RESUMEN
There is unequivocal evidence that alpha-synuclein plays a pivotal pathophysiological role in neurodegenerative diseases, and in particular in synucleinopathies. These disorders present with a variable extent of cognitive impairment and alpha-synuclein is being explored as a biomarker in CSF, blood serum and plasma. Considering key events of aging that include proteostasis, alpha-synuclein may not only be useful as a marker for differential diagnosis but also for aging per se. To explore this hypothesis, we developed a highly specific ELISA to measure alpha-synuclein. In healthy males plasma alpha-synuclein levels correlated strongly with age, revealing much lower concentrations in older (avg. 58.1 years) compared to younger (avg. 27.6 years) individuals. This difference between the age groups was enhanced after acidification of the plasmas (p<0.0001), possibly reflecting a decrease of alpha-synuclein-antibody complexes or chaperone activity in older individuals. Our results support the concept that alpha-synuclein homeostasis may be impaired early on, possibly due to disturbance of the proteostasis network, a key component of healthy aging. Thus, alpha-synuclein may be a novel biomarker of aging, a factor that should be considered when analyzing its presence in biological specimens.
Asunto(s)
Envejecimiento/metabolismo , alfa-Sinucleína/sangre , Adulto , Anciano , Envejecimiento/sangre , Biomarcadores/sangre , Regulación de la Expresión Génica , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Natural self-reactive antibodies in the peripheral blood may play a considerable role in the control of potentially toxic proteins that may otherwise accumulate in the aging brain. The significance of serum antibodies reactive against α-synuclein is not well known. We explored serum IgG levels to monomeric α-synuclein in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) with a novel and validated highly sensitive ELISA assay. Antibody levels revealed stark differences in patients compared to healthy subjects and were dependent on diagnosis, disease duration and age. Anti-α-synuclein IgG levels were increased in both patient groups, but in early DLB to a much greater extent than in AD. Increased antibody levels were most evident in younger patients, while with advanced age relatively low levels were observed, similar to healthy individuals, exhibiting stable antibody levels independent of age. Our data show the presence of differentially altered IgG levels against α-synuclein in DLB and AD, which may relate to a disturbed α-synuclein homeostasis triggered by the disease process. These observations may foster the development of novel, possibly preclinical biomarkers and immunotherapeutic strategies that target α-synuclein in neurodegenerative disease.
Asunto(s)
Enfermedad de Alzheimer/sangre , Autoanticuerpos/sangre , Inmunoglobulina G/sangre , Enfermedad por Cuerpos de Lewy/sangre , alfa-Sinucleína/sangre , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Autoanticuerpos/inmunología , Estudios de Casos y Controles , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/inmunología , Enfermedad por Cuerpos de Lewy/inmunología , Enfermedad por Cuerpos de Lewy/patología , Masculino , Índice de Severidad de la Enfermedad , alfa-Sinucleína/inmunologíaRESUMEN
OBJECTIVES: We analyze the incidence, etiology, outcome of pregnancy and therapeutic regimes of prenatally and postnatally detected isolated and complex congenital talipes equinovarus in a tertiary referral center. METHODS: We included fetuses with at least one prenatal ultrasound examination conducted by a sub-specialized practitioner for prenatal medicine. Retrospective evaluation was made of prenatal, obstetrical and neonatal/pediatric records and where applicable pathological records or records of the involved department of pediatric surgery with a minimum follow-up of 24 months. RESULTS: 106 children with uni- or bilateral CTEV were detected prenatally in a period of 17 years. There were 55 liveborn infants. The majority of the liveborn infants had isolated CTEV (37/55), whereas in the group of the stillborns most of the individuals suffered from complex CTEV (46/51). The gender-distribution showed a majority of male individuals in the liveborn group with isolated CTEV 22/37 and 11/18 in fetuses with non-isolated CTEV. Accordingly, 2/5 fetuses with isolated CTEV and 25/46 with complex CTEV in the group of the terminated pregnancies were males. 33/49 children were treated in a conservative manner, 16/49 needed additional surgery on the CTEV. Twenty-nine of forty-nine had excellent and 19/49 very good outcome. One of forty-nine had a good outcome. Fifteen of fifty-five liveborn children suffered from severe additional anomalies, like arthrogryposis multiplex congenita and spina bifida aperta. In the group of the stillborns all non-isolated CTEV were cases with severe additional anomalies (46/51). Mean time of prenatal diagnosis was 23(3/7) gestational weeks. Six cases with CTEV were detected postnatally only. There was one prenatal false positive diagnosis. CONCLUSIONS: Prenatal detection of CTEV is feasible during pregnancy. The outcome of children with isolated CTEV is good. In complex CTEV outcome depends on the additional anomalies the fetus has. In isolated CTEV fetal karyotyping should be offered; in complex CTEV fetal karyotyping is mandatory. The prenatal diagnosis of an (isolated) CTEV should always include an appropriate parental counseling together with pediatric orthopedics and pediatric surgeons. Repeated ultrasound scans can confirm diagnosis and reduce the risk of misjudgement of additional fetal anomalies as those may be frequently seen in fetuses with CTEV.
