RESUMEN
BACKGROUND: The present study assesses the contributions of axonal degeneration and demyelination in leprosy nerve damage. New clinical strategies can emerge from an in-depth understanding of the pathogenesis of neural leprosy (NL). METHODS: Morphometric analysis of myelinated nerve fibers was performed on 44 nerve biopsy samples collected from leprosy patients. Measures of density, diameter distribution, g-ratios, and the counting of axonal ovoids on the myelinated fibers were taken and compared to those in the control group. RESULTS: The proportion of small myelinated fibers increased in the leprosy group while large fiber frequency decreased. Indicative of axonal atrophy, the g-ratio was lower in the leprosy group. The frequency of axonal ovoids was identical to that found in the non-leprosy neuropathies. CONCLUSIONS: Axonal atrophy, Wallerian degeneration, and demyelination coexist in NL. Axonal degeneration predominates over demyelination in the chronic course of the disease; however, this may change during leprosy reactive episodes. This study regards demyelination and axon degeneration as concurrent mechanisms of damage to nerve fibers in leprosy. It also calls into question the view that demyelination is the primary and predominant mechanism in the complex pathogeny of NL.
Asunto(s)
Axones/patología , Lepra Tuberculoide/patología , Vaina de Mielina/patología , Fibras Nerviosas Mielínicas/patología , Enfermedades del Sistema Nervioso Periférico/patología , Enfermedades Desmielinizantes/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Degeneración Walleriana/patología , Adulto JovenRESUMEN
Leprosy, which is caused by the human pathogen Mycobacterium leprae, causes nerve damage, deformity and disability in over 200,000 people every year. Because of the long doubling time of M. leprae (13 days) and the delayed onset of detectable symptoms, which is estimated to be approximately 3-7 years after infection, there is always a large percentage of subclinically infected individuals in the population who will eventually develop the disease, mainly in endemic countries. piRNAs comprise the largest group of small noncoding RNAs found in humans, and they are distinct from microRNAs (miRNAs) and small interfering RNAs (siRNAs). piRNAs function in transposon silencing, epigenetic regulation, and germline development. The functional role of piRNAs and their associated PIWI proteins have started to emerge in the development of human cancers and viral infections, but their relevance to bacterial diseases has not been investigated. The present study reports the piRNome of human skin, revealing that all but one of the piRNAs examined are downregulated in leprosy skin lesions. Considering that one of the best characterized functions of piRNAs in humans is posttranscriptional mRNA silencing, their functions are similar to what we have described for miRNAs, including acting on apoptosis, M. leprae recognition and engulfment, Schwann cell (SC) demyelination, epithelial-mesenchymal transition (EMT), loss of sensation and neuropathic pain. In addition to new findings on leprosy physiopathology, the discovery of relevant piRNAs involved in disease processes in human skin may provide new clues for therapeutic targets, specifically to control nerve damage, a prominent feature of leprosy that has no currently available pharmaceutical treatment.
Asunto(s)
Transición Epitelial-Mesenquimal , Lepra/genética , Lepra/patología , Mycobacterium leprae/patogenicidad , Neuralgia/patología , ARN Interferente Pequeño/genética , Células de Schwann/patología , Estudios de Casos y Controles , Enfermedades Desmielinizantes , Epigénesis Genética , Humanos , Lepra/microbiología , Neuralgia/metabolismo , Neuralgia/microbiología , Células de Schwann/metabolismo , Células de Schwann/microbiologíaRESUMEN
Leprosy neuropathy is a chronic degenerative infectious disorder of the peripheral nerve caused by the intracellular obligate pathogen Mycobacterium leprae (M. leprae). Among all nonneuronal cells that constitute the nerve, Schwann cells are remarkable in supporting M. leprae persistence intracellularly. Notably, the success of leprosy infection has been attributed to its ability in inducing the demyelination phenotype after contacting myelinated fibres. However, the exact role M. leprae plays during the ongoing process of myelin breakdown is entirely unknown. Here, we provided evidence showing an unexpected predilection of leprosy pathogen for degenerating myelin ovoids inside Schwann cells. In addition, M. leprae infection accelerated the rate of myelin breakdown and clearance leading to increased formation of lipid droplets, by modulating a set of regulatory genes involved in myelin maintenance, autophagy, and lipid storage. Remarkably, the blockage of myelin breakdown significantly reduced M. leprae content, demonstrating a new unpredictable role of myelin dismantling favouring M. leprae physiology. Collectively, our study provides novel evidence that may explain the demyelination phenotype as an evolutionarily conserved mechanism used by leprosy pathogen to persist longer in the peripheral nerve.
