RESUMO
OBJECTIVE: The pathophysiology of primary burning mouth syndrome (BMS) has remained enigmatic, but recent studies suggest pathology within the nervous system at multiple levels. This study aimed to investigate in detail the contribution of either focal or generalized alterations within the peripheral nervous system (PNS) in the etiopathogenesis of BMS. SUBJECTS AND METHODS: Intraepithelial nerve fiber density (IENFD) of tongue mucosa was assessed in 10 carefully characterized BMS, and the results were compared to 19 age- and gender-matched cadaver controls, 6 with lifetime diabetes. Extensive neurophysiologic and psychophysical examinations of the trigeminal system and distal extremities were performed to profile PNS function in BMS. RESULTS: Patients with BMS had significantly fewer intraepithelial nerve fibers (0,27, s.e. 0,18 mm(-1); P = 0.0253) than non-diabetic controls (0,92, s.e. 0,15 mm(-1)). In the subepithelial space, the amount of nerve fibers did not differ between the groups. The majority (9/10) of patients with BMS showed neurophysiologic or psychophysical signs of a more generalized PNS dysfunction. CONCLUSIONS: Our results in neurophysiologically optimally characterized BMS patients confirm that pure focal small fiber neuropathy of the oral mucosa has a role in the pathophysiology of primary BMS. Furthermore, BMS may be related to a more generalized, yet subclinical peripheral neuropathy.
Assuntos
Síndrome da Ardência Bucal/etiologia , Mucosa Bucal/inervação , Sistema Nervoso Periférico/patologia , Sistema Nervoso Periférico/fisiopatologia , Língua/inervação , Idoso , Cadáver , Estudos de Casos e Controles , Diabetes Mellitus/patologia , Epitélio/inervação , Feminino , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Psicofisiologia , Nervo Trigêmeo/patologia , Nervo Trigêmeo/fisiopatologiaRESUMO
Experimental autoimmune encephalomyelitis (EAE) is an autoimmune inflammation of the central nervous system and is used as the experimental model of multiple sclerosis (MS). The exact mechanism behind the disease is still unknown, but interleukin (IL)-17 expressing T cells are thought to mediate the disease. Toll-like receptors (TLRs) are known to have a role in the innate immune response against pathogens, and several TLRs have also a role in the disease course of EAE. Here, we show that treatment with a herpes simplex virus type 1 vector expressing the Th2 cytokine IL-5 ameliorates EAE and decreases the numbers of infiltrating lymphocytes in the brain. The effect involves downregulation of TLR 2, 3 and 9 mRNA expression and upregulation of type I interferons (IFNs) in brains during onset of disease. The elevated expression of type I IFNs was also observed during recovery.
Assuntos
Encefalomielite Autoimune Experimental/terapia , Terapia Genética/métodos , Vetores Genéticos , Herpesvirus Humano 1/genética , Interleucina-5/genética , Animais , Encéfalo/metabolismo , Regulação para Baixo , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos , RNA Mensageiro/metabolismo , Receptores Toll-Like/metabolismoRESUMO
BACKGROUND: Signaling through the leukemia inhibitory factor (LIF) receptor (LIFR) is crucial for nervous system development. There are few studies concerning the expression of LIF and LIFR in normal and degenerating adult human brain. OBJECTIVES: To study the expression of LIF and LIFR in Alzheimer's disease (AD), Parkinson's disease (PD), and control brains. PATIENTS AND METHODS: LIF and LIFR mRNA copy numbers were determined by quantitative real-time RT-PCR from four brain regions of 34 patients with AD, 40 patients with PD, and 40 controls. Immunohistochemistry was performed in seven PD and in four AD patients and in seven normal controls. RESULTS: In general, the LIF copy numbers were 1 log higher than the LIFR copy numbers. In the AD brains, LIF expression was higher than in the controls in the hippocampus and in the temporal cortex, and in the PD brains in the hippocampus and in the anterior cingulated cortex. Expressions of LIF and LIFR in different brain regions were opposite except for the AD hippocampus and PD anterior cingulated cortex, where the expression patterns were parallel. CONCLUSIONS: Co-operative expression of LIF and LIFR in AD hippocampus and PD anterior cingulated cortex may indicate a role for LIF in neuronal damage or repair in these sites.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/patologia , Fator Inibidor de Leucemia/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , Receptores de OSM-LIF/genética , Idoso , Primers do DNA/genética , DNA Complementar/genética , Progressão da Doença , Feminino , Giro do Cíngulo/patologia , Hipocampo/patologia , Humanos , Imuno-Histoquímica , Masculino , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
We measured serum levels of neurotrophic cytokines ciliary neurotrophic factor (CNTF) and leukaemia inhibiting factor (LIF) in 96 patients either with familial amyotrophic lateral sclerosis (FALS, n = 18) or sporadic ALS (SALS, n = 78) and in 27 inflammatory neurological controls (13 multiple sclerosis and 14 Guillain-Barré syndrome) and in 27 healthy controls. Serum level of CNTF was significantly higher in ALS patients than in inflammatory neurological controls or healthy controls, and significantly higher in patients with ALS onset from upper or lower extremities than in patients with a purely bulbar onset of the disease. Serum CNTF levels did not significantly differ between patients with FALS and SALS, and it did not correlate with the age of onset or duration of the disease. No detectable serum levels of LIF were observed in the patient groups or in the healthy controls.
