesions on the skin and peripheral nerves. Some patients do not present an efficient immune response and have a disseminated infection (multibacillary, Mb). Mb patients have lipid accumulation in infected tissues that is important for microorganism survival. High-density lipoprotein (HDL) is composed of proteins and lipids and is produced in the liver. It removes excess of lipids from peripheral tissues and presents anti-inflammatory activity; however, these activities are not being properly performed in leprosy. To understand more about HDL metabolism on leprosy, the chemical composition and functionality of HDL from leprosy patients were analyzed before and after treatment with antibiotics (multidrug therapy, MDT). It was observed that HDL has an altered lipid composition in Mb patients before MDT, which may lead to an impairment of its functions. Apolipoprotein A-I (ApoA-I), the main HDL protein, seems to be highly affected during infection. These functions can be slightly recovered after MDT, but not in the levels of healthy individuals. Our data open new perspectives to elucidate the modulation of lipid metabolism in leprosy and consequently to prevent disease complications.
Assuntos
Hanseníase/complicações , Hanseníase/metabolismo , Lipoproteínas HDL/metabolismo , Mycobacterium leprae/patogenicidade , HepatopatiasRESUMO
Leprosy reactions are acute immunological events that occur during the evolution of chronic infectious disease causing neural damage and disabilities. A study using blood samples of 17 leprosy reaction patients and 17 reaction-free was carried out by means of associations between antigens, receptors, and expression of cytokines, using path analysis providing new insights into the immunological mechanisms involved in triggering leprosy reactions. Toll-like receptors (TLR) such as TLR1 and TLR2, presented balanced expression in the reaction-free multibacillary (MB) group (TLR1: 1.01 ± 0.23, TLR2: 1.22 ± 0.18; p = 0.267). On the other hand, downgrading type 1 reaction (T1R) (TLR1: 1.24 ± 0.17, TLR2: 2.88 ± 0.37; p = 0.002) and erythema nodosum leprosum (ENL) (TLR1: 1.93 ± 0.17, TLR2: 2.81 ± 0.15; p = 0.004) revealed an unbalance in relation to the expression of these receptors. When the path analysis was approached, it was noted that interleukin 10 (IL-10) expression showed a dependence relation with phenolic glycolipid I (PGL-I) in downgrading T1R (direct effect = 0.503 > residual effect = 0.364), whereas in ENL, such relationship occurred with lipoarabinomannan (LAM) (direct effect = 0.778 > residual effect = 0.280). On the contrary, in the reaction-free leprosy group, interferon-gamma (IFN-γ) levels were dependent on the association between TLR2 and TLR1 (0.8735). The high TLR2 expression associated with IL-10 levels, in the leprosy reaction groups, may be hypothetically related to the formation of TLR2/2 homodimers and/or TLR2/6 heterodimers linked to evasion mechanisms in downgrading reactions and pathophysiology of ENL.
Assuntos
Eritema Nodoso/etiologia , Regulação da Expressão Gênica , Interferon gama/genética , Interleucina-10/genética , Hanseníase/etiologia , Receptor 1 Toll-Like/genética , Receptor 2 Toll-Like/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Suscetibilidade a Doenças , Eritema Nodoso/diagnóstico , Eritema Nodoso/epidemiologia , Eritema Nodoso/metabolismo , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Hanseníase/diagnóstico , Hanseníase/epidemiologia , Hanseníase/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Ligação Proteica , Transdução de Sinais , Receptor 1 Toll-Like/metabolismo , Receptor 2 Toll-Like/metabolismo , Adulto JovemRESUMO
Schwann cells (SCs) critically maintain the plasticity of the peripheral nervous system. Peripheral nerve injuries and infections stimulate SCs in order to retrieve homeostasis in neural tissues. Previous studies indicate that Mycobacterium leprae (ML) regulates the expression of key factors related to SC identity, suggesting that alterations in cell phenotype may be involved in the pathogenesis of neural damage in leprosy. To better understand whether ML restricts the plasticity of peripheral nerves, the present study sought to determine the expression of Krox-20, Sox-10, c-Jun and p75NTR in SC culture and mice sciatic nerves, both infected by ML Thai-53 strain. Primary SC cultures were stimulated with two different multiplicities of infection (MOI 100:1; MOI 50:1) and assessed after 7 and 14 days. Sciatic nerves of nude mice (NU-Foxn1nu ) infected with ML were evaluated after 6 and 9 months. In vitro results demonstrate downregulation of Krox-20 and Sox-10 along with the increase in p75NTR-immunolabelled cells. Concurrently, sciatic nerves of infected mice showed a significant decrease in Krox-20 and increase in p75NTR. Our results corroborate previous findings on the interference of ML in the expression of factors involved in cell maturation, favouring the maintenance of a non-myelinating phenotype in SCs, with possible implications for the repair of adult peripheral nerves.