Asunto(s)
Células de Schwann/microbiología , Enfermedades del Sistema Nervioso Periférico/metabolismo , Mycobacterium leprae/patogenicidad , Vaina de Mielina/microbiología , Enfermedades Desmielinizantes/microbiología , Lepra/complicacionesRESUMEN
BACKGROUND: Nerve biopsy has been widely used to investigate patients with peripheral neuropathy and in many centers, it is still a part of the diagnostic armamentarium. In this study, the histopathological spectrum of the nerve biopsies received is being revisited to analyze the various clinical and pathologic features and also to assess their relevance. MATERIALS AND METHODS: Retrospective analysis of the data retrieved was done for 74 cases of nerve biopsies. RESULTS: On the basis of the data and histopathological features, broad diagnoses were obtained in 52 cases and further categorized into biopsies being supportive for patient management (including acute and chronic axonopathies and demyelinating neuropathies) and biopsies considered essential for patient management (including vasculitic neuropathies, leprous neuropathies, hereditary neuropathies, and chronic inflammatory demyelinating neuropathies). Nine nerve biopsies did not show any abnormal histopathological features, while 13 nerve biopsies were found to be inadequate for diagnosis, both these groups were categorized as noncontributory. CONCLUSION: With advanced nerve conduction studies available, nerve biopsy is losing its relevance. However, in our experience, nerve biopsy did complement the clinical findings and nerve conduction studies, with which a close correlation is required to make the histopathology of nerve biopsy more relevant in terms of guiding further specific workup and management.
Asunto(s)
Enfermedades del Sistema Nervioso Periférico/diagnóstico , Nervio Sural/patología , Biopsia/clasificación , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/patología , Registros de Salud Personal , Humanos , Enfermedades del Sistema Nervioso Periférico/patología , Estudios RetrospectivosRESUMEN
Two recent articles advance our understanding of mycobacterial pathogenesis, revealing key roles for bacterially derived phenolic glycolipids (PGLs). In leprosy, Mycobacterium leprae PGL-1 uniquely subverts local macrophages to produce neurotoxic nitric oxide (NO), leading to nerve demyelination. In a related model, Mycobacterium marinum PGL stimulates the recruitment of growth-conducive monocytes to sites of initial infection as an early immune evasion strategy.
Asunto(s)
Glucolípidos/inmunología , Macrófagos/inmunología , Animales , Enfermedades Desmielinizantes/inmunología , Humanos , Evasión Inmune/inmunología , Lepra/inmunología , Mycobacterium leprae/inmunología , Mycobacterium marinum/inmunologíaRESUMEN
Mycobacterium leprae causes leprosy and is unique among mycobacterial diseases in producing peripheral neuropathy. This debilitating morbidity is attributed to axon demyelination resulting from direct interaction of the M. leprae-specific phenolic glycolipid 1 (PGL-1) with myelinating glia and their subsequent infection. Here, we use transparent zebrafish larvae to visualize the earliest events of M. leprae-induced nerve damage. We find that demyelination and axonal damage are not directly initiated by M. leprae but by infected macrophages that patrol axons; demyelination occurs in areas of intimate contact. PGL-1 confers this neurotoxic response on macrophages: macrophages infected with M. marinum-expressing PGL-1 also damage axons. PGL-1 induces nitric oxide synthase in infected macrophages, and the resultant increase in reactive nitrogen species damages axons by injuring their mitochondria and inducing demyelination. Our findings implicate the response of innate macrophages to M. leprae PGL-1 in initiating nerve damage in leprosy.