Assuntos
Esclerose Lateral Amiotrófica/sangue , Fator Neurotrófico Ciliar/sangue , Idade de Início , Idoso , Creatina Quinase/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Fator Inibidor de Leucemia/sangue , Masculino , Pessoa de Meia-Idade , Estatísticas não ParamétricasRESUMO
Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E epsilon4 allele (APOE epsilon4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE epsilon4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and epsilon4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and epsilon4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and epsilon4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and epsilon4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with epsilon4 had a combined effect with regard to the risk of AD.
Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Butirilcolinesterase/genética , Endopeptidases/genética , Predisposição Genética para Doença/genética , Doença de Parkinson/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/enzimologia , Doença de Alzheimer/epidemiologia , Feminino , Finlândia , Frequência do Gene/genética , Heterozigoto , Humanos , Modelos Logísticos , Masculino , Mutação/genética , Razão de Chances , Doença de Parkinson/complicações , Doença de Parkinson/enzimologia , Doença de Parkinson/epidemiologia , Fenótipo , Polimorfismo Genético/genéticaRESUMO
We treated a case of thymoma with immunodeficiency (Good's syndrome) associated with a rare combination of other parathymic syndromes including myasthenia gravis, benign IgG lambda M component, pernicious anemia, and diabetes. The characterization of the patient's immunologic capacity disclosed practically normal T-cell number and mitogenic responses but impaired lymphokine production as well as B-cell function.
Assuntos
Hipergamaglobulinemia/complicações , Imunoglobulina G/análise , Síndromes de Imunodeficiência/complicações , Miastenia Gravis/complicações , Timoma/complicações , Neoplasias do Timo/complicações , Humanos , Hipergamaglobulinemia/imunologia , Síndromes de Imunodeficiência/imunologia , Contagem de Leucócitos , Fatores Inibidores da Migração de Leucócitos/biossíntese , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/imunologia , Síndrome , Timectomia , Timoma/imunologia , Neoplasias do Timo/imunologiaRESUMO
AIM: Neuropeptide Y (NPY) co-localized with noradrenaline in central and sympathetic nervous systems seems to play a role in the control of energy metabolism. In this study, the aim was to elucidate the effects and pathophysiological mechanisms of increased NPY in catecholaminergic neurones on accumulation of body adiposity. METHODS: Transgenic mice overexpressing NPY under the dopamine-beta-hydroxylase promoter (OE-NPY(DßH) ) and wild-type control mice were followed for body weight gain and body fat content. Food intake, energy expenditure, physical activity, body temperature, serum lipid content and markers of glucose homoeostasis were monitored. Thermogenic and lipolytic responses in adipose tissues, and urine catecholamine and tissue catecholamine synthesizing enzyme levels were analysed as indices of sympathetic tone. RESULTS: Homozygous OE-NPY(DßH) mice showed significant obesity accompanied with impaired glucose tolerance and insulin resistance. Increased adiposity was explained by neither increased food intake or fat absorption nor by decreased total energy expenditure or physical activity. Adipocyte hypertrophy and decreased circulating lipid levels suggested decreased lipolysis and increased lipid uptake. Brown adipose tissue thermogenic capacity was decreased and brown adipocytes filled with lipids. Enhanced response to adrenergic stimuli, downregulation of catecholamine synthesizing enzyme expressions in the brainstem and lower adrenaline excretion supported the notion of low basal catecholaminergic activity. CONCLUSION: Increased NPY in catecholaminergic neurones induces obesity that seems to be a result of preferential fat storage. These results support the role of NPY as a direct effector in peripheral tissues and an inhibitor of sympathetic activity in the pathogenesis of obesity.
