RESUMEN
Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
Asunto(s)
Complemento C3/genética , Complemento C4/genética , Lupus Eritematoso Sistémico/genética , Caracteres Sexuales , Síndrome de Sjögren/genética , Adulto , Alelos , Complemento C3/análisis , Complemento C3/líquido cefalorraquídeo , Complemento C4/análisis , Complemento C4/líquido cefalorraquídeo , Femenino , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Haplotipos , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/líquido cefalorraquídeo , Complejo Mayor de Histocompatibilidad/genética , Masculino , Persona de Mediana Edad , Síndrome de Sjögren/sangre , Síndrome de Sjögren/líquido cefalorraquídeo , Adulto JovenRESUMEN
Cholinergic inputs originating from the peripheral nervous system regulate the inflammatory immune responses of macrophages during clearance of blood-based pathogens. Because microglia are involved in clearing amyloid and tau pathology from the central nervous system, we hypothesized that cholinergic input originating from the basal forebrain might similarly regulate inflammatory immune responses to these pathologies in the aging brain. To explore this hypothesis, we leveraged the Alzheimer's Disease Neuroimaging Initiative dataset. Cognitively normal older male and female human adults were differentiated according to the relative concentration of phosphorylated tau and amyloid in their cerebrospinal fluid, yielding neurotypical and preclinical, cognitively healthy, subgroups. We then tracked these two groups longitudinally with structural MRI and biomarkers of inflammation, including soluble sTREM2 levels in the CSF and complement C3 expression in the blood transcriptome. Longitudinal loss of basal forebrain volume was larger in the preclinical compared with the neurotypical subgroup. Across preclinical adults, loss of basal forebrain volume was associated with greater longitudinal accumulation of sTREM2 and higher peripheral blood C3 expression. None of these relationships were attributable to degeneration in the whole-brain gray matter volume. Preclinical APOE e4 carriers exhibited the largest loss of basal forebrain volume and highest C3 expression. Consistent with the known anti-inflammatory influence of the peripheral cholinergic pathways on macrophages, our findings indicate that a loss of central cholinergic input originating from the basal forebrain might remove a key check on microglial inflammation induced by amyloid and tau accumulation.SIGNIFICANCE STATEMENT In the peripheral nervous system, cholinergic modulation holds the reactivity of macrophages to blood-based pathogens in check, promoting clearance while preventing runaway inflammation and immune-triggered cell death. Microglia are the brain's resident macrophages and play an important role in clearing accumulated amyloid and tau from neurons. Here, we demonstrate that a loss of cholinergic integrity in the CNS, indexed by longitudinal decreases of basal forebrain volume, interacts with multiple biomarkers of inflammation in cognitively normal older adults with abnormal amyloid and tau pathology. These interactions were not detected in cognitively normal older adults with "neurotypical" levels of amyloid and tau. An age-related loss of cholinergic neuromodulation may remove key checks on microglial reactivity to amyloid and tau.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Prosencéfalo Basal/patología , Complemento C3/metabolismo , Encefalitis/metabolismo , Encefalitis/patología , Glicoproteínas de Membrana/metabolismo , Enfermedades Neurodegenerativas/patología , Receptores Inmunológicos/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Amiloide/metabolismo , Apolipoproteínas E/metabolismo , Prosencéfalo Basal/crecimiento & desarrollo , Biomarcadores , Complemento C3/líquido cefalorraquídeo , Complemento C3/genética , Encefalitis/genética , Femenino , Sustancia Gris/metabolismo , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Glicoproteínas de Membrana/líquido cefalorraquídeo , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Neuroimagen , Receptores Inmunológicos/genética , Proteínas tau/metabolismoRESUMEN
Complement pathway overactivation can lead to neuronal damage in various neurological diseases. Although Alzheimer's disease (AD) is characterized by ß-amyloid plaques and tau tangles, previous work examining complement has largely focused on amyloidosis models. We find that glial cells show increased expression of classical complement components and the central component C3 in mouse models of amyloidosis (PS2APP) and more extensively tauopathy (TauP301S). Blocking complement function by deleting C3 rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in TauP301S mice, improving neurophysiological and behavioral measurements. In addition, C3 protein is elevated in AD patient brains, including at synapses, and levels and processing of C3 are increased in AD patient CSF and correlate with tau. These results demonstrate that complement activation contributes to neurodegeneration caused by tau pathology and suggest that blocking C3 function might be protective in AD and other tauopathies.
