RESUMEN
BACKGROUND: Consensus guidelines on the definition, investigation, and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been previously published in European Journal of Neurology and Journal of the Peripheral Nervous System. OBJECTIVES: To revise these guidelines. METHODS: Disease experts, including a representative of patients, considered references retrieved from MEDLINE and Cochrane Systematic Reviews published between August 2004 and July 2009 and prepared statements that were agreed in an iterative fashion. RECOMMENDATIONS: The Task Force agreed on Good Practice Points to define clinical and electrophysiological diagnostic criteria for CIDP with or without concomitant diseases and investigations to be considered. The principal treatment recommendations were: (i) intravenous immunoglobulin (IVIg) (Recommendation Level A) or corticosteroids (Recommendation Level C) should be considered in sensory and motor CIDP; (ii) IVIg should be considered as the initial treatment in pure motor CIDP (Good Practice Point); (iii) if IVIg and corticosteroids are ineffective, plasma exchange (PE) should be considered (Recommendation Level A); (iv) if the response is inadequate or the maintenance doses of the initial treatment are high, combination treatments or adding an immunosuppressant or immunomodulatory drug should be considered (Good Practice Point); (v) symptomatic treatment and multidisciplinary management should be considered (Good Practice Point).
Asunto(s)
Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Corticoesteroides/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Intercambio PlasmáticoRESUMEN
To develop diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), a retrospective series of patients' records diagnosed by sexpert consensus as CIDP or other chronic polyneuropathies were analyzed. Classification and regression tree analysis was applied to 150 patients to derive a classification rule. According to the rule, diagnosis of CIDP required that a patient have a chronic non-genetic polyneuropathy, progressive for at least eight weeks, without a serum paraprotein and either 1) recordable compound muscle action potentials in > or =75% of motor nerves and either abnormal distal latency in >50% of nerves or abnormal motor conduction velocity in >50% of nerves or abnormal F wave latency in >50% of nerves; or 2) symmetrical onset of motor symptoms, symmetrical weakness of four limbs, and proximal weakness in > or =1 limb. When validated in 117 patients, the rule had 83% sensitivity (95% confidence interval 69%-93%) and 97% specificity (95% confidence interval 89%-99%) and performed better than published criteria.
Asunto(s)
Técnicas de Diagnóstico Neurológico/normas , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Humanos , Guías de Práctica Clínica como Asunto , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Several diagnostic criteria for multifocal motor neuropathy have been proposed in recent years and a beneficial effect of intravenous immunoglobulin (IVIg) and various other immunomodulatory drugs has been suggested in several trials and uncontrolled studies. The objectives were to prepare consensus guidelines on the definition, investigation and treatment of multifocal motor neuropathy. Disease experts and a patient representative considered references retrieved from MEDLINE and the Cochrane Library in July 2004 and prepared statements which were agreed in an iterative fashion. The Task Force agreed good practice points to define clinical and electrophysiological diagnostic criteria for multifocal motor neuropathy and investigations to be considered. The principal recommendations and good practice points were: (i) IVIg (2 g/kg given over 2-5 days) should be considered as the first line treatment (level A recommendation) when disability is sufficiently severe to warrant treatment. (ii) Corticosteroids are not recommended (good practice point). (iii) If initial treatment with IVIg is effective, repeated IVIg treatment should be considered (level C recommendation). The frequency of IVIg maintenance therapy should be guided by the individual response (good practice point). Typical treatment regimens are 1 g/kg every 2-4 weeks or 2 g/kg every 4-8 weeks (good practice point). (iv) If IVIg is not or not sufficiently effective then immunosuppressive treatment may be considered. Cyclophosphamide, ciclosporin, azathioprine, interferon beta1a, or rituximab are possible agents (good practice point). (v) Toxicity makes cyclophosphamide a less desirable option (good practice point).
