RESUMO
Monocytes represent a heterogeneous population of primary immune effector cells. At least three different subsets can be distinguished based on expression of the low-affinity FcγRIII: CD14(++)CD16 -: classical monocytes, CD14(++)CD16(+) intermediate monocytes, and CD14(+)CD16 ++: non-classical monocytes. Whereas CD16 -: classical monocytes are considered key players in multiple sclerosis (MS), little is known on CD16(+) monocytes and how they contribute to the disease. In this study, we examined the frequency and phenotype of monocyte subpopulations in peripheral blood, cerebrospinal fluid (CSF), and brain biopsy material derived from MS patients and controls. Furthermore, we addressed a possible monocyte dysfunction in MS and analyzed migratory properties of monocyte subsets using human brain microvascular endothelial cells. Our ex vivo studies demonstrated that CD16(+) monocyte subpopulations are functional but numerically reduced in the peripheral blood of MS patients. CD16(+) monocytes with an intermediate-like phenotype were found to be enriched in CSF and dominated the CSF monocyte population under noninflammatory conditions. In contrast, an inversed CD16(+) to CD16 -: CSF monocyte ratio was observed in MS patients with relapsing-remitting disease. Newly infiltrating, hematogenous CD16(+) monocytes were detected in a perivascular location within active MS lesions, and CD16(+) monocytes facilitated CD4(+) T cell trafficking in a blood -: brain barrier model. Our findings support an important role of CD16(+) monocytes in the steady-state immune surveillance of the CNS and suggest that CD16(+) monocytes shift to sites of inflammation and contribute to the breakdown of the blood-brain barrier in CNS autoimmune diseases.
Assuntos
Encéfalo/imunologia , Sistema Nervoso Central/imunologia , Vigilância Imunológica , Monócitos/imunologia , Esclerose Múltipla/imunologia , Receptores de IgG/imunologia , Adulto , Doenças Autoimunes do Sistema Nervoso/imunologia , Barreira Hematoencefálica/imunologia , Encéfalo/citologia , Movimento Celular , Líquido Cefalorraquidiano/citologia , Células Endoteliais , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/fisiologia , Esclerose Múltipla/fisiopatologia , FenótipoRESUMO
To investigate the genetics of late-onset myasthenia gravis (LOMG), we conducted a genome-wide association study imputation of>6 million single nucleotide polymorphisms (SNPs) in 532 LOMG cases (anti-acetylcholine receptor [AChR] antibody positive; onset age≥50 years) and 2,128 controls matched for sex and population substructure. The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10-7, odds ratio [OR] 1.42) and identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10-10, OR 0.53). Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10-6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases. In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG. Many SNPs within the major histocompatibility complex (MHC) region showed strong associations in LOMG, but with smaller effect sizes than in EOMG (highest OR ~2 versus ~6 in EOMG). Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10-12) versus 2.82 in EOMG (P = 3.86 × 10-45). Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs. Conditioning studies of human leukocyte antigen (HLA) amino acid residues also suggest potential functional correlates. Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG.
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The present guidelines on dermatomyositis (DM) represent an excerpt from the interdisciplinary S2k guidelines on myositis syndromes of the German Society of Neurology (available at www.awmf.org). The cardinal symptom of myositis in DM is symmetrical proximal muscle weakness. Elevated creatine kinase, CRP or ESR as well as electromyography and muscle biopsy also provide important diagnostic clues. Pharyngeal, respiratory, cardiac, and neck muscles may also be affected. Given that approximately 30% of patients also develop interstitial lung disease, pulmonary function tests should be part of the diagnostic workup. Although the cutaneous manifestations in DM are variable, taken together, they represent a characteristic and crucial diagnostic criterion for DM. Approximately 5-20% of individuals exhibit typical skin lesions without any clinically manifest muscle involvement (amyopathic DM). About 30% of adult DM cases are associated with a malignancy. This fact, however, should not delay the treatment of severe myositis. Corticosteroids are the therapy of choice in myositis (1-2 mg/kg). Additional immunosuppressive therapy is frequently required (azathioprine, for children methotrexate). In case of insufficient therapeutic response, the use of intravenous immunoglobulins is justified. The benefit of rituximab has not been conclusively ascertained yet. Acute therapeutic management is usually followed by low-dose maintenance therapy for one to three years. Skin lesions do not always respond sufficiently to myositis therapy. Effective treatment for such cases consists of topical corticosteroids and sometimes also calcineurin inhibitors. Systemic therapies shown to be effective include antimalarial agents (also in combination), methotrexate, and corticosteroids. Intravenous immunoglobulins or rituximab may also be helpful. UV protection is an important prophylactic measure.