Asunto(s)
Enfermedad de Alzheimer/inmunología , Amiloidosis/inmunología , Complemento C3/metabolismo , Degeneración Nerviosa/inmunología , Tauopatías/inmunología , Enfermedad de Alzheimer/genética , Animales , Atrofia , Conducta Animal , Biomarcadores/metabolismo , Encéfalo/patología , Complemento C1q/metabolismo , Complemento C3/líquido cefalorraquídeo , Complemento C3/genética , Modelos Animales de Enfermedad , Femenino , Eliminación de Gen , Regulación de la Expresión Génica , Humanos , Masculino , Ratones Transgénicos , Degeneración Nerviosa/genética , Neuronas/metabolismo , Neuronas/patología , Placa Amiloide/metabolismo , Sinapsis/metabolismoRESUMEN
Although quotient of alpha2 macroglobulin (Qα2MG) was previously reported to be useful for the evaluation of blood-brain barrier (BBB) function, it is not commonly used. We therefore evaluated BBB function among the various subsets of neuropsychiatric systemic lupus erythematosus (NPSLE) using quotient Q α2MG. Furthermore, we determined the correlation between Q α2MG and cerebrospinal (CSF) interleukin (IL)-6 level and quotient complement component 3 (Q C3). To determine intrathecal production of C3, the C3 index (Q C3/Q α2MG) was also calculated. Fifty-six patients with SLE were included in this study. Of these, 48 were diagnosed with NPSLE, consisting of 30 diffuse NPSLE patients (acute confusional state (ACS): n = 14, non-ACS: n = 16) and 18 patients with focal NPSLE. CSF IL-6 concentration, and paired serum and CSF levels of α2MG and C3, were measured by enzyme-linked immuno solvent assay (ELISA). The Q α2MG, Q C3, and C3 index were then calculated. Q α2MG, Q C3, and IL-6 concentrations in the CSF were significantly elevated in NPSLE compared with non-NPSLE. Among the subsets of NPSLE, significant increases in Q α2MG, CSF IL-6, and Q C3 were observed in ACS compared with non-ACS or focal NPSLE. There was a positive correlation between CSF IL-6 level and Q α2MG, as well as between Q C3 and Q α2MG, in diffuse NPSLE. There were no significant differences in C3 index between NPSLE and non-NPSLE, as well as among the subgroups of NPSLE. Our study suggests that BBB disruption is present in ACS, and elevated levels of IL-6 and C3 in CSF in diffuse NPSLE, especially in ACS, might result from their entry to the CSF from the systemic circulation through the damaged BBB, as well as increased intrathecal production. Furthermore, Q α2MG might be useful for the evaluation of BBB integrity.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Complemento C3/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Vasculitis por Lupus del Sistema Nervioso Central/líquido cefalorraquídeo , alfa-Macroglobulinas/líquido cefalorraquídeo , Adulto , Estudios de Casos y Controles , Femenino , Glucosa/líquido cefalorraquídeo , Humanos , Vasculitis por Lupus del Sistema Nervioso Central/sangre , MasculinoRESUMEN
Inflammation is becoming increasingly recognized as an important contributor to Alzheimer's disease (AD) pathogenesis. As a part of the innate immune system, the complement cascade enhances the body's ability to destroy and remove pathogens and has recently been shown to influence Alzheimer's associated amyloid and tau pathology. However, little is known in humans about the effects of the complement system and genetic modifiers of AD risk like the ε4 allele of apolioprotein E (APOE ε4) on AD pathobiology. We evaluated cerebrospinal fluid (CSF) protein levels from 267 individuals clinically diagnosed as cognitively normal, mild cognitive impairment, and AD. Using linear models, we assessed the relationship between APOE ε4 genotype, CSF Complement 3 (C3), CSF amyloid-ß (amyloid) and CSF hyperphosphorylated tau (ptau). We found a significant interaction between APOE ε4 and CSF C3 on both CSF amyloid and CSF ptau. We also found that CSF C3 is only associated with CSF ptau after accounting for CSF amyloid. Our results support a conceptual model of the AD pathogenic cascade where a synergistic relationship between the complement cascade (C3) and APOE ε4 results in elevated Alzheimer's neurodegeneration and in turn, amyloid further regulates the effect of the complement cascade on downstream tau pathology.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Complemento C3/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Amiloide/líquido cefalorraquídeo , Análisis de Varianza , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/genética , Estudios de Cohortes , Femenino , Humanos , Modelos Lineales , Masculino , FosforilaciónRESUMEN
The complement system (C1q/C3) is a key mediator of synaptic pruning during normal development. HIV inappropriately induces C1q and C3 production in the brain, and reduces neuronal complement inhibition. HIV may thus alter neural connectivity in the developing brain by excessively targeting synapses for elimination. The resultant pattern of neuronal injury may fundamentally alter neurodevelopmental and cognitive processes differentially across ages. This study aimed to (1) measure the association between the cerebrospinal fluid (CSF) complement factors (C1q/C3) and a marker of neuronal injury (NFL) in HIV+ subjects; (2) quantify the differences in CSF C1q/C3 between HIV+ youth and older adults; and (3) define the relationship between CSF C1q/C3 and cognitive impairment in each age group. We performed a retrospective cross-sectional study of 20 HIV+ 18-24-year-old youth and 20 HIV+ 40-46-year-old adults with varying levels of cognitive impairment enrolled in the CNS Antiretroviral Therapy Effects Research study. We quantified C3, C1q, and NFL by ELISA in paired CSF/plasma specimens. We found that CSF C1q correlates with NFL in all subjects not receiving antiretroviral therapy (n = 16, rho = 0.53, p = 0.035) when extreme NFL outliers were eliminated (n = 1). There was no difference in plasma/CSF C1q or C3 between older adults and youth. In 18-24-year-old youth, a nearly significant (p = 0.052) elevation of CSF C1q expression was observed in cognitively impaired subjects compared to cognitively normal subjects. Further investigation into the role of the CNS complement system in the neuropathogenesis of HIV is warranted and should be considered in a developmentally specific context.