Asunto(s)
Enfermedad de la Neurona Motora/terapia , Neurología , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/terapia , Guías de Práctica Clínica como Asunto , Sociedades Médicas , Comités Consultivos , Europa (Continente) , Humanos , MEDLINE/estadística & datos numéricos , Nervios PeriféricosRESUMEN
BACKGROUND: Paraprotein-associated neuropathies have heterogeneous clinical, neurophysiological, neuropathological and haematological features. Objectives. To prepare evidence-based and consensus guidelines on the clinical management of patients with both a demyelinating neuropathy and a paraprotein (paraproteinaemic demyelinating neuropathy, PDN). METHODS: Search of MEDLINE and the Cochrane library, review of evidence and consensus agreement of an expert panel. RECOMMENDATIONS: In the absence of adequate data, evidence based recommendations were not possible but the panel agreed the following good practice points: (1) Patients with PDN should be investigated for a malignant plasma cell dyscrasia. (2) The paraprotein is more likely to be causing the neuropathy if the paraprotein is immunoglobulin (Ig)M, antibodies are present in serum or on biopsy, or the clinical phenotype is chronic distal sensory neuropathy. (3) Patients with IgM PDN usually have predominantly distal and sensory impairment, with prolonged distal motor latencies, and often anti-myelin associated glycoprotein antibodies. (4) IgM PDN sometimes responds to immune therapies. Their potential benefit should be balanced against their possible side-effects and the usually slow disease progression. (5) IgG and IgA PDN may be indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy, clinically, electrophysiologically, and in response to treatment. (6) For POEMS syndrome, local irradiation or resection of an isolated plasmacytoma, or melphalan with or without corticosteroids, should be considered, with haemato-oncology advice.
Asunto(s)
Enfermedades Desmielinizantes , Neurología , Paraproteinemias , Nervios Periféricos , Guías de Práctica Clínica como Asunto , Sociedades Médicas , Comités Consultivos , Conducta Cooperativa , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/terapia , Europa (Continente) , Medicina Basada en la Evidencia , Humanos , MEDLINE/estadística & datos numéricos , Paraproteinemias/diagnóstico , Paraproteinemias/terapiaRESUMEN
Numerous sets of diagnostic criteria have sought to define chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and randomized trials and systematic reviews of treatment have been published. The objective is to prepare consensus guidelines on the definition, investigation and treatment of CIDP. Disease experts and a patient representative considered references retrieved from MEDLINE and Cochrane Systematic Reviews in May 2004 and prepared statements which were agreed in an iterative fashion. The Task Force agreed on good practice points to define clinical and electrophysiological diagnostic criteria for CIDP with or without concomitant diseases and investigations to be considered. The principal treatment recommendations were: (1) intravenous immunoglobulin (IVIg) or corticosteroids should be considered in sensory and motor CIDP (level B recommendation); (2) IVIg should be considered as the initial treatment in pure motor CIDP (Good Practice Point); (3) if IVIg and corticosteroids are ineffective plasma exchange (PE) should be considered (level A recommendation); (4) If the response is inadequate or the maintenance doses of the initial treatment are high, combination treatments or adding an immunosuppressant or immunomodulatory drug should be considered (Good Practice Point); (5) Symptomatic treatment and multidisciplinary management should be considered (Good Practice Point).
Asunto(s)
Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Humanos , Sistema Nervioso Periférico/patologíaRESUMEN
Intravenous gamma globulin (IVIg) is used in the treatment of immunologic diseases that affect the entire neuroaxis, including the brain, spinal cord, peripheral nerves, muscles, and neuromuscular junction. The panel reviewed the available literature on the use of IVIg in order to evaluate the efficacy of this therapy in neuroimmunologic diseases. In prospective, rigorously controlled, double-blinded clinical trials, IVIg was found to have proven efficacy in the Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, dermatomyositis, and Lambert-Eaton myasthenic syndrome. It was found to be probably effective in myasthenia gravis and polymyositis, and possibly effective in several other neuroimmunologic diseases. Further studies are needed to evaluate the use of IVIg for neuroimmunologic diseases in which its efficacy is suspected but not proven and to elucidate its mechanisms of action.