Assuntos
Neurônios Adrenérgicos/metabolismo , Neuropeptídeo Y/metabolismo , Obesidade/metabolismo , Sistema Nervoso Simpático/fisiologia , Tecido Adiposo Marrom , Animais , Metabolismo Energético , Regulação da Expressão Gênica , Hipotálamo/metabolismo , Camundongos , Camundongos Transgênicos , Neuropeptídeo Y/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
We studied the effect of selegiline (deprenyl) treatment on the number of Lewy bodies and neuron counts in the substantia nigra in patients with Parkinson's disease (PD). The number of medial nigral neurons was greater and the number of Lewy bodies fewer in those PD patients who had been treated with selegiline in combination with levodopa as compared with patients who had received levodopa alone. This suggests that selegiline treatment may retard the death of nigral neurons, but alternative explanations, such as the reduction of levodopa dosage in selegiline-treated patients, are possible.
Assuntos
Doença de Parkinson/tratamento farmacológico , Selegilina/uso terapêutico , Substância Negra/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Sobrevivência Celular , Humanos , Neurônios/patologia , Doença de Parkinson/patologia , Substância Negra/patologiaRESUMO
We studied the effect of unilateral ligation of two spinal nerves on behavioral pain responses evoked by various types of cutaneous stimuli in the adult rat. Furthermore, we determined the effect of spinal nerve ligation on morphology of the peripheral nerves. The most consistent behavioral finding (83%) was a marked decrease in monofilament-induced hindlimb withdrawal thresholds (mechanical allodynia) ipsilateral to the spinal nerve ligation. This mechanical allodynia was observed as early as during the 1st post-operative day and it persisted up to 2 months (the maximum length of the observation period). In contrast, hyperalgesia to noxious mechanical stimulation (Randal-Sellitto test) was not observed in allodynic rats until the 3rd post-operative day. In a minority of rats (13%), spinal nerve ligation-induced mechanical hyperalgesia without a concomitant mechanical allodynia. There was no corresponding heat hyperalgesia in the injured hindlimb (hot water immersion-, radiant heat- or hot-plate-induced hindlimb withdrawal tests). In contrast, hypoalgesia to heat was observed on the 1st postoperative day, but not later. Neuropathological analysis of the peripheral nerves revealed a dramatic decrease in the number of myelinated nerve fibers distal to the spinal nerve ligation site. The results support the previous evidence indicating that ligation of spinal nerves induces a marked allodynia to mechanical stimulation. However, this mechanical allodynia may differentially dissociate from mechanical and thermal hyperalgesia at various post-operative time points. The marked mechanical allodynia together with a dramatic decrease in the number of myelinated nerve fibers is paradoxical, since the activation of myelinated nerve fibers by monofilaments produced abnormally strong behavioral responses. This paradox may be explained by spinal nerve ligation-induced amplification or disinhibition of tactile signals at central levels.
Assuntos
Doenças do Sistema Nervoso Periférico/fisiopatologia , Transtornos de Sensação/fisiopatologia , Nervos Espinhais/fisiopatologia , Animais , Hiperalgesia/fisiopatologia , Ligadura , Masculino , Medição da Dor , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/patologia , Estimulação Física , Ratos , Ratos Wistar , Tempo de Reação , Transtornos de Sensação/etiologia , Transtornos de Sensação/patologia , Pele/fisiopatologia , Temperatura Cutânea , Nervos Espinhais/patologiaRESUMO