Asunto(s)
Pie Equinovaro/diagnóstico por imagen , Adolescente , Adulto , Pie Equinovaro/epidemiología , Femenino , Alemania/epidemiología , Humanos , Nacimiento Vivo , Masculino , Persona de Mediana Edad , Embarazo , Mortinato , Ultrasonografía Prenatal , Adulto JovenRESUMEN
PURPOSE: Inflammatory stenoses of cerebral arteries cause stroke in patients with florid vasculitis. However, diagnosis is often difficult even with digital subtraction angiography (DSA) and biopsy. The purpose of this study was to establish the value of contrast-enhanced MRI, proven to be sensitive to extradural arteritis, for the identification of intracranial vessel wall inflammation. PATIENTS AND METHODS: Twenty-seven patients with a diagnosis of cerebral vasculitis affecting large brain vessels were retrieved from the files: 8 children (2-10 years, 7 female, 1 male) and 19 adults (16-76 years, 10 female, 9 male). Diagnosis was based on histological or serological proof of vasculitis or on clinical and imaging criteria. All MRI examinations included diffusion-weighted imaging, time-of-flight magnetic resonance angiography (TOF-MRA) and contrast-enhanced scans. MRI scans were assessed for the presence of ischemic brain lesions, arterial stenoses, vessel wall thickening and contrast uptake. RESULTS: Ischemic changes of the brain tissue were seen in 24/27 patients and restricted diffusion suggestive of recent ischemia in 17/27; 25/27 patients had uni- or multifocal stenoses of intracranial arteries on TOF-MRA and 5/6 had stenoses on DSA. Vessel wall thickening was identified in 25/27, wall enhancement in 23/27 patients. CONCLUSION: Wall thickening and intramural contrast uptake are frequent findings in patients with active cerebral vasculitis affecting large brain arteries. Further prospective studies are required to determine the specificity of this finding.
Asunto(s)
Arterias Cerebrales/patología , Medios de Contraste , Imagen de Difusión por Resonancia Magnética , Angiografía por Resonancia Magnética , Vasculitis del Sistema Nervioso Central/patología , Adolescente , Adulto , Anciano , Isquemia Encefálica/patología , Enfermedades Arteriales Cerebrales/patología , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Experimental autoimmune encephalomyelitis (EAE) in rats is a highly valuable model of multiple sclerosis (MS) because it mimics major hallmarks of the human disease. EAE induced with myelin-oligodendrocyte-glycoprotein (MOG) in DA rats is relapsing/remitting, and lesions in the central nervous system show inflammation, demyelination, and axonal and neuronal loss. Recently, bone marrow transplantation (BMT) was introduced as a novel strategy to treat MS, but its efficiency and the underlying mechanism are debatable. In MOG-induced EAE we found that BMT at the peak of EAE but not in the chronic phase leads to disease attenuation. In both settings, rats receiving bone marrow (BM) transplants were protected from subsequently induced relapses. These findings could be confirmed by histopathology in which rats receiving BM transplants did not have lesions compared with controls not receiving transplants. Importantly, the protective effect was achieved by allogeneic, syngeneic, and BM grafts from diseased rats. BMT resulted in increased numbers of CD4(+)CD25(bright) regulatory T cells, increased Foxp3 expression, a shift in T-cell epitope recognition, and a strong reduction of autoantibodies even after rechallenge with MOG. Thus, our results indicate potential mechanisms of how BMT may contribute to the improvement of MS and provide a rationale for its application in patients suffering from various autoimmune diseases.