Asunto(s)
Enfermedades del Sistema Inmune/terapia , Inmunoglobulinas Intravenosas/uso terapéutico , Enfermedades del Sistema Nervioso/terapia , Ensayos Clínicos como Asunto , HumanosRESUMEN
Sublytic C5b-9 induces cell cycle activation, proliferation, and rescue from apoptosis in Schwann cells. The signaling pathways for C5b-9-mediated rescue were investigated. Following serum withdrawal, DNA fragmentation, detected by TUNEL and FACS analysis, was 56.7% +/- 7.3 and 91.9% +/- 2.4 in cultured sciatic nerve Schwann cells from 6-day-old rats after 18 h and 24 h, respectively. Apoptosis was confirmed by inhibition of DNA fragmentation in a dose-dependent manner by DMQD-CHO, a caspase-3 inhibitor. Treatment with sublytic C5b-9 generated with purified components (C5*9) or Ab+C7-depleted serum (C7dHS)+C7 rescued 89% and 86% of Schwann cells, respectively, as compared with cells treated with C5*6, C8, C9, or Ab+C7dHS. Sublytic C5b-9 increased Schwann cell PI-3 kinase and Akt activity maximally at 5 min 3.14 +/- 0.5-fold and 3.56 +/- 0.4-fold, respectively, over controls. ERK-1 activity was maximally stimulated 2.98-fold at 15 min. Inhibition of PI-3 kinase by LY294002 abrogated the C5b-9-mediated Schwann cell rescue from apoptosis, while inhibition of ERK-1 with PD098,059 did not. PI-3 kinase-Akt pathway activation by C5b-9 induced, within 15 min, a 6.34 +/- 1.2-fold increase in BAD phosphorylation at Ser 136, but not at Ser 112. Downstream Bcl-x(L) protein was increased 2.61-fold +/- 0.34-fold by 18 h and 3.9-fold +/- 0.84-fold by 24 h over controls. LY294002 prevented both BAD phosphorylation at Ser 136 and Bcl-x(L) protein induction, while PD098,059 did not. Our data indicated that sublytic C5b-9 rescued Schwann cell from apoptosis via activation of PI-3 kinase-Akt, BAD phosphorylation on Ser 136 and increased expression of Bcl-x(L). Sublytic C5b-9 detected on Schwann cell in vivo during inflammatory neuropathy may facilitate survival of Schwann cell capable of remyelination.
Asunto(s)
Apoptosis/fisiología , Proteínas Portadoras/metabolismo , Supervivencia Celular/fisiología , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas , Células de Schwann/metabolismo , Transducción de Señal/fisiología , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas/citología , Células Cultivadas/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/farmacología , Medio de Cultivo Libre de Suero/farmacología , Inhibidores Enzimáticos/farmacología , Etiquetado Corte-Fin in Situ , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Polirradiculoneuropatía/metabolismo , Polirradiculoneuropatía/fisiopatología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Sprague-Dawley , Células de Schwann/citología , Células de Schwann/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína Letal Asociada a bcl , Proteína bcl-XRESUMEN
Experimental allergic encephalitis, (EAE) a Th1-cell-dependent autoimmune disease of the central nervous system (CNS) used to study immune responses relevant to multiple sclerosis (MS) displays gender susceptibility. The underlying basis of the sexual dimorphism may reflect multiple factors including gender-specific hormones. To study the relationship between ovarian hormones and CNS inflammation, we induced EAE in susceptible female Lewis rats ovariectomized (OVX) 7 days earlier and implanted with blank capsules or capsules containing estradiol (E), progesterone (P), or both (EP). Rats were immunized with complete Freunds' adjuvant alone or combined with guinea pig myelin basic protein. Motor function was scored 0-5 on standard criteria (days 7-11 postimmunization). On day 11, the rats were euthanized and the lumbar spinal cord was analyzed for Nissl, neuron nuclear antigen, and DNA fragmentation with a TUNEL assay. Inflammation was judged qualitatively on a scale of 0-4. Our immunization protocol induced limited sensorimotor deficits in OVX rats (2.3 +/- 0.6, mean +/- SEM) with moderate inflammation (2.5 +/- 0.4). E limited both behavioral impairments (1.0 +/- 0.4) and inflammation (0.5 +/- 0.2). P-treated rats had more severe sensorimotor deficits (3.1 +/- 0.5) with increased inflammatory infiltrates (3.6 +/- 0.4) and markedly increased numbers of TUNEL(+) neurons. Neuron counts of the outer two Rexed lamina (L3-L5) showed a 20% neuron loss (P < 0.02) in P-treated rats with EAE in comparison to other groups. Coadministration of E with P prevented the consequences of P, including neuronal apoptosis (behavioral score, 0.6 +/- 0.6; inflammation, 1.4 +/- 0.5). Our results suggest a potential and novel function of P that increases the vulnerability of neurons to apoptotic injury in EAE and may have pathophysiologic implications in the progression of disability in women with MS.