Asunto(s)
Antígenos Bacterianos/metabolismo , Modelos Animales de Enfermedad , Glucolípidos/metabolismo , Lepra/microbiología , Lepra/patología , Macrófagos/inmunología , Mycobacterium leprae/fisiología , Animales , Axones/metabolismo , Axones/patología , Enfermedades Desmielinizantes , Larva/crecimiento & desarrollo , Lepra/inmunología , Mycobacterium marinum/metabolismo , Vaina de Mielina/química , Vaina de Mielina/metabolismo , Vaina de Mielina/ultraestructura , Neuroglía/metabolismo , Neuroglía/patología , Óxido Nítrico/metabolismo , Pez CebraRESUMEN
Mycobacterium leprae (ML) infection causes nerve damage that often leads to permanent loss of cutaneous sensitivity and limb deformities, but understanding of the pathogenesis of leprous neuropathy that would lead to more effective treatments is incomplete. We studied reactional leprosy patients with (n = 9) and without (n = 8) acute neuritis. Nerve conduction studies over the course of the reactional episode showed the findings of demyelination in all patients with neuritis. Evaluation of patient sera revealed no correlation of the presence of antibodies against gangliosides and the clinical demyelination. In nerve biopsies of 3 patients with neuritis, we identified tumor necrosis factor (TNF), TNF receptors, and TNF-converting enzyme in Schwann cells (SCs) using immunofluorescence. To elucidate immunopathogenetic mechanisms, we performed experiments using a human SC line. ML induced transmembrane TNF and TNF receptor 1 expression in the SCs; TNF also induced interleukin (IL)- 6 and IL-8 production by the SCs; and ML induced IL-23 secretion, indicating involvement of this previously unrecognized factor in leprosy nerve damage. These data suggest that ML may contribute to TNF-mediated inflammation and focal demyelination by rendering SCs more sensitive to TNF within the nerves of patients with leprous neuropathy.
Asunto(s)
Citocinas/metabolismo , Enfermedades Desmielinizantes/complicaciones , Enfermedades Desmielinizantes/metabolismo , Lepra/complicaciones , Neuritis/complicaciones , Adulto , Anciano , Línea Celular Transformada , Citocinas/genética , Enfermedades Desmielinizantes/patología , Estimulación Eléctrica , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/fisiología , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium leprae/fisiología , Proteínas del Tejido Nervioso/metabolismo , Conducción Nerviosa/fisiología , Examen Neurológico , Tiempo de Reacción , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Adulto JovenRESUMEN
This study aims to evaluate the types of neuropathy in a cohort of restless leg syndrome (RLS) patients and compare them with primary RLS. RLS symptoms can occur in peripheral neuropathy and may cause diagnostic confusion, and there is a paucity of studies comparing neuropathic RLS and primary RLS. Patients with RLS diagnosed according to the international restless legs syndrome study group criteria were categorized as primary RLS or secondary. Those with evidence of peripheral neuropathy were categorized as neuropathic RLS. The demographic, clinical, laboratory profile and therapeutic response to dopamine agonists at 6 months and 1 year of neuropathic RLS patients were compared between primary and secondary RLS patients. There were 82 patients with RLS of whom 22 had peripheral neuropathy and 28 had primary RLS. The etiology of neuropathic RLS was diabetes mellitus in 13, renal failure in six, hypothyroidism in five, demyelinating in two, nutritional deficiency in three, leprosy in one, and miscellaneous etiologies in four patients. The neuropathic RLS patients were older (46.0±14.1 versus 35.8±15.4 years), had shorter duration of illness (1.4±1.4 versus 6.2±6.2 years) and were more frequently symptomatic. RLS symptoms were asymmetric in primary RLS patients compared to neuropathic RLS (25% versus 0%). The therapeutic response was similar in both groups.