Asunto(s)
Trasplante de Médula Ósea , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/terapia , Tolerancia Inmunológica , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/terapia , Animales , Autoanticuerpos/farmacología , Trasplante de Médula Ósea/efectos adversos , Modelos Animales de Enfermedad , Linfocitos/inmunología , Esclerosis Múltiple/patología , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Fenotipo , Ratas , Ratas Endogámicas ACI , Ratas Endogámicas , Recurrencia , Factores de TiempoRESUMEN
Antibodies against native glycosylated myelin-oligodendrocyte-glycoprotein (MOG) were measured by ELISA in patients with multiple sclerosis (MS) and controls. Anti-MOG IgM antibodies were elevated during the first demyelinating event. Higher MOG-specific IgG antibodies were found in patients during relapses and in secondary chronic progressive MS compared to patients in remission and healthy controls. Antibodies against native MOG may be a potential biomarker for MS.
Asunto(s)
Autoanticuerpos/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Esclerosis Múltiple Crónica Progresiva/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Glicoproteína Asociada a Mielina/inmunología , Procesamiento Proteico-Postraduccional , Adulto , Anciano , Animales , Especificidad de Anticuerpos , Autoanticuerpos/sangre , Enfermedades Desmielinizantes , Femenino , Glicosilación , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Masculino , Ratones , Persona de Mediana Edad , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/química , Glicoproteína Asociada a Mielina/aislamiento & purificación , Glicoproteína Mielina-OligodendrócitoRESUMEN
The nicotinic acetylcholine receptor (nAChR) is the autoantigen in seropositive myasthenia gravis (MG) that is a T cell-dependent B cell-mediated autoimmune disorder. We tested the immunogenicity and myasthenogenicity of the extracellular and first transmembrane domain of the epsilon-chain(1-221) of the nAChR in inbred and MHC congenic rat strains. Immunodominant T and B cell determinants did not induce experimental autoimmune myasthenia gravis (EAMG), although immunization resulted in strong Th1 and B cell responses, which could be mapped with overlapping peptides of the nAChR epsilon-subunit in eight different rat strains. Our data underscores the concept that immunodominant autoantigen-specific T and B cell responses can lack pathogenicity in autoimmune disease and might be of relevance for the physiological integrity of the organism.
Asunto(s)
Linfocitos B/inmunología , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito T/inmunología , Receptores Nicotínicos/inmunología , Células TH1/inmunología , Secuencia de Aminoácidos , Animales , Animales Congénicos , Autoantígenos/inmunología , Modelos Animales de Enfermedad , Humanos , Masculino , Datos de Secuencia Molecular , Miastenia Gravis Autoinmune Experimental/inmunología , Péptidos/inmunología , Ratas , Ratas Endogámicas LewRESUMEN
The nicotinic acetylcholine receptor (nAChR) is the autoantigen in seropositive myasthenia gravis (MG), a T-cell-dependent B-cell-mediated autoimmune disease. The nAChR is a pentameric transmembrane receptor comprising alpha alpha beta gamma delta chains. During early postnatal development the nAChR gamma chain is replaced by the nAChR epsilon chain. We tested the myasthenogenicity in experimental autoimmune myasthenia gravis (EAMG) of the native nAChR derived from the electric ray Torpedo californica (T-nAChR) in various inbred and MHC -congenic rat strains. Differences in the disease course emerged dependent on the MHC haplotype and non-MHC genes. Interestingly, no tested rat strain was completely resistant to EAMG, but there were strong differences in disease severity mainly depending on the MHC haplotype. In the LEW non-MHC genome, the B-cell response and the severity of EAMG were dependent on the expressed MHC haplotype. This study underscores the influence of genetic factors on disease severity, disease course and on the degree of the emerging antibody responses in EAMG.