Asunto(s)
Disfunción Cognitiva/diagnóstico , Complemento C1q/líquido cefalorraquídeo , Complemento C3/líquido cefalorraquídeo , Infecciones por VIH/diagnóstico , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Adolescente , Adulto , Fármacos Anti-VIH/uso terapéutico , Biomarcadores/líquido cefalorraquídeo , Encéfalo/metabolismo , Encéfalo/patología , Cognición/fisiología , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/tratamiento farmacológico , Conectoma , Estudios Transversales , Transmisión de Enfermedad Infecciosa , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , Humanos , Masculino , Persona de Mediana Edad , Neuronas/metabolismo , Neuronas/patología , Estudios Retrospectivos , Sinapsis/metabolismo , Sinapsis/patologíaRESUMEN
Besides its vital role in immunity, the complement system also contributes to the shaping of the synaptic circuitry of the brain. We recently described that soluble Complement Receptor 2 (sCR2) is part of the nerve injury response in rodents. We here study CR2 in context of multiple sclerosis (MS) and explore the molecular effects of CR2 on C3 activation. Significant increases in sCR2 levels were evident in cerebrospinal fluid (CSF) from both patients with relapsing-remitting MS (n=33; 6.2ng/mL) and secondary-progressive MS (n=9; 7.0ng/mL) as compared to controls (n=18; 4.1ng/mL). Furthermore, CSF sCR2 levels correlated significantly both with CSF C3 and C1q as well as to a disease severity measure. In vitro, sCR2 inhibited the cleavage and down regulation of C3b to iC3b, suggesting that it exerts a modulatory role in complement activation downstream of C3. These results propose a novel function for CR2/sCR2 in human neuroinflammatory conditions.
Asunto(s)
Complemento C3/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple/inmunología , Receptores de Complemento 3d/inmunología , Adulto , Activación de Complemento/inmunología , Complemento C1q/líquido cefalorraquídeo , Complemento C1q/inmunología , Complemento C3/líquido cefalorraquídeo , Electroforesis en Gel de Poliacrilamida , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/patología , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/patología , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
INTRODUCTION: CSF levels of established Alzheimer's disease (AD) biomarkers remain stable despite disease progression, and non-amyloid non-tau biomarkers have the potential of informing disease stage and progression. We previously identified complement 3 (C3) to be decreased in AD dementia, but this change was not found by others in earlier AD stages. We hypothesized that levels of C3 and associated factor H (FH) can potentially distinguish between mild cognitive impairment (MCI) and dementia stages of AD, but we also found their levels to be influenced by age and disease status. RESULTS: We developed a biochemical/bioinformatics pipeline to optimize the handling of complex interactions between variables in validating biochemical markers of disease. We used data from the Alzheimer's Disease Neuro-imaging Initiative (ADNI, n = 230) to build parallel machine learning models, and objectively tested the models in a test cohort (n = 73) of MCI and mild AD patients independently recruited from Emory University. Whereas models incorporating age, gender, APOE ε4 status, and CSF amyloid and tau levels failed to reliably distinguish between MCI and mild AD in ADNI, introduction of CSF C3 and FH levels reproducibly improved the distinction between the two AD stages in ADNI (p < 0.05) and the Emory cohort (p = 0.014). Within each AD stage, the final model also distinguished between fast vs. slower decliners (p < 0.001 for MCI, p = 0.007 for mild AD), with lower C3 and FH levels associated with more advanced disease and faster progression. CONCLUSIONS: We propose that CSF C3 and FH alterations may reflect stage-associated biomarker changes in AD, and can complement clinician diagnosis in diagnosing and staging AD using the publically available ADNI database as reference.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Complemento C3/líquido cefalorraquídeo , Factor H de Complemento/líquido cefalorraquídeo , Factores de Edad , Anciano , Anciano de 80 o más Años , Algoritmos , Péptidos beta-Amiloides/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Estudios de Cohortes , Femenino , Humanos , Aprendizaje Automático , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.