Assuntos
Dermatologia/normas , Dermatomiosite/diagnóstico , Dermatomiosite/terapia , Técnicas de Diagnóstico Neurológico , Neurologia/normas , Guias de Prática Clínica como Assunto , Corticosteroides/uso terapêutico , Alemanha , Imunossupressores/uso terapêuticoRESUMO
BACKGROUND: The family of 14-3-3 proteins plays an important role in the regulation of cell survival and death. Here, we investigate the role of the 14-3-3 gamma (14-3-3 γ) subunit for glial responses in autoimmune demyelination. METHODS: Expression of 14-3-3 γ in glial cell culture was investigated by reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry. 14-3-3 γ knockout mice were subjected to murine myelin oligodendrocyte-induced experimental autoimmune encephalomyelitis (MOG-EAE), an animal model mimicking inflammatory features and neurodegenerative aspects of multiple sclerosis (MS). RESULTS: Expression studies in cell culture confined expression of 14-3-3 γ to both, oligodendrocytes (OL) and astrocytes. RT-PCR analysis revealed an increased expression of 14-3-3 γ mRNA in the spinal cord during the late chronic phase of MOG-EAE. At that stage, EAE was more severe in 14-3-3 γ knockout mice as compared to age- and gender-matched controls. Histopathological analyses on day 56 post immunization (p.i.) revealed significantly enhanced myelin damage as well as OL injury and secondary, an increase in axonal injury and gliosis in 14-3-3 γ -/- mice. At the same time, deficiency in 14-3-3 γ protein did not influence the immune response. Further histological studies revealed an increased susceptibility towards apoptosis in 14-3-3 γ-deficient OL in the inflamed spinal cord. CONCLUSION: These data argue for a pivotal role of 14-3-3 γ-mediated signalling pathways for OL protection in neuroinflammation.
Assuntos
Proteínas 14-3-3/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Neuroglia/metabolismo , Proteínas 14-3-3/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Axônios/patologia , Células Cultivadas , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Proteína Glial Fibrilar Ácida/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas da Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidade , Proteínas Nogo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Fragmentos de Peptídeos/toxicidade , Fosfopiruvato Hidratase/metabolismo , RNA Mensageiro/metabolismo , Fatores de TempoRESUMO
Neural stem/progenitor cells (NSPCs) have the ability to migrate into the central nervous system (CNS) to replace damaged cells. In inflammatory CNS disease, cytokine transduced neural stem cells may be used as vehicles to specifically reduce inflammation and promote cell replacement. In this study, we used NSPCs overexpressing IL-10, an immunomodulatory cytokine, in an animal model for CNS inflammation and multiple sclerosis (MS). Intravenous injection of IL-10 transduced neural stem/progenitor cells (NSPC(IL-10)) suppressed myelin oligodendrocyte glycoprotein aa 35-55 (MOG35-55)- induced experimental autoimmune encephalomyelitis (EAE) and, following intravenous injection, NSPC(IL-10) migrated to peripheral lymphoid organs and into the CNS. NSPC(IL-10 )suppressed antigen-specific proliferation and proinflammatory cytokine production of lymph node cells obtained from MOG35-55 peptide immunized mice. In this model, IL-10 producing NSPCs act via a peripheral immunosuppressive effect to attenuate EAE.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Interleucina-10/imunologia , Células-Tronco Neurais/imunologia , Células-Tronco Neurais/transplante , Transplante de Células-Tronco/métodos , Animais , Ensaio de Imunoadsorção Enzimática , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução GenéticaRESUMO
OBJECTIVE: The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG). METHODS: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. RESULTS: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 × 10(-92) ; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 × 10(-113) ; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 × 10(-10) ), an imputed coding variant (rs2233290) at position 151 (ProâAla) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 × 10(-10) ). INTERPRETATION: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis.