Assuntos
Regulação para Baixo , Proteína 2 de Resposta de Crescimento Precoce/biossíntese , Hanseníase/metabolismo , Células de Schwann/metabolismo , Nervo Isquiático/metabolismo , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Hanseníase/microbiologia , Hanseníase/patologia , Camundongos Nus , Mycobacterium leprae/isolamento & purificação , Plasticidade Neuronal/fisiologia , Receptores de Fator de Crescimento Neural/metabolismo , Células de Schwann/microbiologia , Células de Schwann/patologia , Nervo Isquiático/microbiologia , Nervo Isquiático/patologia , Técnicas de Cultura de TecidosRESUMO
Schwann cells (SCs) critically maintain the plasticity of the peripheral nervous system. Peripheral nerve injuries and infections stimulate SCs in order to retrieve homeostasis in neural tissues. Previous studies indicate that Mycobacterium leprae (ML) regulates the expression of key factors related to SC identity, suggesting that alterations in cell phenotype may be involved in the pathogenesis of neural damage in leprosy. To better understand whether ML restricts the plasticity of peripheral nerves, the present study sought to determine the expression of Krox20, Sox10, cJun and p75NTR in SC culture and mice sciatic nerves, both infected by ML Thai53 strain. Primary SC cultures were stimulated with two different multiplicities of infection (MOI 100:1; MOI 50:1) and assessed after 7 and 14 days. Sciatic nerves of nude mice (NUFoxn1nu) infected with ML were evaluated after 6 and 9 months. In vitro results demonstrate downregulation of Krox20 and Sox10 along with the increase in p75NTRimmunolabelled cells. Concurrently, sciatic nerves of infected mice showed a significant decrease in Krox20 and increase in p75NTR. Our results corroborate previous findings on the interference of ML in the expression of factors involved in cell maturation, favouring the maintenance of a nonmyelinating phenotype in SCs, with possible implications for the repair of adult peripheral nerves(AU).
Assuntos
Animais , Camundongos , Células de Schwann/microbiologia , Hanseníase/metabolismo , Hanseníase/microbiologia , Mycobacterium leprae/isolamento & purificação , Nervos Periféricos/microbiologia , Células de Schwann/metabolismo , Técnicas In Vitro , Regulação para Baixo , Receptores de Fator de Crescimento Neural/fisiologia , Proteína 2 de Resposta de Crescimento Precoce/biossíntese , Plasticidade Neuronal/fisiologiaRESUMO
BACKGROUND: Since macrophages are one of the major cell types involved in the Mycobacterium leprae immune response, roles of the M1 and M2 macrophage subpopulations have been well defined. However, the role of M4 macrophages in leprosy or other infectious diseases caused by mycobacteria has not yet been clearly characterized. This study aimed to investigate the presence and potential role of M4 macrophages in the immunopathology of leprosy. METHODS: We analyzed the presence of M4 macrophage markers (CD68, MRP8, MMP7, IL-6, and TNF-α) in 33 leprosy skin lesion samples from 18 patients with tuberculoid leprosy and 15 with lepromatous leprosy by immunohistochemistry. RESULTS: The M4 phenotype was more strongly expressed in patients with the lepromatous form of the disease, indicating that this subpopulation is less effective in the elimination of the bacillus and consequently is associated with the evolution to one of the multibacillary clinical forms of infection. CONCLUSION: M4 macrophages are one of the cell types involved in the microbial response to M. leprae and probably are less effective in controlling bacillus replication, contributing to the evolution to the lepromatous form of the disease.