Asunto(s)
Enfermedades del Sistema Nervioso Periférico/complicaciones , Síndrome de las Piernas Inquietas/complicaciones , Adulto , Edad de Inicio , Anciano , Estudios de Cohortes , Enfermedades Desmielinizantes/epidemiología , Enfermedades Desmielinizantes/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mononeuropatías/epidemiología , Mononeuropatías/etiología , Conducción Nerviosa , Examen Neurológico , Enfermedades del Sistema Nervioso Periférico/epidemiología , Enfermedades del Sistema Nervioso Periférico/patología , Polineuropatías/epidemiología , Polineuropatías/etiología , Síndrome de las Piernas Inquietas/tratamiento farmacológico , Síndrome de las Piernas Inquietas/epidemiología , Factores SocioeconómicosRESUMEN
Autoantibodies against various components of host are known to occur in leprosy. Nerve damage is the primary cause of disability associated with leprosy. The aim of this study was to detect the level of autoantibodies and lympho-proliferative response against myelin basic protein (MBP) in leprosy patients (LPs) and their correlation with clinical phenotypes of LPs. Further, probable role of molecular mimicry in nerve damage of LPs was investigated. We observed significantly high level of anti-MBP antibodies in LPs across the spectrum and a positive significant correlation between the level of anti-MBP antibodies and the number of nerves involved in LPs. We report here that 4 B cell epitopes of myelin A1 and Mycobacterium leprae proteins, 50S ribosomal L2 and lysyl tRNA synthetase are cross-reactive. Further, M. leprae sonicated antigen hyperimmunization was responsible for induction of autoantibody response in mice which could be adoptively transferred to naive mice. For the first time our findings suggest the role of molecular mimicry in nerve damage in leprosy.
Asunto(s)
Enfermedades Desmielinizantes/microbiología , Lepra/microbiología , Lisina-ARNt Ligasa/fisiología , Imitación Molecular/fisiología , Mycobacterium leprae/patogenicidad , Proteína Básica de Mielina/fisiología , Proteínas Ribosómicas/fisiología , Animales , Enfermedades Desmielinizantes/complicaciones , Enfermedades Desmielinizantes/etiología , Humanos , Lepra/complicaciones , Lepra/etiología , Ratones , Ratones Endogámicos BALB C/sangre , ConejosRESUMEN
Demyelination is a common pathologic feature in many neurodegenerative diseases including infection with leprosy-causing Mycobacterium leprae. Because of the long incubation time and highly complex disease pathogenesis, the management of nerve damage in leprosy, as in other demyelinating diseases, is extremely difficult. Therefore, an important challenge in therapeutic interventions is to identify the molecular events that occur in the early phase before the progression of the disease. Here we provide evidence that M. leprae-induced demyelination is a result of direct bacterial ligation to and activation of ErbB2 receptor tyrosine kinase (RTK) signaling without ErbB2-ErbB3 heterodimerization, a previously unknown mechanism that bypasses the neuregulin-ErbB3-mediated ErbB2 phosphorylation. MEK-dependent Erk1 and Erk2 (hereafter referred to as Erk1/2) signaling is identified as a downstream target of M. leprae-induced ErbB2 activation that mediates demyelination. Herceptin (trastuzumab), a therapeutic humanized ErbB2-specific antibody, inhibits M. leprae binding to and activation of ErbB2 and Erk1/2 in human primary Schwann cells, and the blockade of ErbB2 activity by the small molecule dual ErbB1-ErbB2 kinase inhibitor PKI-166 (ref. 11) effectively abrogates M. leprae-induced myelin damage in in vitro and in vivo models. These results may have implications for the design of ErbB2 RTK-based therapies for both leprosy nerve damage and other demyelinating neurodegenerative diseases.
Asunto(s)
Enfermedades Desmielinizantes/metabolismo , Lepra/metabolismo , Mycobacterium leprae/metabolismo , Receptor ErbB-2/metabolismo , Transducción de Señal , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Butadienos/farmacología , Células COS , Células Cultivadas , Chlorocebus aethiops , Técnicas de Cocultivo , Enfermedades Desmielinizantes/patología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Células HeLa , Humanos , Lepra/microbiología , Ratones , Ratones Noqueados , Ratones Desnudos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Mycobacterium leprae/genética , Nitrilos/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Ratas , Células de Schwann/enzimología , Células de Schwann/metabolismo , Nervio Ciático/metabolismo , Nervio Ciático/microbiología , Nervio Ciático/ultraestructura , TrastuzumabRESUMEN
Demyelination is a common pathologic feature in many neurodegenerative diseases including infection with leprosy-causing Mycobacterium leprae. Because of the long incubation time and highly complex disease pathogenesis, the management of nerve damage in leprosy, as in other demyelinating diseases, is extremely difficult. Therefore, an important challenge in therapeutic interventions is to identify the molecular events that occur in the early phase before the progression of the disease. Here we provide evidence that M. leprae-induced demyelination is a result of direct bacterial ligation to and activation of ErbB2 receptor tyrosine kinase (RTK) signaling without ErbB2-ErbB3 heterodimerization, a previously unknown mechanism that bypasses the neuregulin-ErbB3-mediated ErbB2 phosphorylation. MEK-dependent Erk1 and Erk2 (hereafter referred to as Erk1/2) signaling is identified as a downstream target of M. leprae-induced ErbB2 activation that mediates demyelination. Herceptin (trastuzumab), a therapeutic humanized ErbB2-specific antibody, inhibits M. leprae binding to and activation of ErbB2 and Erk1/2 in human primary Schwann cells, and the blockade of ErbB2 activity by the small molecule dual ErbB1-ErbB2 kinase inhibitor PKI-166 (ref. 11) effectively abrogates M. leprae-induced myelin damage in in vitro and in vivo models. These results may have implications for the design of ErbB2 RTK-based therapies for both leprosy nerve damage and other demyelinating neurodegenerative diseases.