Asunto(s)
Encefalomielitis Autoinmune Experimental/fisiopatología , Estrógenos/farmacología , Neuronas/patología , Progesterona/farmacología , Médula Espinal/patología , Animales , Péptido Relacionado con Gen de Calcitonina/análisis , Supervivencia Celular , Implantes de Medicamentos , Encefalomielitis Autoinmune Experimental/patología , Estrógenos/administración & dosificación , Femenino , Etiquetado Corte-Fin in Situ , Inflamación/patología , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Ovariectomía , Progesterona/administración & dosificación , Ratas , Ratas Endogámicas Lew , Médula Espinal/efectos de los fármacos , Factores de TiempoRESUMEN
The consequences of sublytic terminal complement complex (TCC) assembly on Schwann cell proliferation and apoptosis were examined by using purified complement proteins (C5*-9) or antibody-sensitized Schwann cells in the presence of a serum that was depleted of the seventh component of complement (C7dHS) and reconstituted with purified C7. Stimulation of cultured Schwann cells with antibody plus 10% C7dHS and C7 or C5*-9 induced DNA synthesis over antibody plus 10% C7dHS alone or in Schwann cells in which C5*-9 insertion was inhibited by heat inactivation, respectively. Cell cycle analysis with propidium iodide showed that, at 24 h, viable Schwann cells in defined medium were synchronized in G1/G0 phase. C5*-9 shifted 64% of these cells into S or G2/M phases in a manner similar to beta-neuregulin (beta-NRG), a known Schwann cell mitogen. Furthermore, antibody with 10% C7dHS and C7 or purified C5*-9 induced proliferation of viable Schwann cells. These effects were mediated by signal-transduction pathways involving p44 ERK1 (extracellular-regulated kinase 1), Gi proteins, and protein kinase C. Culturing in defined medium for 24 h resulted in apoptosis of up to 50% of Schwann cells that was prevented by treatment with beta-NRG or TCC. Sublytic C5*-9 significantly inhibited apoptosis 41% by 24 h, as determined by a terminal deoxyuridine triphosphate-biotin nick end labeling assay, and also decreased annexin-V binding at 4 h. Collectively, these data suggest that sublytic TCC, like beta-NRG, is a potent Schwann cell trophic factor that is capable of stimulating mitogenesis and apoptotic rescue. TCC assembly on Schwann cells during inflammatory demyelination of peripheral nerves may promote survival of mature cells to enhance repair and remyelination processes.
Asunto(s)
Apoptosis/efectos de los fármacos , Complejo de Ataque a Membrana del Sistema Complemento/farmacología , Células de Schwann/citología , Animales , División Celular/efectos de los fármacos , Células Cultivadas , Complejo de Ataque a Membrana del Sistema Complemento/aislamiento & purificación , ADN/biosíntesis , Etiquetado Corte-Fin in Situ , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mitosis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Células de Schwann/enzimología , Nervio Ciático/citologíaRESUMEN
The pathogenesis of the axonal degeneration in acquired or hereditary amyloidosis is unknown. In this immunohistochemistry study, we examined 20 sural nerve biopsies from individuals with amyloid neuropathy (14 acquired and 6 hereditary) for evidence of complement activation. Complement activation products were detected on and around amyloid deposits within peripheral nerves. We found no difference in the extent, location or pattern of complement activation products between the 2 forms of amyloidosis. The presence of early classical pathway activation markers in the absence of antibody in hereditary cases suggests an antibody-independent activation of the classical pathway through binding of C1q. The lack of Factor Bb-suggested alternative pathway activation was not significant in these cases. The detection of C5b-9 neoantigen on amyloid deposits demonstrated that the full complement cascade was activated. Complement activation on amyloid deposits and the generation of C5b-9 in vivo may contribute to bystander injury of axons in the vicinity of amyloid deposits.