Assuntos
Alanina/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Antígeno HLA-B8/genética , Miastenia Gravis/genética , Polimorfismo de Nucleotídeo Único/genética , Prolina/genética , Adulto , Idade de Início , Estudos de Casos e Controles , Europa (Continente) , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Metanálise como Assunto , População Branca/genética , Adulto JovemRESUMO
BACKGROUND: Cognitive impairment is a common symptom of multiple sclerosis (MS), but little is known about cognitive decline in patients in the long-term course of progressive MS. Because advancing age is the most significant risk factor for Alzheimer's Disease (AD), AD-related pathology must be considered in elderly patients with MS. Amnestic mild cognitive impairment (aMCI) represents the prodromal phase of AD with subjects showing memory impairment that does not improve with recognition testing. OBJECTIVE: We sought to identify disease-dependent deterioration patterns by comparing elderly patients with secondary progressive MS (SPMS) and with aMCI using the Consortium to Establish a Registry for Alzheimer's Disease test battery. METHODS: This study included 120 age-, education- and gender-matched participants, including healthy controls (n=40), SPMS patients (n=40), and aMCI patients (n=40). RESULTS: Episodic memory deficits appeared in the long-term course of SPMS. Deficits were associated with deterioration of executive function, but not impairment of memory storage as recognition was preserved in SPMS in contrast to the patients with aMCI. CONCLUSION: Through neuropsychological testing, MS-related episodic memory impairment due to deteriorated executive function can be distinguished from AD-related encoding and storage deficits. Hence, neuropsychological testing may help to identify AD-related pathology in SPMS patients.
Assuntos
Envelhecimento/psicologia , Amnésia/psicologia , Cognição , Disfunção Cognitiva/psicologia , Memória Episódica , Esclerose Múltipla Crônica Progressiva/psicologia , Reconhecimento Psicológico , Fatores Etários , Idoso , Amnésia/diagnóstico , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/diagnóstico , Testes Neuropsicológicos , Valor Preditivo dos Testes , Fatores de TempoRESUMO
Glioblastoma multiforme is the most frequent and most malignant primary brain tumor with poor prognosis despite surgical removal and radio-chemotherapy. In this setting, immunotherapeutical strategies have great potential, but the reported repertoire of tumor associated antigens is only for HLA-A 02 positive tumors. We describe the first analysis of HLA-peptide presentation patterns in HLA-A 02 negative glioma tissue combined with gene expression profiling of the tumor samples by oligonucleotide microarrays. We identified numerous candidate peptides for immunotherapy. These are peptides derived from proteins with a well-described role in glioma tumor biology and suitable gene expression profiles such as PTPRZ1, EGFR, SEC61G and TNC. Information obtained from complementary analyses of HLA-A 02 negative tumors not only contributes to the discovery of novel shared glioma antigens, but most importantly provides the opportunity to tailor a patient-individual cocktail of tumor-associated peptides for a personalized, targeted immunotherapeutic approach in HLA-A 02 negative patients.