A novel form of adjuvant-neuroantigen formulation was established which was highly encephalitogenic in previously resistant BALB/c mice. The antigen formulation contained mouse whole spinal cord homogenate (MSCH), mycobacteria, and mineral oil, identically to the conventional preparation, but emulsification was completed by sonication instead of extrusion. Sonication of MSCH alone did not render a conventionally prepared emulsion encephalitogenic. The novel adjuvant formulation showed reduced water-oil droplet size, and the neuroantigen was located on the surface of the droplets as well as in the intermicellar space, while in the extruded formulation the material was buried in the droplet interior. Mice inoculated with the sonicated emulsion showed strong brain and spinal cord infiltration of lymphoid cells. The sonicated emulsion was highly encephalitogenic in all six BALB/c substrains tested. The results suggest that availability of the neuroantigen is of critical importance for the development of clinical EAE in the BALB/c mouse.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Camundongos Endogâmicos BALB C/imunologia , Proteínas do Tecido Nervoso/imunologia , Adjuvantes Imunológicos/química , Animais , Emulsões , Feminino , Camundongos , Microscopia Eletrônica , Proteínas do Tecido Nervoso/química , Sonicação , Medula Espinal/imunologiaRESUMO
BALB/c mice were irradiated with 350 R and injected with mouse spinal cord homogenate (MSCH) in complete Freund's adjuvant. Only 15-30% of these animals developed signs of experimental allergic encephalomyelitis (EAE) at 21-28 days after inoculation. Intraperitoneal infection with the non-lethal A7 strain of Semliki forest virus (SFV) 7 days after sensitization reduced the mean appearance time of the EAE symptoms to 14 days and the number of animals with clinical EAE increased up to 70%. In contrast, virus inoculation 10 days before induction of EAE decreased significantly the incidence of clinical EAE in both BALB/c and SJL mice. Demyelination with increased cellularity, presence of macrophages, stripping of myelin from the axons and sparing of oligodendrocytes was observed in spinal cords of animals at days 13-16 after induction of EAE and subsequent virus infection. No demyelination was seen in specimens taken at the same time from mice inoculated with MSCH or SFV alone. Combined MSCH and virus inoculations induced changes in the general immune response which may be one of the major reasons for the increase or decrease in demyelination in this model.
Assuntos
Encefalomielite Autoimune Experimental/etiologia , Infecções por Togaviridae/complicações , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Vírus da Floresta de Semliki , Medula Espinal/imunologia , Fatores de Tempo , Infecções por Togaviridae/imunologia , Infecções por Togaviridae/patologia , Irradiação Corporal TotalRESUMO
Experimental allergic encephalomyelitis (EAE) is facilitated in resistant BALB/c mice by intraperitoneal infection with an avirulent Semliki Forest virus (SFV-A7). Viral infection increases the incidence of EAE from 15-30% to 60-90% and speeds up appearance of paralysis from 24 to 14 days. In this paper, we describe treatment of virus-facilitated EAE with monoclonal antibodies (mAbs) against leukocyte and/or endothelial cell adhesion molecules. Therapy with mAb against ICAM-1 (intercellular adhesion molecule-1) had a modest effect, but caused hemorrhagic brain and spinal cord lesions. Therapy with mAb against Mac-1 (alpha M beta 2-integrin) was well tolerated but had no effect. Therapy with mAb against VLA-4 (alpha 4 beta 1-integrin) was safe, diminished both clinical and histopathological signs of EAE, decreased induction of VCAM-1 (vascular cell adhesion molecule-1) on brain vessels and diminished infiltration of VLA-4+ cells into the brain. The amount of viral antigen in the brain was not altered. We conclude that facilitation of leukocyte entry into the brain is a major mechanism for viral facilitation of EAE in the BALB/c mouse, and that facilitation can be inhibited by anti-adhesion therapy. This may have implications for treatment of relapses triggered by viral infections in multiple sclerosis.
