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2.
EBioMedicine ; 6: 190-198, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27211560

RESUMO

BACKGROUND: Human endogenous retroviruses HERV-W encode a pro-inflammatory protein, named MSRV-Env from its original identification in Multiple Sclerosis. Though not detected in various neurological controls, MSRV-Env was found in patients with chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs). This study investigated the expression of MSRV in CIDP and evaluated relevant MSRV-Env pathogenic effects. METHODS: 50 CIDP patients, 19 other neurological controls (ONDs) and 65 healthy blood donors (HBDs) were recruited from two different countries. MSRV-env and -pol transcripts, IL6 and CXCL10 levels were quantified from blood samples. MSRV-Env immunohistology was performed in distal sensory nerves from CIDP and neurological controls biopsies. MSRV-Env pathogenic effects and mode of action were assayed in cultured primary human Schwann cells (HSCs). FINDINGS: In both cohorts, MSRV-env and -pol transcripts, IL6 positivity prevalence and CXCL10 levels were significantly elevated in CIDP patients when compared to HBDs and ONDs (statistically significant in all comparisons). MSRV-Env protein was detected in Schwann cells in 5/7 CIDP biopsies. HSC exposed to or transfected with MSRV-env presented a strong increase of IL6 and CXCL10 transcripts and protein secretion. These pathogenic effects on HSC were inhibited by GNbAC1, a highly specific and neutralizing humanized monoclonal antibody targeting MSRV-Env. INTERPRETATION: The present study showed that MSRV-Env may trigger the release of critical immune mediators proposed as instrumental factors involved in the pathophysiology of CIDP. Significant MSRV-Env expression was detected in a significant proportion of patients with CIDP, in which it may play a role according to its presently observed effects on Schwann cells along with previously known effects on immune cells. Experimental results also suggest that a biomarker-driven therapeutic strategy targeting this protein with a neutralizing antibody such as GNbAC1 may offer new perspectives for treating CIDP patients with positive detection of MSRV-Env expression. FUNDING: Geneuro-Innovation, France.


Assuntos
Quimiocina CXCL10/genética , Retrovirus Endógenos/patogenicidade , Produtos do Gene env/genética , Interleucina-6/genética , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Linhagem Celular , Retrovirus Endógenos/genética , Retrovirus Endógenos/imunologia , Feminino , França , Produtos do Gene pol/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/genética , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/virologia , Células de Schwann/efeitos dos fármacos , Células de Schwann/virologia , Adulto Jovem
4.
J Neuroimmunol ; 270(1-2): 61-6, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24657030

RESUMO

Chronic-inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated disease with no known biomarkers for diagnosing the disease or assessing its prognosis. We performed transcriptional profiling microarray analysis on skin punch biopsies from 20 CIDP patients and 17 healthy controls to identify disease-associated gene expression changes. We demonstrate changes in expression of genes involved in immune and chemokine regulation, growth and repair. We also found a combination of two upregulated genes that can be proposed as a novel biomarker of the disorder.


Assuntos
Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/genética , Transcriptoma , Adulto , Idoso , Biomarcadores/análise , Biópsia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Pele
5.
J Peripher Nerv Syst ; 18(3): 241-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24028192

RESUMO

Twenty patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) meeting the EFNS/PNS criteria were examined in order to assess differences/similarities between the various grading systems according to CIDP disease activity status (CDAS). A principal component (PC) analysis and the correlations between the following scores were performed: Neurological Symptom Score; MRC sum score; Neurological Impairment Score; Hammersmith Functional Motor Scale; Inflammatory Neuropathy Cause and Treatment (INCAT) Sensory Sum Score; Overall Disability Sum Score; INCAT Disability Score; Rasch-built Overall Disability Scale. Our analysis outlined two main sets of scales, with high influence in the top two PCs. The first PC that best explained the variability within the cohort consisted of CDAS, general disability scores and motor scores; these parameters were also strongly correlated amongst each other. The second PC explained less the variability and consisted mainly of sensory scores and disease duration; these parameters did not correlate with the scores of the first PC or with the CDAS. Our findings suggest separating screening for motor and sensory deficits when evaluating CIDP patients, as only the motor scores correlate with CDAS.