Asunto(s)
Amiloidosis/inmunología , Amiloidosis/patología , Activación de Complemento/inmunología , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/patología , Anciano , Amiloidosis/genética , Biopsia , Complemento C1q/análisis , Complemento C1q/inmunología , Complemento C3d/análisis , Complemento C3d/inmunología , Complemento C4/análisis , Complemento C4/inmunología , Complejo de Ataque a Membrana del Sistema Complemento/análisis , Complejo de Ataque a Membrana del Sistema Complemento/inmunología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/genética , Nervio Sural/inmunología , Nervio Sural/patologíaRESUMEN
Complement cascade activation on peripheral nerve myelin can cause myelin destruction. Although terminal complement complexes (TCCs) are transiently detected on Schwann cells (SchCs) during inflammatory neuropathy, SchCs appear resistant to complement-mediated lysis, and little is known about the functional consequences of sublytic TCC deposition on SchCs. We studied the effects of sublytic complement in modulating myelin gene expression at the posttranscriptional and transcriptional levels. Cultured SchCs, stimulated to express protein zero (P0), were treated with sensitizing antibody (Ab) and normal human serum (NHS) complement. P0 mRNA content decreased by 71% during 12 h. In the presence of actinomycin D, P0 mRNA levels declined 50% following incubation with Ab plus 10% NHS over 6 h, compared with control levels, suggesting enhanced P0 mRNA degradation. The decreases, in part, reflected TCC formation because C7 reconstitution of Ab plus C7-depleted human serum (C7dHS) or TCCs assembled from purified components down-regulated P0 mRNA 53 and 55% over that of Ab plus C7dHS or heat-activated components, respectively. Expression of a P0 promoter/luciferase reporter construct transiently transfected into SchCs was reduced 70% by sublytic TCCs at 6 h, demonstrating that P0 gene transcription was also inhibited. c-jun mRNA was up-regulated within 30 min by sublytic TCCs, before the reduction in P0 mRNA expression. Our data suggest that sublytic complement activation on SchCs may contribute to peripheral nerve demyelination by decreasing expression of genes important in myelin formation and compaction.
Asunto(s)
Complejo de Ataque a Membrana del Sistema Complemento/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Proteína P0 de la Mielina/genética , Células de Schwann/efectos de los fármacos , Animales , Membrana Celular/efectos de los fármacos , Membrana Celular/ultraestructura , Células Cultivadas , Activación de Complemento , Complemento C7/fisiología , ADN Complementario/genética , Dactinomicina/farmacología , Genes jun , Humanos , Proteína P0 de la Mielina/biosíntesis , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Factor 6 de Transcripción de Unión a Octámeros , Proteínas Proto-Oncogénicas c-jun/biosíntesis , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Células de Schwann/metabolismo , Nervio Ciático , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Transcripción Genética/efectos de los fármacos , TransfecciónRESUMEN
Fifteen patients with chronic inflammatory demyelinating neuropathy (CIDP) were treated with pulse intravenous cyclophosphamide (IVCY) monthly for up to 6 months. Eleven patients reached a complete remission; only one patient worsened. Complications included nausea, vomiting, anemia, and hair loss. This case series suggests that monthly IVCY is beneficial in the treatment of CIDP and warrants a controlled study.
