RESUMO
Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.
Assuntos
Transtornos Psicóticos , Esquizofrenia , Humanos , Complemento C4a/genética , Complemento C4a/líquido cefalorraquidiano , Esquizofrenia/genética , Esquizofrenia/metabolismo , Transtornos Psicóticos/genética , Fatores de RiscoRESUMO
Complement plays a pivotal role in the pathogenesis of multiple sclerosis. C4a, an activated fragment of complement component C4, has been linked to disease activity. We correlated plasma C4 and plasma and CSF C4a with clinical disease in a well-characterised cohort of patients and controls. Plasma C4 was non-significantly and CSF C4a was significantly elevated overall in patients compared to controls. Plasma C4a was raised only in acute relapse, decreasing over 2 months. Results demonstrate intrathecal and systemic activation of complement, reflected in changes in CSF and plasma C4a. The data support a role for complement activation in pathogenesis and suggest a systemic component to the disease.
Assuntos
Complemento C4a/metabolismo , Esclerose Múltipla/imunologia , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Ativação do Complemento/imunologia , Complemento C4a/líquido cefalorraquidiano , Complemento C4a/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidianoAssuntos
Doença de Alzheimer/líquido cefalorraquidiano , Proteínas do Líquido Cefalorraquidiano/análise , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Proteômica/métodos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/fisiopatologia , Apolipoproteínas E/análise , Apolipoproteínas E/líquido cefalorraquidiano , Biomarcadores/análise , Biomarcadores/líquido cefalorraquidiano , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Complemento C4a/análise , Complemento C4a/líquido cefalorraquidiano , Diagnóstico Diferencial , Proteínas do Olho/análise , Proteínas do Olho/líquido cefalorraquidiano , Humanos , Complexos Multienzimáticos/análise , Complexos Multienzimáticos/líquido cefalorraquidiano , Fatores de Crescimento Neural/análise , Fatores de Crescimento Neural/líquido cefalorraquidiano , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Fosfodiesterase I/análise , Fosfodiesterase I/líquido cefalorraquidiano , Diester Fosfórico Hidrolases , Valor Preditivo dos Testes , Pirofosfatases/análise , Pirofosfatases/líquido cefalorraquidiano , Serpinas/análise , Serpinas/líquido cefalorraquidiano , Superóxido Dismutase/análise , Superóxido Dismutase/líquido cefalorraquidiano , Superóxido Dismutase-1 , Regulação para Cima/fisiologiaRESUMO
We report the case of a multiple sclerosis (MS) patient without oligoclonal bands (OCB) in three cerebrospinal fluid samples. Restriction fragment length polymorphism analysis of Class 3 genes with radiolabelled specific cDNA probes showed a homozygous deletion of the complement 4A (C4A) genes. Consequent lack of C4A protein can alter the development of humoral immune response probably preventing OCB production. Our observation may suggest a link between a rare immunogenetic pattern and the absence of OCB in MS.
Assuntos
Complemento C4a/líquido cefalorraquidiano , Imunoglobulinas/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Adulto , Deleção Cromossômica , Complemento C4a/genética , Diagnóstico Diferencial , Feminino , Haplótipos , Homozigoto , Humanos , Imunoglobulinas/genética , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Exame Neurológico , Bandas OligoclonaisRESUMO
The cerebrospinal fluid (CSF) and plasma levels of the complement components C3a and C4a in 40 patients suffering from subarachnoid hemorrhage (SAH) were quantitated by radioimmunoassay. Serial measurements of the lumbar CSF levels revealed that the C3a and C4a levels were significantly elevated in the initial stage of SAH, but decreased rapidly. Within 48 hours after SAH, the mean C3a and C4a levels in the cisternal, lumbar, and ventricular CSF were significantly higher in patients with delayed ischemic neurological deficits (DIND) than in those without DIND. The serially measured plasma levels of C3a and C4a in patients with DIND were elevated more than in those without DIND, but they did not show a significant change over time. Simultaneous levels of fibrinopeptide A (FPA), an indicator of thrombin activity in CSF, were also measured by radioimmunoassay. There was a significant correlation between CSF-activated complement components and CSF FPA. These results suggest that complement activation occurred in the subarachnoid space soon after SAH, chiefly due to activation of the coagulation system. The higher CSF levels of C3a and C4a in patients with DIND may indicate a relationship between these components and the pathogenesis of cerebral vasospasms.