Assuntos
Hanseníase/metabolismo , Macrófagos/metabolismo , Mycobacterium leprae/imunologia , Dermatopatias/metabolismo , Pele/metabolismo , Adulto , Biomarcadores/metabolismo , Brasil , Feminino , Humanos , Imuno-Histoquímica , Hanseníase/imunologia , Hanseníase/patologia , Hanseníase Virchowiana/imunologia , Hanseníase Virchowiana/metabolismo , Hanseníase Virchowiana/patologia , Hanseníase Tuberculoide/imunologia , Hanseníase Tuberculoide/metabolismo , Hanseníase Tuberculoide/patologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Pele/imunologia , Pele/patologia , Dermatopatias/imunologia , Dermatopatias/microbiologia , Dermatopatias/patologiaRESUMO
Mycobacterium leprae, an obligate intracellular bacillus, infects Schwann cells (SCs), leading to peripheral nerve damage, the most severe leprosy symptom. In the present study, we revisited the involvement of phenolic glycolipid I (PGL I), an abundant, private, surface M. leprae molecule, in M. leprae-SC interaction by using a recombinant strain of M. bovis BCG engineered to express this glycolipid. We demonstrate that PGL I is essential for bacterial adhesion and SC internalization. We also show that live mycobacterium-producing PGL I induces the expression of the endocytic mannose receptor (MR/CD206) in infected cells in a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent manner. Of note, blocking mannose recognition decreased bacterial entry and survival, pointing to a role for this alternative recognition pathway in bacterial pathogenesis in the nerve. Moreover, an active crosstalk between CD206 and the nuclear receptor PPARγ was detected that led to the induction of lipid droplets (LDs) formation and prostaglandin E2 (PGE2), previously described as fundamental players in bacterial pathogenesis. Finally, this pathway was shown to induce IL-8 secretion. Altogether, our study provides evidence that the entry of live M. leprae through PGL I recognition modulates the SC phenotype, favoring intracellular bacterial persistence with the concomitant secretion of inflammatory mediators that may ultimately be involved in neuroinflammation.
Assuntos
Antígenos de Bactérias/metabolismo , Glicolipídeos/metabolismo , Lectinas Tipo C/metabolismo , Hanseníase/metabolismo , Lectinas de Ligação a Manose/metabolismo , PPAR gama/metabolismo , Receptores de Superfície Celular/metabolismo , Células de Schwann/virologia , Humanos , Receptor de Manose , Mycobacterium leprae/metabolismo , Receptor Cross-Talk/fisiologiaRESUMO
Neurotrophins are a family of proteins that regulate different aspects of biological development and neural function and are of great importance in neuroplasticity. This group of proteins has multiple functions in neuronal cells, as well as in other cellular populations. Nerve growth factor (NGF) is a neurotrophin that is endogenously produced during development and maturation by multiple cell types, including neurons, Schwann cells, oligodendrocytes, lymphocytes, mast cells, macrophages, keratinocytes, and fibroblasts. These cells produce proNGF, which is transformed by proteolytic cleavage into the biologically active NGF in the endoplasmic reticulum. The present review describes the role of NGF in the pathogenesis of leprosy and its correlations with different clinical forms of the disease and with the phenomena of regeneration and neural injury observed during infection. We discuss the involvement of NGF in the induction of neural damage and the pathophysiology of pain associated with peripheral neuropathy in leprosy. We also discuss the roles of immune factors in the evolution of this pathological process. Finally, we highlight avenues of investigation for future research to broaden our understanding of the role of NGF in the pathogenesis of leprosy. Our analysis of the literature indicates that NGF plays an important role in the evolution and outcome of Mycobacterium leprae infection. The findings described here highlight an important area of investigation, as leprosy is one of the main causes of infection in the peripheral nervous system.
Assuntos
Hanseníase/etiologia , Hanseníase/metabolismo , Fator de Crescimento Neural/metabolismo , Animais , Autoimunidade , Regulação da Expressão Gênica , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunomodulação , Hanseníase/patologia , Fator de Crescimento Neural/genética , Transdução de SinaisRESUMO
For those with leprosy, the extent of host infection by Mycobacterium leprae and the progression of the disease depend on the ability of mycobacteria to shape a safe environment for its replication during early interaction with host cells. Thus, variations in key genes such as those in pattern recognition receptors (NOD2 and TLR1), autophagic flux (PARK2, LRRK2, and RIPK2), effector immune cytokines (TNF and IL12), and environmental factors, such as nutrition, have been described as critical determinants for infection and disease progression. While parkin-mediated autophagy is observed as being essential for mycobacterial clearance, leprosy patients present a prominent activation of the type I IFN pathway and its downstream genes, including OASL, CCL2, and IL10. Activation of this host response is related to a permissive phenotype through the suppression of IFN-γ response and negative regulation of autophagy. Finally, modulation of host metabolism was observed during mycobacterial infection. Both changes in lipid and glucose homeostasis contribute to the persistence of mycobacteria in the host. M. leprae-infected cells have an increased glucose uptake, nicotinamide adenine dinucleotide phosphate generation by pentose phosphate pathways, and downregulation of mitochondrial activity. In this review, we discussed new pathways involved in the early mycobacteria-host interaction that regulate innate immune pathways or metabolism and could be new targets to host therapy strategies.