Asunto(s)
Ciclofosfamida/administración & dosificación , Enfermedades Desmielinizantes/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Polineuropatías/tratamiento farmacológico , Adulto , Enfermedad Crónica , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Flujo PulsátilRESUMEN
BACKGROUND: The number of reports of influenza-vaccine-associated Guillain-Barré syndrome to the national Vaccine Adverse Event Reporting System increased from 37 in 1992-1993 to 74 in 1993-1994, arousing concern about a possible increase in vaccine-associated risk. METHODS: Patients given a diagnosis of the Guillain-Barré syndrome in the 1992-1993 and 1993-1994 influenza-vaccination seasons were identified in the hospital-discharge data bases of four states. Vaccination histories were obtained by telephone interviews during 1995-1996 and were confirmed by the vaccine providers. Disease with an onset within six weeks after vaccination was defined as vaccine-associated. Vaccine coverage in the population was measured through a random-digit-dialing telephone survey. RESULTS: We interviewed 180 of 273 adults with the Guillain-Barré syndrome; 15 declined to participate, and the remaining 78 could not be contacted. The vaccine providers confirmed influenza vaccination in the six weeks before the onset of Guillain-Barré syndrome for 19 patients. The relative risk of the Guillain-Barré syndrome associated with vaccination, adjusted for age, sex, and vaccine season, was 1.7 (95 percent confidence interval, 1.0 to 2.8; P=0.04). The adjusted relative risks were 2.0 for the 1992-1993 season (95 percent confidence interval, 1.0 to 4.3) and 1.5 for the 1993-1994 season (95 percent confidence interval, 0.8 to 2.9). In 9 of the 19 vaccine-associated cases, the onset was in the second week after vaccination, all between day 9 and day 12. CONCLUSIONS: There was no increase in the risk of vaccine-associated Guillain-Barré syndrome from 1992-1993 to 1993-1994. For the two seasons combined, the adjusted relative risk of 1.7 suggests slightly more than one additional case of Guillain-Barré syndrome per million persons vaccinated against influenza.
Asunto(s)
Vacunas contra la Influenza/efectos adversos , Polirradiculoneuropatía/etiología , Adolescente , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos , Anciano , Anciano de 80 o más Años , Recolección de Datos , Femenino , Humanos , Vacunas contra la Influenza/administración & dosificación , Masculino , Persona de Mediana Edad , Polirradiculoneuropatía/epidemiología , Riesgo , Estados Unidos/epidemiologíaRESUMEN
Inflammatory demyelination of nerve in Guillain-Barré syndrome is triggered in most patients by prior infection with one of a series of organisms, including Campylobacter jejuni. The resulting inflammatory cascade, involving T cells, macrophages, complement, and cytokines, disrupts physiologic function of the peripheral nerve in part by targeting Schwann cells, the multipotential glial cells that synthesize multilamellar, compacted myelin and secrete growth factors. In vitro evidence suggests that the Schwann cell may itself be able to modulate the cascade by serving as an antigen-presenting cell and by producing cytokines and other acute-phase reactants.
Asunto(s)
Polirradiculoneuropatía/inmunología , Polirradiculoneuropatía/patología , Células de Schwann/inmunología , Células de Schwann/patología , Animales , Presentación de Antígeno , Infecciones por Campylobacter/complicaciones , Proteínas del Sistema Complemento/inmunología , Citocinas/inmunología , Humanos , Infecciones/complicaciones , Macrófagos/inmunología , Neuritis/complicaciones , Neuritis/inmunología , Nervios Periféricos/inmunología , Nervios Periféricos/patología , Polirradiculoneuropatía/etiología , Ratas , Células de Schwann/fisiología , Linfocitos T/inmunologíaRESUMEN
Schwann cells (SchC), the myelinating glia of the peripheral nervous system, are immunocompetent cells and secrete a variety of immune and inflammatory mediators. In this report, we show that rat SchC in vitro express both C3 mRNA and protein in response to dibutyryl cyclic AMP (dbcAMP) and the cytokines IFN-gamma, TNF-alpha, and IL-1beta. SchC in culture constitutively expressed low levels of C3 which were significantly upregulated upon stimulation with 1mM dbcAMP by 24 hours, and persisted up to 120 hours. This response was minimally enhanced by costimulation with 100 U/ml IFN-gamma, whereas costimulation with 100 U/ml IFN-gamma together with 150-450 ng/ml TNF-alpha induced a greatly increased C3 response. TNF-alpha alone did not induce C3 expression in SchC. Cycloheximide inhibited this dbcAMP-dependent delayed C3 production, thus implying an intermediary signal in the induction pathway requiring protein synthesis. Treatment with 0.1-10 ng/ml IL-1beta for 0-72 hours induced C3 mRNA and protein in a dose-dependent manner. C3 mRNA was detectable at 1 hour and mRNA and protein peaked by 6-12 hours on stimulation with 10 ng/ml IL-1beta, or at 48 hours with 1.0 ng/ml IL-1beta. Furthermore, IL-1beta mRNA was detected at 6 hours in dbcAMP-treated SchC, preceding the dbcAMP-induced C3 expression by 18 hours. Induction of C3 mRNA and protein by dbcAMP at 24 hours was inhibited >85% by a neutralizing anti-IL-1beta antibody and 76% with an IL-1 receptor antagonist. This suggests that dbcAMP-induced synthesis of IL-1beta mediates the C3 production by SchC in an autocrine/paracrine fashion by binding to a functional IL-1 receptor expressed on the surface of SchC. Endoneurial IL-1 and C3 production by SchC may therefore contribute to the inflammatory events associated with peripheral nerve demyelination.