Assuntos
Pessoas com Deficiência , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/fisiopatologia , Adulto , Idoso , Estudos de Coortes , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Análise de Componente Principal , Índice de Gravidade de Doença
6.
Respir Physiol Neurobiol ; 189(1): 22-6, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23811192

RESUMO

Myotonic dystrophy (DM1) is a multisystemic disease caused by an expansion of CTG repeats in the region of DMPK, the gene encoding DM protein kinase. The severity of muscle disability in DM1 correlates with the size of CTG expansion. As respiratory failure is one of the main causes of death in DM1, we investigated the correlation between respiratory impairment and size of the (CTG)n repeat in DM1 animal models. Using pressure plethysmography the respiratory function was assessed in control and transgenic mice carrying either 600 (DM600) or >1300 CTG repeats (DMSXL). The statistical analysis of respiratory parameters revealed that both DM1 transgenic mice sub-lines show respiratory impairment compared to control mice. In addition, there is no significant difference in breathing functions between the DM600 and DMSXL mice. In conclusion, these results indicate that respiratory impairment is present in both transgenic mice sub-lines, but the severity of respiratory failure is not related to the size of the (CTG)n expansion.


Assuntos
Distrofia Miotônica/genética , Insuficiência Respiratória/genética , Expansão das Repetições de Trinucleotídeos/genética , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Distrofia Miotônica/complicações , Distrofia Miotônica/fisiopatologia , Pletismografia , Repetições de Trinucleotídeos/genética
7.
Dis Model Mech ; 6(3): 622-31, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23180777

RESUMO

Acute and chronic respiratory failure is one of the major and potentially life-threatening features in individuals with myotonic dystrophy type 1 (DM1). Despite several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely understood. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibits respiratory disorders and, if so, to identify the pathological changes underlying these respiratory problems. Using pressure plethysmography, we assessed the breathing function in control mice and DMSXL mice generated after large expansions of the CTG repeat in successive generations of DM1 transgenic mice. Statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. Histological and morphometric analysis showed pathological changes in diaphragmatic muscle of DMSXL mice, characterized by an increase in the percentage of type I muscle fibers, the presence of central nuclei, partial denervation of end-plates (EPs) and a significant reduction in their size, shape complexity and density of acetylcholine receptors, all of which reflect a possible breakdown in communication between the diaphragmatic muscles fibers and the nerve terminals. Diaphragm muscle abnormalities were accompanied by an accumulation of mutant DMPK RNA foci in muscle fiber nuclei. Moreover, in DMSXL mice, the unmyelinated phrenic afferents are significantly lower. Also in these mice, significant neuronopathy was not detected in either cervical phrenic motor neurons or brainstem respiratory neurons. Because EPs are involved in the transmission of action potentials and the unmyelinated phrenic afferents exert a modulating influence on the respiratory drive, the pathological alterations affecting these structures might underlie the respiratory impairment detected in DMSXL mice. Understanding mechanisms of respiratory deficiency should guide pharmaceutical and clinical research towards better therapy for the respiratory deficits associated with DM1.


Assuntos
Distrofia Miotônica/patologia , Distrofia Miotônica/fisiopatologia , Respiração , Animais , Axônios/patologia , Tronco Encefálico/patologia , Tronco Encefálico/fisiopatologia , Diafragma/patologia , Diafragma/fisiopatologia , Modelos Animais de Doenças , Humanos , Hibridização in Situ Fluorescente , Camundongos , Camundongos Transgênicos , Neurônios Motores/patologia , Músculos/inervação , Músculos/patologia , Músculos/fisiopatologia , Bainha de Mielina/metabolismo , Junção Neuromuscular/patologia , Junção Neuromuscular/fisiopatologia , Nervo Frênico/patologia , Nervo Frênico/ultraestrutura , Testes de Função Respiratória
8.
J Neuropathol Exp Neurol ; 70(8): 678-85, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21760538

RESUMO

Myotonic dystrophy type 1 (DM1) is a multisystem disorder with a variable phenotype. The involvement of peripheral nerves in DM1 disease is controversial. The DM1 animal model DM300 transgenic mice that carry 350 to 500 CTG repeats express a mild DM1 phenotype but do not exhibit motor or sensory pathology. Here, we investigated the presence or absence of peripheral neuropathy in transgenic mice (DMSXL) that carry more than 1,300 CTG repeats and display a severe form of DM1. Electrophysiologic, histologic, and morphometric methods were used to investigate the structure and function of peripheral nerves. We observed lower compound muscle action potentials recorded from hind limb muscles and slowing of sciatic nerve conduction velocity in DMSXL versus control mice. Morphometric analyses showed an axonopathy and neuronopathy in the DMSXL mice characterized by a decrease in numbers of myelinated motor axons in sciatic nerve and in spinal cord motor neurons. Pathologic alterations in the structure of hind limb neuromuscular junctions were also detected in the DMSXL mice. These results suggest that peripheral neuropathy can be linked to a large CTG expansion and a severe form of DM1.