Asunto(s)
Ratas , Ratones , Humanos , Animales , Anticuerpos Monoclonales , Activación Enzimática , Butadienos , Ratones Noqueados , Chlorocebus aethiops , Células COS , Células Cultivadas , Células HeLa , Células de Schwann , Enfermedades Desmielinizantes , Lepra , Inhibidores Enzimáticos , Mycobacterium leprae , Nervio Ciático , Nitrilos , Pirimidinas , Pirroles , Proteína Quinasa 1 Activada por Mitógenos , Research Support, N.I.H., Extramural , Transducción de Señal , Técnicas de CocultivoRESUMEN
Using a specific antibody (SMI 31), the state of phosphorylation of high and medium molecular weight neurofilaments (NF-H and NF-M) was studied in 22 leprous and four nonleprous human peripheral nerves by means of immunohistochemistry, sodium dodecyl sulfate-poly acrylamide gel electrophoresis (SDS-PAGE) and Western immunoblot (WB). The results thus obtained were compared with morphological changes in the respective nerves studied through light and electron microscopy. Many of the leprous nerves showing minimal pathology revealed lack of or weak staining with SMI 31, denoting dephosphorylation. Remyelinated fibres stained intensely with SMI 31 antibody. The WB analysis of Triton X-100 insoluble cytoskeletal preparation showed absence of regular SMI 31 reactive bands corresponding to 200 and 150 kDa molecular weight (NF-H and NF-M, respectively) in 10 nerves. Three of the 10 nerves revealed presence of NF protein bands in SDS-PAGE but not in WB. Presence of additional protein band (following NF-M) was seen in four nerves. Two nerves revealed NF-H band but not NF-M band and one nerve showed trace positivity. In the remaining five nerves presence of all the three NF bands was seen. Thus, 77.3% (17/22) of human leprous nerves studied showed abnormal phosphorylation of NF protein(s). The ultrastructural study showed abnormal compaction and arraying of NF at the periphery of the axons in the fibres with altered axon to myelin thickness ratio (atrophied fibres) as well as at the Schmidt-Lantermann (S-L) cleft region. Such NF changes were more pronounced in the severely atrophied axons suggesting a direct correlation. The observed well-spaced NF in the remyelinated fibres under ultrastructural study was in keeping with both intense SMI 31 staining and presence of NF triplet bands seen in WBs in four of leprous nerves that showed a large number of regenerating fibres suggesting reversal of changes with regeneration. Findings in the present study suggest that atrophy, that is, the reduction in axonal calibre and paranodal demyelination, seen in leprous nerves may result from dephosphorylation of NF-H and NF-M proteins.