Asunto(s)
Bucladesina/farmacología , Complemento C3/biosíntesis , Citocinas/farmacología , Células de Schwann/metabolismo , Animales , Northern Blotting , Células Cultivadas , Sondas de ADN , Ensayo de Inmunoadsorción Enzimática , Interferón gamma/farmacología , Interleucina-1/farmacología , Cinética , Reacción en Cadena de la Polimerasa , ARN Mensajero/biosíntesis , ARN Mensajero/aislamiento & purificación , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes , Células de Schwann/efectos de los fármacos , Estimulación Química , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Neuroborreliosis can cause a wide variety of seemingly unrelated neurologic abnormalities. Although the epidemiology, etiology, and pathology of this infection have been well documented, the pathogenesis and diagnosis continue to be problematic. In the current study we report a case of Lyme disease in which subarachnoid hemorrhage was the presenting feature of a patient with polyradiculoneuropathy and encephalopathy. Magnetic resonance imaging of the spine demonstrated diffuse pial and meningeal enhancement with more focal nodular areas of involvement.
Asunto(s)
Enfermedad de Lyme/complicaciones , Hemorragia Subaracnoidea/etiología , Adulto , Femenino , Humanos , Enfermedad de Lyme/diagnóstico , Imagen por Resonancia Magnética , Hemorragia Subaracnoidea/diagnósticoRESUMEN
To further investigate the role of complement activation in Experimental Allergic Neuritis (EAN), the effect of systemic complement blockade by soluble CR1 (sCR1) was compared to complement depletion by Cobra Venom Factor (CVF) in EAN rats immunized with bovine peripheral nerve myelin. EAN rats treated with CVF (n = 10) had significantly reduced clinical scores compared to rats treated with sCR1 (n = 9) or saline (n = 10) (score: sCR1 0.66 +/- 0.7; CVF 0; saline 0.6 +/- 0.8; mean +/- SD). CVF treatment more effectively decreased inflammation and demyelination compared to sCR1 treatment which had only a partial effect (inflammation: sCR1 1.8 +/- 1.4; CVF 0.3 +/- 0.7; saline 1.9 +/- 1.2; demyelination; sCR1 1.3 +/- 1; CVF 0.1 +/- 0.6; saline 1.7 +/- 1.2). In lumbosacral nerve roots significantly less infiltrating ED1 positive macrophages and CD11bc (expressing complement receptor 3 or CR3) positive inflammatory cells were present in CVF treated EAN rats while there was a limited decrease in inflammation in the sCR1 treated animals compared to the saline treated rats (ED1: sCR1 1.4 +/- 1.2; CVF 0.5 +/- 0.6; saline 1.7 +/- 1.2; CD11bc: sCR1 1.9 +/- 1.2; CVF 0.9 +/- 1; saline 2.1 +/- 1.2). Our findings suggest that complement depletion by CVF is more effective than complement blockade by sCR1 in reducing the severity of inflammatory peripheral nerve demyelination.