Assuntos
Encefalomielite Autoimune Experimental/terapia , Integrinas/imunologia , Receptores de Retorno de Linfócitos/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Antígenos Virais/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/virologia , Imuno-Histoquímica , Imunoterapia , Integrina alfa4beta1 , Integrina beta1/imunologia , Molécula 1 de Adesão Intercelular/imunologia , Antígeno de Macrófago 1/química , Antígeno de Macrófago 1/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Vírus da Floresta de Semliki/imunologiaRESUMO
Infection with an avirulent strain of Semliki Forest virus (SFV-A7) facilitates the development of experimental allergic encephalomyelitis (EAE) in a genetically resistant BALB/c mouse strain. Irradiation which is necessary for EAE induction caused a decrease in the total number of lymphocytes and an increase in CD4+/CD8+ T cell ratio in the spleen of BALB/c mice. EAE induction increased the ratio further until clinical and histological signs of EAE appeared. Entry of perivascular CD4+ and CD8+ cells preceded the onset of clinical signs and the appearance of MAC-1+ cells in the central nervous system (CNS). In the acute phase of EAE, cellular infiltrates, which were sparse, consisted mainly of MAC-1+ cells and a few CD4+ and CD8+ cells. Inflammatory cells gradually disappeared during the recovery phase. SFV-A7 infection after irradiation and EAE induction did not significantly change the CD4+/CD8+ ratio in the spleen or in the CNS infiltrates but enhanced the entry of inflammatory cell into the CNS. Similar perivascular cell influx was also seen in untreated mice infected with SFV-A7. We conclude that observed rapid reduction of splenic mononuclear cells and increase of the CD4+/CD8+ T cell ratio caused by irradiation prior EAE induction are early crucial events in disease induction in this resistant strain of mice. SFV-A7 infection, which further facilitates the development of EAE, does not induce immunoregulatory changes but provides its effect by enhancing the entry of inflammatory cells into the CNS. The combination of these two mechanisms thus effectively breaks the natural resistance against EAE in this genetically resistant mouse strain.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Vírus da Floresta de Semliki/fisiologia , Irradiação Corporal Total , Animais , Encéfalo/imunologia , Encéfalo/patologia , Relação CD4-CD8 , Encefalomielite Autoimune Experimental/virologia , Feminino , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Baço/imunologia , Fatores de TempoRESUMO
Linomide (quinoline-3-carboxamide) is an immunomodulator with diverse effects on the immune system. Its beneficial effects on experimental autoimmune disease models have been linked to downregulation of Th1 cytokines and altered macrophage functions. We studied this effect of downregulation of Th1-type of immune response on Semliki Forest A7 virus infection in experimental autoimmune encephalomyelitis (EAE) susceptible Th1-prone SJL mice and in EAE-resistant Th2-prone BALB/c mice. We aimed at addressing the target-cell population of Linomide responsible for this Th1 downregulation. Treatment with Linomide led to increased virus infection in brain and this effect coincided with decreased production of IL-12 and IFN-gamma from stimulated spleen cells in SJL mice. In contrast, IL-12 and IFN-gamma expression were increased in Linomide-treated BALB/c mice. Treatment of infected SJL mice resulted in decreased percentage of CD11b+ and CD11c+ cells. Thus, the target cell population of Linomide may be antigen-presenting cells (APC) which are considered as candidates for regulatory cells of Th1/Th2 balance.
Assuntos
Adjuvantes Imunológicos/farmacologia , Infecções por Alphavirus/imunologia , Hidroxiquinolinas/farmacologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Encéfalo/virologia , Antígeno CD11b/análise , Encefalomielite Autoimune Experimental/imunologia , Interferon gama/biossíntese , Interleucina-12/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , RNA Viral/análise , Vírus da Floresta de Semliki , Baço/citologia , Carga ViralRESUMO
Axotomy of a peripheral nerve leads to interruption of axon continuity with Wallerian degeneration in the distal segment and regenerative events in the proximal remaining neuron. Local inflammation is a consequence of trauma in general and signal molecules regulating inflammation, such as cytokines, participate in the outcome of nerve trauma. We studied a broad set of potent immunoregulatory cytokines after transection of rat sciatic nerve. The endoneurium of the transected rat sciatic nerve was taken from both proximal and distal stumps. The pooled endoneurium of 6 rats was studied using reverse transcription polymerase chain reaction (RT-PCR) after 14 h; 1, 3, 5, 7 days; 2 and 4 weeks after transection. A new observation was that TNF-alpha mRNA showed phasic expression pattern; three distinct peaks were seen, immediately (14 h), after 5 days and in the distal part also after 2 weeks. This phenomenon may be related to the breakdown of the blood-nerve barrier and to the recruitment of circulating macrophages. We further noticed that IFN-gamma mRNA was expressed between 5 days and 2 weeks. This suggests that T-cells may also take part in the regenerative processes. Furthermore, we observed that IL-10 mRNA is expressed continuously during Wallerian degeneration. The continuous expression of IL-10 mRNA may attenuate the production of inflammatory cytokines by macrophages and other cells.