Assuntos
Distrofia Miotônica/complicações , Distrofia Miotônica/genética , Proteínas Serina-Treonina Quinases/genética , Neuropatia Ciática/etiologia , Expansão das Repetições de Trinucleotídeos/genética , Animais , Bungarotoxinas/farmacocinética , Modelos Animais de Doenças , Eletromiografia/métodos , Potencial Evocado Motor/genética , Potencial Evocado Motor/fisiologia , Membro Posterior/patologia , Humanos , Camundongos , Camundongos Transgênicos , Neurônios Motores/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miotonina Proteína Quinase , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Mielinizadas/fisiologia , Condução Nervosa/fisiologia , Proteínas de Neurofilamentos/metabolismo , Junção Neuromuscular/metabolismo , Junção Neuromuscular/fisiopatologia , Neuropatia Ciática/genética , Neuropatia Ciática/patologia , Medula Espinal/patologia
9.
J Neurosci Res ; 88(8): 1751-63, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20127814

RESUMO

Improvement of nerve regeneration and functional recovery following nerve injury is a challenging problem in clinical research. We have already shown that following rat sciatic nerve transection, the local administration of triiodothyronine (T3) significantly increased the number and the myelination of regenerated axons. Functional recovery is a sum of the number of regenerated axons and reinnervation of denervated peripheral targets. In the present study, we investigated whether the increased number of regenerated axons by T3-treatment is linked to improved reinnervation of hind limb muscles. After transection of rat sciatic nerves, silicone or biodegradable nerve guides were implanted and filled with either T3 or phosphate buffer solution (PBS). Neuromuscular junctions (NMJs) were analyzed on gastrocnemius and plantar muscle sections stained with rhodamine alpha-bungarotoxin and neurofilament antibody. Four weeks after surgery, most end-plates (EPs) of operated limbs were still denervated and no effect of T3 on muscle reinnervation was detected at this stage of nerve repair. In contrast, after 14 weeks of nerve regeneration, T3 clearly enhanced the reinnervation of gastrocnemius and plantar EPs, demonstrated by significantly higher recovery of size and shape complexity of reinnervated EPs and also by increased acetylcholine receptor (AChRs) density on post synaptic membranes compared to PBS-treated EPs. The stimulating effect of T3 on EP reinnervation is confirmed by a higher index of compound muscle action potentials recorded in gastrocnemius muscles. In conclusion, our results provide for the first time strong evidence that T3 enhances the restoration of NMJ structure and improves synaptic transmission.


Assuntos
Axônios/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Neuropatia Ciática , Tri-Iodotironina/uso terapêutico , Animais , Axônios/fisiologia , Bungarotoxinas/metabolismo , Colina O-Acetiltransferase/metabolismo , Modelos Animais de Doenças , Potencial Evocado Motor/efeitos dos fármacos , Potencial Evocado Motor/fisiologia , Lateralidade Funcional , Técnicas In Vitro , Masculino , Regeneração Nervosa/fisiologia , Proteínas de Neurofilamentos/metabolismo , Junção Neuromuscular/fisiopatologia , Ratos , Ratos Wistar , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/cirurgia
10.
J Neuropathol Exp Neurol ; 67(8): 763-72, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18648326

RESUMO

Myotonic dystrophy Type 1 (DM-1) is caused by abnormal expansion of a (CTG) repeat located in the DM protein kinase gene. Respiratory problems have long been recognized to be a major feature of this disorder. Because respiratory failure can be associated with dysfunction of phrenic nerves and diaphragm muscle, we examined the diaphragm and respiratory neural network in transgenic mice carrying the human genomic DM-1 region with expanded repeats of more than 300 CTG, a valid model of the human disease. Morphologic and morphometric analyses revealed distal denervation of diaphragm neuromuscular junctions in DM-1 transgenic mice indicated by a decrease in the size and shape complexity of end-plates and a reduction in the concentration of acetyl choline receptors on the postsynaptic membrane. More importantly, there was a significant reduction in numbers of unmyelinated, but not of myelinated, fibers in DM-1 phrenic nerves; no morphologic alternations of the nerves or loss of neuronal cells were detected in medullary respiratory centers or cervical phrenic motor neurons. Because neuromuscular junctions are involved in action potential transmission and the afferent phrenic unmyelinated fibers control the inspiratory activity, our results suggest that the respiratory impairment associated with DM-1 may be partially due to pathologic alterations in neuromuscular junctions and phrenic nerves.


Assuntos
Diafragma/patologia , Distrofia Miotônica/genética , Distrofia Miotônica/patologia , Junção Neuromuscular/patologia , Nervo Frênico/patologia , Animais , Axônios/patologia , Bungarotoxinas/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Neurônios Motores/patologia , Proteínas de Neurofilamentos/metabolismo , Expansão das Repetições de Trinucleotídeos/genética
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