Asunto(s)
Venenos Elapídicos/uso terapéutico , Neuritis Autoinmune Experimental/tratamiento farmacológico , Receptores de Complemento/uso terapéutico , Animales , Biomarcadores , Bovinos , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/inmunología , Femenino , Inmunización , Inmunohistoquímica , Macrófagos/química , Vaina de Mielina/inmunología , Ratas , Ratas Endogámicas Lew , Receptores de Complemento/sangre , Solubilidad , Raíces Nerviosas Espinales/inmunología , Raíces Nerviosas Espinales/patologíaRESUMEN
Antibody (Ab) sensitized sciatic nerve Schwann cells (SchC) of 2-day-old rats (SchC/2d) were significantly more susceptible to cytolysis by both heterologous, guinea pig (GP), and homologous rat serum complement (40 +/- 3.8% and 21.2 +/- 3.1%, respectively) than SchC of 6-day-old rats (SchC/6d) (7.9 +/- 5.9% and 2.6 +/- 3.1%, respectively). To determine if resistance to complement (C)-mediated cytolysis correlated with expression of membrane proteins which regulate C activation, we used Western blot and FACS analysis. Binding of specific polyclonal Ab demonstrated similar concentrations of Crry, a regulator of C3 convertase formation, on plasma membranes of SchC 2d and 6d. During C activation, both C3b deposition and iC3b formation were greater on SchC/6d than on SchC/2d and the C3b deposition did not correlate with enhanced cytolysis. In contrast, 2.1-fold more rat CD59, a regulator of C8 and C9 incorporation into C5b-9, detected with Western blot on SchC/6d compared with SchC/2d was confirmed by FACS. Further, both rat and GP C8/C9 lysed SchC/2d expressing human C5b-7 (20.1 +/- 3.7 and 21.6 +/- 4.7%, respectively), while only GP C8/C9 caused cytolysis of 10.7 +/- 4.3% SchC/6d expressing hu C5b-7 and rat C8/C9 did not (0.5 +/- 0.5%). Preincubation of SchC/6d with an F(ab)2 fragment of an mAb to rCD59 with blocking capacity, increased cytolysis mediated by rat serum C more than 6-fold to 16.7 +/- 3.0% but only 1.7-fold (maximum cytolysis 37.4 +/- 11.2%) in SchC/2d. Our data suggest that expression of rat CD59 on SchC increased almost two-fold between postnatal days 2 and 6, and this increased expression on more terminally differentiated SchC is a significant factor in regulating terminal complement complex formation and limiting cytolysis of rat SchC by homologous serum complement.
Asunto(s)
Antígenos CD59/fisiología , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Proteínas del Sistema Complemento/fisiología , Citotoxicidad Inmunológica , Células de Schwann/inmunología , Animales , Antígenos de Superficie , Células Cultivadas , Complemento C3/metabolismo , Complemento C8/metabolismo , Complemento C9/metabolismo , Cobayas , Ratas , Ratas Sprague-Dawley , Receptores de Superficie Celular , Receptores de Complemento/metabolismo , Nervio CiáticoRESUMEN
The expression of decay-accelerating factor CD55, membrane cofactor protein CD46, and CD59 was studied on Schwann cells cultured from human sural nerve and myelin membranes prepared from human cauda equina and spinal cord. These proteins are regulatory membrane molecules of the complement system. CD55 and CD46 are inhibitors of C3 and C5 convertases and CD59 inhibits C8 and C9 incorporation into C5b-9 complex and C9-C9 polymerization. The presence of these proteins was assessed by using antibodies to each of the proteins by fluorescent microscopy, fluorescence-activated cell sorter analysis, and also sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot analysis. Schwann cells in culture expressed CD55, CD46, and CD59. It is interesting that only CD59 was detected on myelin from both central and peripheral nerve tissue. The ability of these proteins to limit C3 peptide deposition and C9 polymerization in myelin was studied by western blot analysis. C3b deposition was readily detected on antibody-sensitized myelin incubated with normal human serum used as a source of complement but not with EDTA-treated or heat-inactivated serum. C3b deposition was not affected by anti-CD55 antibody. On the other hand, poly-C9 formation in myelin, which was maximum when 50% normal human serum was used, was increased four-to fivefold when myelin was preincubated with anti-CD59. Our data suggest that complement activation on myelin is down-regulated at the step of the assembly of terminal complement complexes, including C5b-9, due to the presence of CD59.