Asunto(s)
Lepra/metabolismo , Proteínas de Neurofilamentos/metabolismo , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Alzheimer/patología , Esclerosis Amiotrófica Lateral/patología , Atrofia , Axones/patología , Western Blotting , Citoesqueleto/metabolismo , Citoesqueleto/patología , Enfermedades Desmielinizantes/patología , Electroforesis en Gel de Poliacrilamida , Humanos , Inmunohistoquímica , Fibras Nerviosas/patología , Neuronas/ultraestructura , Adhesión en Parafina , FosforilaciónRESUMEN
Using a specific antibody (SMI 31), the state of phosphorylation of high and medium molecular weight neurofilaments (NF-H and NF-M) was studied in 22 leprous and four nonleprous human peripheral nerves by means of immunohistochemistry, sodium dodecyl sulfate-poly acrylamide gel electrophoresis (SDS-PAGE) and Western immunoblot (WB). The results thus obtained were compared with morphological changes in the respective nerves studied through light and electron microscopy. Many of the leprous nerves showing minimal pathology revealed lack of or weak staining with SMI 31, denoting dephosphorylation. Remyelinated fibres stained intensely with SMI 31 antibody. The WB analysis of Triton X-100 insoluble cytoskeletal preparation showed absence of regular SMI 31 reactive bands corresponding to 200 and 150 kDa molecular weight (NF-H and NF-M, respectively) in 10 nerves. Three of the 10 nerves revealed presence of NF protein bands in SDS-PAGE but not in WB. Presence of additional protein band (following NF-M) was seen in four nerves. Two nerves revealed NF-H band but not NF-M band and one nerve showed trace positivity. In the remaining five nerves presence of all the three NF bands was seen. Thus, 77.3% (17/22) of human leprous nerves studied showed abnormal phosphorylation of NF protein(s). The ultrastructural study showed abnormal compaction and arraying of NF at the periphery of the axons in the fibres with altered axon to myelin thickness ratio (atrophied fibres) as well as at the Schmidt-Lantermann (S-L) cleft region. Such NF changes were more pronounced in the severely atrophied axons suggesting a direct correlation. The observed well-spaced NF in the remyelinated fibres under ultrastructural study was in keeping with both intense SMI 31 staining and presence of NF triplet bands seen in WBs in four of leprous nerves that showed a large number of regenerating fibres suggesting reversal of changes with regeneration. Findings in the present study suggest that atrophy, that is, the reduction in axonal calibre and paranodal demyelination, seen in leprous nerves may result from dephosphorylation of NF-H and NF-M proteins.
Asunto(s)
Humanos , Atrofia , Axones , Citoesqueleto , Enfermedad de Alzheimer , Enfermedades Desmielinizantes , Electroforesis en Gel de Poliacrilamida , Esclerosis Amiotrófica Lateral , Fibras Nerviosas , Fosforilación , Lepra , Inmunohistoquímica , Adhesión en Parafina , Neuronas , Proteínas de Neurofilamentos , Western BlottingAsunto(s)
Enfermedades Desmielinizantes/microbiología , Lepra/microbiología , Mycobacterium leprae/patogenicidad , Adhesión Bacteriana , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/patología , Humanos , Lepra/inmunología , Lepra/patología , Mycobacterium leprae/fisiología , Células de Schwann/microbiologíaAsunto(s)
Antígenos Bacterianos , Enfermedades Desmielinizantes/microbiología , Lepra/microbiología , Lepra/fisiopatología , Proteínas Musculares , Mycobacterium leprae/patogenicidad , Vaina de Mielina/fisiología , Células de Schwann/microbiología , Células de Schwann/fisiología , Animales , Axones/fisiología , Muerte Celular , Diferenciación Celular , Membrana Celular/metabolismo , Técnicas de Cocultivo , Proteínas del Citoesqueleto/metabolismo , Distroglicanos , Distrofina/metabolismo , Glucolípidos/metabolismo , Humanos , Laminina/metabolismo , Lepra/patología , Glicoproteínas de Membrana/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Mycobacterium leprae/crecimiento & desarrollo , Mycobacterium leprae/metabolismo , Células de Schwann/citología , UtrofinaRESUMEN
Demyelination results in severe disability in many neurodegenerative diseases and nervous system infections, and it is typically mediated by inflammatory responses. Mycobacterium leprae, the causative organism of leprosy, induced rapid demyelination by a contact-dependent mechanism in the absence of immune cells in an in vitro nerve tissue culture model and in Rag1-knockout (Rag1-/-) mice, which lack mature B and T lymphocytes. Myelinated Schwann cells were resistant to M. leprae invasion but undergo demyelination upon bacterial attachment, whereas nonmyelinated Schwann cells harbor intracellular M. leprae in large numbers. During M. leprae-induced demyelination, Schwann cells proliferate significantly both in vitro and in vivo and generate a more nonmyelinated phenotype, thereby securing the intracellular niche for M. leprae.