Assuntos
Neoplasias Encefálicas/patologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioblastoma/patologia , Antígenos HLA/metabolismo , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/metabolismo , Receptores ErbB/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Glioblastoma/classificação , Glioblastoma/metabolismo , Humanos , Ligantes , Proteínas de Membrana/metabolismo , Peptídeos/metabolismo , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Canais de Translocação SEC , Espectrometria de Massas em TandemRESUMO
We describe a 13-year-old girl presenting with steroid-resistant bilateral optic neuritis. After plasma exchange (PE), the girl experienced full recovery of her visual acuity. During a 4-year follow-up no relapse occurred. As far as we know, this is the first report of PE treatment in optic neuritis in a child.
Assuntos
Neurite Óptica/terapia , Troca Plasmática , Adolescente , Feminino , Glucocorticoides/uso terapêutico , Humanos , Metilprednisolona/uso terapêutico , Neurite Óptica/tratamento farmacológico , Resultado do TratamentoRESUMO
Platelet collagen receptor glycoprotein VI (pGPVI) is elevated in patients with acute coronary syndrome (ACS) and ischemic stroke. Recently, we developed a novel bead-based sandwich immunoassay to determine soluble GPVI (sGPVI), which has been validated in ACS patients. This study aimed to evaluate the plasma levels of sGPVI and pGPVI expression in patients with suspected stroke. We consecutively evaluated 176 patients, who were admitted to the stroke unit. Surface expression of pGPVI was determined by flow cytometry, sGPVI concentrations were determined using our sandwich immunoassay. Unlike patients with TIA, patients with stroke showed significantly decreased plasma levels of sGPVI compared to patients with non-ischemic (NI) events (TIA: mean [µg/L] ± standard deviation): 6.1 ± 2.1 vs. NI: 8 ± 4; p = 0.192; stroke: 5.9 ± 2.3 vs. NI; p = 0.013), whereas for pGPVI, patients with TIA and ischemic stroke revealed a significantly increased platelet surface expression compared to NI patients (TIA: mean fluorescence intensity [MFI] ± standard deviation): 20.9 ± 5.4 vs. NI: 17.6 ± 5.2; p = 0.021; stroke: 20.3 ± 6.2 vs. NI; p = 0.016). Using logistic regression analysis, both sGPVI (p = 0.002) and pGPVI (p = 0.012) are independently associated with ischemic stroke compared to other laboratory markers. To predict the individual risk for ischemic stroke using the plasma levels of sGPVI, receiver operating characteristic (ROC) analysis determined an optimal cutoff value of sGPVI at 6.5 µg/l, thus, patients with decreased plasma levels (<6.5 µg/l) have a 1.5-fold adjusted odds ratio (95%confidence interval, 1.4-2.7). Lower plasma levels of sGPVI are associated with the slightly elevated risk of stroke and may be a promising novel biomarker.
Assuntos
Glicoproteínas da Membrana de Plaquetas/metabolismo , Acidente Vascular Cerebral/sangue , Idoso , Feminino , Humanos , MasculinoRESUMO
Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.
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BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.
Assuntos
Anticorpos/sangue , Aquaporina 4/imunologia , Neuromielite Óptica/sangue , Neuromielite Óptica/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Tronco Encefálico/patologia , Estudos de Coortes , Avaliação da Deficiência , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/mortalidade , Bandas Oligoclonais/líquido cefalorraquidiano , Recidiva , Estudos Retrospectivos , Estatística como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
The interaction of developing thymocytes with peptide-MHC complexes on thymic antigen presenting cells (APC) is crucial for T cell development, both for positive selection of "useful" thymocytes as well as negative selection of autoreactive thymocytes to prevent autoimmunity. The peptides presented on MHC II molecules are generated by lysosomal proteases such as the cathepsins. At the same time, lysosomal proteases will also destroy other potential T cell epitopes from self-antigens. This will lead to a lack of presentation on negatively selecting thymic antigen presenting cells and consequently, escape of autoreactive T cells recognizing these epitopes. In order to understand the processes that govern generation or destruction of self-epitopes in thymic APC, we studied the antigen processing machinery and epitope processing in the human thymus. We find that each type of thymic APC expresses a different signature of lysosomal proteases, providing indirect evidence that positive and negative selection of CD4(+) T cells might occur on different sets of peptides, in analogy to what has been proposed for CD8(+) T cells. We also find that myeloid dendritic cells (DC) are more efficient in processing autoantigen than plasmacytoid DC. In addition, we observed that cathepsin S plays a central role in processing of the autoantigens myelin basic protein and proinsulin in thymic dendritic cells. Cathepsin S destroyed a number of known T cell epitopes, which would be expected to result in lack of presentation and consequently, escape of autoreactive T cells. Cathepsin S therefore appears to be an important factor that influences selection of autoreactive T cells.