Assuntos
Interferon gama/genética , Interleucina-10/genética , Nervos Periféricos/metabolismo , RNA Mensageiro/metabolismo , Nervo Isquiático/lesões , Fator de Necrose Tumoral alfa/genética , Ferimentos Penetrantes/metabolismo , Animais , Imuno-Histoquímica , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
This report describes two mechanisms by which virus infection can facilitate demyelinating autoimmune inflammation in the murine CNS. In the BALB/c mouse model of experimental allergic encephalomyelitis (EAE), peripheral infection with an avirulent strain (A7) of Semliki Forest virus (SFV) increased the morbidity to EAE by infecting endothelial cells and damaging the blood-brain barrier (BBB). An influx of hematogenous CD18+ (LFA-1+ and MAC-1+) cells into the CNS compartment was followed by a local increase in intercellular adhesion molecule 1 (ICAM-1) expression on the vascular endothelium. Although SFV A7 infection without EAE induction caused multifocal cerebral vascular endothelial cell infection and BBB damage followed by cellular infiltration and transient increase of ICAM-1, inflammation and demyelination of CNS white matter with classical clinical signs of EAE was observed only in EAE-induced BALB/c mice, whereas the control mice remained neurologically healthy. The upregulation of ICAM-1 after virus infection was detected after the CD18+ (LFA-1+ and MAC-1+) cells had infiltrated the CNS both after EAE induction and also in nonsensitized control mice. The observed increase in ICAM-1 expression was transient in nonsensitized SFV A7 infected mice just as in the cellular infiltrates in the CNS, but EAE induction resulted in prolongation in both the cellular infiltrates and upregulation of ICAM-1. Thus, SFV A7 infection causes BBB damage and prolongs increased ICAM-1 expression on brain endothelium. This results in increased and more rapid morbidity to EAE in mice which have been sensitized with neuroantigen. However, SFV A7-infected mice without neuroantigen sensitization remain neurologically healthy.
Assuntos
Infecções por Alphavirus , Barreira Hematoencefálica , Encefalomielite Autoimune Experimental/fisiopatologia , Encefalomielite Autoimune Experimental/virologia , Molécula 1 de Adesão Intercelular/metabolismo , Vírus da Floresta de Semliki , Animais , Antígenos Virais/análise , Antígenos CD18/análise , Permeabilidade Capilar , Encefalomielite Autoimune Experimental/imunologia , Feminino , Fibrinogênio/análise , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Susceptibility to autoimmunity has been associated with polarization of Th1/Th2 balance in immune system towards the Th1-type of reactivity. We report here that orally administered quinoline-3-carboxamide (Linomide) selectively downregulates Th1 response in BALB/c and SJL mice, leading to reduction of autoimmunity in the BALB/c and SJL models of experimental allergic encephalomyelitis (EAE). This was shown by prevention of EAE in Th1 responding SJL mice and partial downregulation of EAE in Th2-prone BALB/c mice. In a BALB/c model of EAE, in which infection with Semliki Forest A7 virus (SFV-A7) is used for enhancement of autoimmunity, clinical signs of EAE were reduced while mortality due to viral infection in the CNS was enhanced. Selective downregulation of the Th1 response by Linomide also rendered initially resistant SJL mice susceptible to SFV-A7 CNS infection. This was shown by immunohistochemical detection of extensive deposits of viral antigen in numerous perivascular foci within the CNS and abolished virus antigen-specific lymphocyte reactivity in Linomide-treated SJL mice. In addition, analysis of spleen cell cytokine mRNA production profile revealed decreased number of IFN-gamma producing cells in both SJL and BALB/c mice, reduced number of IL-12p40 producing cells in SJL and increased number of 12p40 producing cells in BALB/c mice along with slightly increased IL-4 production in both strains of mice. These results indicate that oral treatment with Linomide induces selective downregulation of Th1 reactivity causing reduction of autoimmunity and increased susceptibility to SFV-A7 CNS infection. Selective downregulation of Th1 response is a desired effect in the treatment of autoimmune diseases but our results suggest that the benefits have to be balanced against the possible loss in immunoprotection against pathogens.