Assuntos
Autofagia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Interferon Tipo I/imunologia , Hanseníase/imunologia , Citocinas/imunologia , Progressão da Doença , Glucose/metabolismo , Humanos , Interferon Tipo I/genética , Hanseníase/metabolismo , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/terapia , Mycobacterium leprae/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Transdução de SinaisRESUMO
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.
Assuntos
Anexina A1/biossíntese , Anexina A1/imunologia , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/metabolismo , Hanseníase/imunologia , Hanseníase/metabolismo , Mastócitos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Brasil , Quimases/metabolismo , Epiderme/imunologia , Epiderme/patologia , Feminino , Humanos , Hanseníase/patologia , Hanseníase Virchowiana/metabolismo , Hanseníase Tuberculoide/metabolismo , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Mycobacterium leprae/patogenicidade , Pele/patologia , Dermatopatias/metabolismo , Dermatopatias/patologia , Triptases/metabolismo , Adulto JovemRESUMO
Mycobacterium leprae causes leprosy, a dermatoneurological disease which affects the skin and peripheral nerves. One of several cellular structures affected during M. leprae infection is the endoplasmic reticulum (ER). Infection by microorganisms can result in ER stress and lead to the accumulation of unfolded or poorly folded proteins. To restore homeostasis in the cell, the cell induces a series of signaling cascades known as the unfolded protein response called UPR (unfolded protein response). The present work is aimed at investigating the in situ expression of these markers in cutaneous lesions of clinical forms of leprosy and establish possible correlation expression patterns and types of lesion. A total of 43 samples from leprosy patients were analyzed by immunohistochemistry with monoclonal antibodies against GRP78/BiP, PERK, IRE1α, and ATF6. A statistically significant difference between the indeterminate, tuberculoid, and lepromatous clinical forms was detected, with high expression of GRP78/BiP, PERK, IRE1α, and ATF6 in tuberculoid forms (TT) when compared to lepromatous leprosy (LL) and indeterminate (I) leprosy. These results represent the first evidence of ER stress in samples of skin lesions from leprosy patients. We believe that they will provide better understanding of the complex pathogenesis of the disease and facilitate further characterization of the cascade of molecular events elicited during infection.
Assuntos
Biomarcadores/metabolismo , Estresse do Retículo Endoplasmático , Hanseníase Virchowiana/diagnóstico , Hanseníase Tuberculoide/diagnóstico , Fator 6 Ativador da Transcrição/metabolismo , Diagnóstico Diferencial , Chaperona BiP do Retículo Endoplasmático , Endorribonucleases/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Hanseníase/classificação , Hanseníase/metabolismo , Hanseníase Virchowiana/metabolismo , Hanseníase Tuberculoide/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Regulação para Cima , eIF-2 Quinase/metabolismoRESUMO
Leprosy is a chronic infectious disease caused by Mycobacterium leprae mainly affecting skin and peripheral nerves. Leprosy has a broad range of clinical manifestations that range from mild (tuberculoid leprosy) to severe (lepromatous leprosy) forms, and are highly dependent on the host's immune response. Among the immune response elements involved in the pathogenesis of leprosy are the Toll-like receptors (TLRs), vitamin D receptor (VDR), natural killer cells (NK), and T cells. These innate and adaptive immune response elements may be related to the Notch signaling pathway, which is involved in immune cell growth, differentiation, and proliferation. We hypothesize that failure in Notch signaling in leprosy patients may be associated to: 1) compromising NK cell maturation, lysing of infected cells, and CD4+ Th1 differentiation. 2) VDR alterations and TLR polymorphisms may affect expression of Notch Delta-like ligands (DLL) in antigen presenting cells (APCs). 3) altered DLL expression by APCs could compromise CD4+ T cell differentiation towards the Th1 and Th17 effector phenotypes; and finally 4) expression of Notch Jagged ligands would induce CD4+ T cell differentiation towards Th2 effector phenotype and alternative activation of macrophages. Altogether, these signaling failures could favor proliferation of M. leprae in the host. Therefore, evidence of the proposed immunologic failures in leprosy patients would be essential for the better understanding of immunopathogenesis of this disease, and would ultimately enable detection of susceptible individuals, providing a valuable tool for prevention of this debilitating disease.