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Apresentação de Antígeno/imunologia , Autoantígenos/imunologia , Catepsinas/metabolismo , Células Dendríticas/imunologia , Timo/imunologia , Sequência de Aminoácidos , Autoantígenos/metabolismo , Células Dendríticas/metabolismo , Humanos , Dados de Sequência Molecular , Proteína Básica da Mielina/imunologia , Proteína Básica da Mielina/metabolismo , Proinsulina/imunologia , Proinsulina/metabolismo , Timo/metabolismoRESUMO
Interventional therapies using angioplasty and stenting of symptomatic stenosis of the proximal supraaortic vessels have evolved as safe and effective treatment strategies. The aim of this paper is to summarize the current treatment concepts for stenosis in the subclavian and brachiocephalic artery with regard to clinical indication, interventional technique including selection of the appropriate vascular approach and type of stent, angiographic and clinical short-term and long-term results and follow-up. The role of hybrid interventions for tandem stenoses of the carotid bifurcation and brachiocephalic artery is analysed. A systematic review of data for angioplasty and stenting of symptomatic extracranial vertebral artery stenosis is discussed with a special focus on restenosis rate.
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Angioplastia com Balão/métodos , Tronco Braquiocefálico , Estenose das Carótidas/terapia , Stents , Síndrome do Roubo Subclávio/terapia , Insuficiência Vertebrobasilar/terapia , Angiografia , Estenose das Carótidas/diagnóstico por imagem , Terapia Combinada , Endarterectomia das Carótidas , Humanos , Embolia Intracraniana/prevenção & controle , Recidiva , Síndrome do Roubo Subclávio/diagnóstico por imagem , Insuficiência Vertebrobasilar/diagnóstico por imagemRESUMO
The role of regulatory T cell populations within the CNS in the regulation of CNS-autoimmunity is controversial. We show that during recovery from relapsing remitting experimental autoimmune encephalomyelitis, regulatory T cells accumulate within the CNS that express high levels of CD62L. These CD62L(high) Treg cells express increased amounts of CTLA-4, ICOS and TGF-ß and are more potent than CD62L(low) Treg cells in suppressing proliferation and inducing apoptosis in effector T cells. CD62L(high) Treg cells thus represent a population of Treg cells that display superior immunosuppressive properties and accumulate in the CNS during recovery from CNS-autoimmunity.