Assuntos
Adjuvantes Imunológicos/farmacologia , Infecções por Alphavirus/imunologia , Autoimunidade/efeitos dos fármacos , Hidroxiquinolinas/farmacologia , Vírus da Floresta de Semliki , Células Th1/efeitos dos fármacos , Animais , Formação de Anticorpos/efeitos dos fármacos , Antígenos Virais/imunologia , Sistema Nervoso Central/virologia , Citocinas/genética , Suscetibilidade a Doenças/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , RNA Mensageiro/metabolismo , Vírus da Floresta de Semliki/imunologia , Vírus da Floresta de Semliki/isolamento & purificação , Baço/metabolismo , Baço/patologia , Células Th1/imunologia , Células Th1/fisiologiaRESUMO
A traumatic injury of a peripheral nerve leads to Wallerian degeneration. It includes the recruitment of macrophages and the phagocytosis of myelin and the remnants of axons. We have previously studied the recruitment of macrophages and now wished to determine if the immunosuppressant cyclosporin A (CsA) affects the number of macrophages at the site of nerve injury. The primary target of CsA is T-cells, but it may also have an effect on mononuclear phagocytes which exert a key role during Wallerian degeneration. Rats were divided into two groups: CsA-treated animals and control animals. Following transection of the sciatic nerve in the treatment group, the animals received 5 mg/kg CsA subcutaneously. The groups were further subdivided into a freely regenerating nerve group and a sutured nerve group. The number of macrophages and MHC class II positive cells were counted 3 days, 7 days, 2 weeks, 4 weeks, and 8 weeks posttransection; also CD4, CD8, IL-2 receptor positive cells, B cells, and the axonal sprouting were studied. In the CsA-treated group, there were more macrophages in the distal areas under 8 weeks than in the controls (p < 0.05); thus, the clearance of macrophages is delayed in the CsA-treated rats compared to the control rats. In the proximal area, the difference in macrophage number did not gain statistical significance. Additionally, CsA retarded axonal degeneration. CsA affects number of macrophages during Wallerian degeneration, while retarding axonal degeneration and subsequent reinnervation. Its mechanism of action appears to involve either direct or indirect via T-cells-mediated responses.
Assuntos
Axônios/efeitos dos fármacos , Axônios/patologia , Ciclosporina/farmacologia , Imunossupressores/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Traumatismos dos Nervos Periféricos , Nervos Periféricos/patologia , Degeneração Walleriana/patologia , Degeneração Walleriana/fisiopatologia , Animais , Axônios/imunologia , Contagem de Células , Tamanho Celular , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/patologia , Macrófagos/imunologia , Masculino , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Nervos Periféricos/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de Tempo , Degeneração Walleriana/tratamento farmacológicoRESUMO
TGF-beta is a multifunctional regulatory protein with important effects on cell proliferation and differentiation, immune reactivity and extracellular matrix (ECM). During peripheral regeneration it can have growth promoting effects for axonal sprouting, but on the other hand, it may be involved in epineurial scarring and neuroma formation. We studied the expression of TGF-beta1 mRNA in the rat peripheral nerve with real time-PCR at 1, 3, 5, 7, 14, 21, 28, 35, and 42 days after transection. The sciatic nerve was sutured after transection to prevent axonal regeneration. Samples from both proximal and distal stumps were collected. To distinguish the possible different expression in the endo- and epineurium these two compartments were studied separately. The most significant finding was observed in the epineurium of the proximal stump 35 days after the operation. The expression of TGF-beta1 mRNA was over 700 times higher than that found in the non-operated controls. At the same time the expression of TGF-beta1 mRNA in the endoneurium was only twice as high as the values measured from the non-operated controls. Distally the TGF-beta1 mRNA expression in the endoneurium reached its peak after 2 weeks, and at weeks 3-6, the expression was two to four times higher than in the controls. This study supports the concept that TGF-beta1 can affect epineurial scarring.
Assuntos
Degeneração Neural/metabolismo , Nervos Periféricos/metabolismo , Nervo Isquiático/fisiologia , Fator de Crescimento Transformador beta/biossíntese , Animais , Axotomia , Masculino , Regeneração Nervosa/fisiologia , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta1RESUMO
We asked whether reinnervating axons are Schwann cell mitogens in vivo as they are in vitro. Left sciatic nerves of 50 Wistar rats were transected. In one-half of the animals, axonal reinnervation from the proximal to the distal stump was allowed to take place, while in the other half, sutures were placed on the transected nerve ends to prevent reinnervation. Samples were collected from 3 days up to 8 weeks after the transection proximally and distally from the point of transection. PCNA-immunostaining was performed on paraffin sections to determine the number of proliferating cells. Axonal reinnervation was followed by Bielschowsky staining and Schwann cell number was determined by counting S-100-immunopositive cells from paraffin sections. In the distal stump Schwann cell proliferation was similar in both experimental groups. There was no statistical evidence of S-100 negative cell proliferation during the study. Proximally to the site of transection the number of small initial axonal sprouts and also the number of Schwann cells increased if the nerve stump had been sutured. In conclusion, although axons may be mitogenic for Schwann cells, axonal reinnervation into the distal stump of the transected peripheral nerve does not influence the proliferation of Schwann cells to a greater extent than other potential effects associated with nerve transection.