Assuntos
Sistema Nervoso Central/citologia , Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Terapia de Imunossupressão , Selectina L/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Anexina A5/metabolismo , Antígenos CD/biossíntese , Apoptose/efeitos dos fármacos , Antígeno CTLA-4 , Caspase 3/metabolismo , Feminino , Citometria de Fluxo , Imunização , Ligante Coestimulador de Linfócitos T Induzíveis , Camundongos , Proteína Proteolipídica de Mielina/imunologia , Fragmentos de Peptídeos/imunologia , Proteínas/genética , Proteínas/metabolismo , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/genéticaRESUMO
BACKGROUND: A new autoantibody (termed NMO-IgG, or AQP4-Ab) has recently been described in patients with neuromyelitis optica (NMO) and its formes frustes, longitudinally extensive transverse myelitis (LETM) and recurrent optic neuritis (rON). However, AQP4-Ab has been found also in patients with co-existing rheumatic diseases such as systemic lupus erythematosus (SLE) or Sjögren's syndrome (SS), conditions which are characterized by broad, polyspecific B cell activation. OBJECTIVES: In this study, we aimed at evaluating the syndrome specificity and frequency of AQP4-Ab in patients with rheumatic diseases and neurological symptoms. METHODS: For this purpose, serum samples from 109 neurological patients with established connective tissue disorders (CTD) (n = 54), possible CTD (n = 42), or vasculitis (n = 13) were analysed for the presence of AQP4-Ab by a cell-based assay employing recombinant human AQP4. RESULTS: AQP4-Ab was detectable in 31/40 (78%) patients with CTD and NMO spectrum disorders (median titre, 1:1000) but in none of the samples obtained from patients with CTD or vasculitis and neurological disorders other than NMO, LETM, or rON (n = 69). CONCLUSION: The high syndrome specificity of the antibody for neuromyelitis optica spectrum disorders (NMOSDs) in patients with CTD supports the concept of AQP4-Ab being involved in the pathogenesis of these neurological conditions, and argues against AQP4-Ab simply being part of the polyclonal B cell activation generally associated with rheumatic diseases. Moreover, the finding that AQP4-Ab is present in patients with CTD and co-existing NMOSD with approximately the same frequency as in patients without CTD strengthens the case of CTD and AQP4-Ab positive NMOSD representing two co-existing yet distinct entities in the majority of patients.
Assuntos
Aquaporina 4/imunologia , Autoanticorpos/imunologia , Doenças do Tecido Conjuntivo/imunologia , Neuromielite Óptica/imunologia , Doenças Reumáticas/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mielite Transversa/imunologia , Neurite Óptica/imunologiaRESUMO
FOXP3-expressing naturally occurring CD4(+)CD25(high) T regulatory cells (Treg) are relevant in the control of autoimmunity, and a defect in this cell population has been observed in several human autoimmune diseases. We hypothesized that altered functions of peripheral Treg cells might play a role in the immunopathogenesis of myasthenia gravis, a T cell-dependent autoimmune disease characterized by the presence of pathogenic autoantibodies specific for the nicotinic acetylcholine receptor. We report in this study a significant decrease in the in vitro suppressive function of peripheral Treg cells isolated from myasthenia patients in comparison to those from healthy donors. Interestingly, Treg cells from prednisolone-treated myasthenia gravis patients showed an improved suppressive function compared with untreated patients, suggesting that prednisolone may play a role in the control of the peripheral regulatory network. Indeed, prednisolone treatment prevents LPS-induced maturation of monocyte-derived dendritic cells by hampering the up-regulation of costimulatory molecules and by limiting secretion of IL-12 and IL-23, and enhancing IL-10. In addition, CD4(+) T cells cultured in the presence of such tolerogenic dendritic cells are hyporesponsive and can suppress autologous CD4(+) T cell proliferation. The results shown in this study indicate that prednisolone treatment promotes an environment that favors immune regulation rather than inflammation.
Assuntos
Células Dendríticas/imunologia , Tolerância Imunológica/efeitos dos fármacos , Miastenia Gravis/tratamento farmacológico , Prednisolona/farmacologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoimunidade/efeitos dos fármacos , Estudos de Casos e Controles , Proliferação de Células , Técnicas de Cocultura , Humanos , Interleucinas/metabolismo , Lipopolissacarídeos , Pessoa de Meia-Idade , Miastenia Gravis/imunologia , Prednisolona/uso terapêuticoRESUMO
OBJECTIVE: To update the 2016 formal consensus-based guidance for the management of myasthenia gravis (MG) based on the latest evidence in the literature. METHODS: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness method was used to develop consensus recommendations pertaining to 7 treatment topics. In February 2019, the international panel was reconvened with the addition of one member to represent South America. All previous recommendations were reviewed for currency, and new consensus recommendations were developed on topics that required inclusion or updates based on the recent literature. Up to 3 rounds of anonymous e-mail votes were used to reach consensus, with modifications to recommendations between rounds based on the panel input. A simple majority vote (80% of panel members voting "yes") was used to approve minor changes in grammar and syntax to improve clarity. RESULTS: The previous recommendations for thymectomy were updated. New recommendations were developed for the use of rituximab, eculizumab, and methotrexate as well as for the following topics: early immunosuppression in ocular MG and MG associated with immune checkpoint inhibitor treatment. CONCLUSION: This updated formal consensus guidance of international MG experts, based on new evidence, provides recommendations to clinicians caring for patients with MG worldwide.
Assuntos
Imunossupressores/uso terapêutico , Miastenia Gravis/terapia , Anticorpos Monoclonais Humanizados/uso terapêutico , Consenso , Gerenciamento Clínico , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Metotrexato/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/cirurgia , Rituximab/uso terapêutico , TimectomiaRESUMO
Butyrylcholinesterase (BChE) genotypes and protein (BuChE) activity, especially in combination with Apolipoprotein E4 (ApoE4), have been investigated as risk factors for developing Alzheimer disease (AD) and may be associated with the rate of progression of cognitive decline. Despite similar pathologic (e.g. amyloid deposition) and neurochemical (e.g. cholinergic deficits) aspects between AD and Lewy body diseases (LBD), scarce data is obtainable about BChE genotypes and BuChE activity in LBD. We measured BuChE activity levels in serum and cerebrospinal fluid (CSF) of 114 LBD subjects (59 of them were demented) and 31 elderly controls. We found higher CSF BuChE activity in males compared to females, and a negative correlation of serum BuChE activity with age and cognitive function. Demented LBD patients, non-demented LBD patients and controls did not differ significantly with regard to serum and CSF BuChE activity. Furthermore, BChE K variant and ApoE4 allele frequencies were determined. The BChE K variant was significantly associated with lower serum activity; the same trend was observable in CSF. The subgroups did not differ significantly with regard to BChE K/ApoE4 occurrence. These data confirm and extend previous results on the relationship between BChE gene and BuChE activity, and argue rather against a major impact of BuChE on LBD-associated pathologies.
Assuntos
Butirilcolinesterase/genética , Butirilcolinesterase/metabolismo , Frequência do Gene , Doença por Corpos de Lewy/enzimologia , Doença por Corpos de Lewy/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Apolipoproteína E4/genética , Cognição/fisiologia , Transtornos Cognitivos/enzimologia , Transtornos Cognitivos/genética , Enzimas/sangue , Enzimas/líquido cefalorraquidiano , Enzimas/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Caracteres SexuaisRESUMO
About one fourth of Lewy body disease (LBD) patients show cortical beta-amyloid load, basically a hallmark of Alzheimer disease (AD). Using [11C]PIB-PET, we tested whether LBD patients with beta-amyloid burden differ from those without with respect to demographic, clinical, biochemical and genetic parameters. Thirty-five LBD subjects (9 patients with Lewy body dementia, DLB; 12 demented Parkinson patients, PDD; 14 non-demented PD, PDND) underwent [11C]PIB-PET, and were classified as either PIB(+) or PIB(-) according to cortical PIB uptake. PIB+ and PIB(-) patients were then compared according to demographic, clinical, biochemical and genetic parameters. None of the PDND, but four PDD and four DLB subjects were PIB+. In PIB+ subjects, ApoE4 prevalence was higher, CSF Abeta42 levels were lower and, among demented patients, PIB-binding was associated with a lower MMSE score. Motor symptoms were not associated with PIB binding. Thus, LBD patients with cortical beta-amyloid show characteristics usually observed in AD.