Asunto(s)
Butirilcolinesterasa/líquido cefalorraquídeo , Complemento C3/líquido cefalorraquídeo , Traumatismos del Nervio Craneal/líquido cefalorraquídeo , Nervios Craneales/metabolismo , Esclerosis Múltiple/líquido cefalorraquídeo , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Acetilcolinesterasa/líquido cefalorraquídeo , Adulto , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Traumatismos del Nervio Craneal/tratamiento farmacológico , Traumatismos del Nervio Craneal/inmunología , Traumatismos del Nervio Craneal/patología , Nervios Craneales/efectos de los fármacos , Nervios Craneales/inmunología , Nervios Craneales/patología , Evaluación de la Discapacidad , Femenino , Proteínas Ligadas a GPI/líquido cefalorraquídeo , Humanos , Factores Inmunológicos/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Recurrencia , Inducción de Remisión , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Risk factors for susceptibility to bacterial meningitis have been identified, but basic causes of inter-individual differences in susceptibility are largely unknown. METHODS: To determine the effect of genetic variation in the complement system on susceptibility to bacterial meningitis we performed a prospective nationwide genetic association study in patients with community-acquired bacterial meningitis. We genotyped 17 common SNPs (minor allele frequencies >5%) in genes coding for complement components and evaluated functional consequences by measuring complement levels in the cerebrospinal fluid. RESULTS: From March 2006 to June 2009 we included 636 adults with community-acquired bacterial meningitis. DNA was available for 439 patients and 302 controls. Rs1047286 (Pro314Leu) in complement component 3 was associated with reduced susceptibility to bacterial meningitis after correction for multiple testing: the protective Leu/Leu genotype was found in 5 of 435 patients (1%) compared to 15 of 302 controls (5%; odds ratio [OR] 4.50, 95% confidence interval [CI] 1.62-12.50, p = 0.0017). Rs1047286 is in strong linkage disequilibrium with Rs2230199 (C3 Arg102Gly), of which the Arg/Arg genotype was associated with higher CSF levels of C3 and lower levels of C5a and terminal complement complex (TCC; soluble C5b-9), indicating decreased consumption of C3 and less activation of the complement system. Rs1047286 was associated with susceptibility albeit not significantly after Bonferroni correction (OR 1.37, 95% CI 1.01-1.87; p = 0.04). CONCLUSIONS: This study shows an association between a common single nucleotide polymorphism in C3 and susceptibility for community-acquired bacterial meningitis.
Asunto(s)
Complemento C3/genética , Predisposición Genética a la Enfermedad , Meningitis Bacterianas/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Líquido Cefalorraquídeo/microbiología , Infecciones Comunitarias Adquiridas , Complemento C3/líquido cefalorraquídeo , Complemento C5/líquido cefalorraquídeo , Complemento C5/genética , Proteínas del Sistema Complemento/líquido cefalorraquídeo , Proteínas del Sistema Complemento/genética , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo GenéticoRESUMEN
To identify response biomarkers for pharmaceutical treatment of multiple sclerosis, we induced experimental autoimmune encephalomyelitis (EAE) in rats and treated symptomatic animals with minocycline. Cerebrospinal fluid (CSF) samples were collected 14 days after EAE induction at the peak of neurological symptoms, and proteomics analysis was performed using nano-LC-Orbitrap mass spectrometry. Additionally, the minocycline concentration in CSF was determined using quantitative matrix-assisted laser desorption/ionization-triple-quadrupole tandem mass spectrometry (MALDI-MS/MS) in the selected reaction monitoring (SRM) mode. Fifty percent of the minocycline-treated EAE animals did not show neurological symptoms on day 14 ("responders"), while the other half displayed neurological symptoms ("nonresponders"), indicating that minocycline delayed disease onset and attenuated disease severity in some, but not all, animals. Neither CSF nor plasma minocycline concentrations correlated with the onset of symptoms or disease severity. Analysis of the proteomics data resulted in a list of 20 differentially abundant proteins between the untreated animals and the responder group of animals. Two of these proteins, complement C3 and carboxypeptidase B2, were validated by quantitative LC-MS/MS in the SRM mode. Differences in the CSF proteome between untreated EAE animals and minocycline-treated responders were similar to the differences between minocycline-treated responders and nonresponders (70% overlap). Six proteins that remained unchanged in the minocycline-treated animals but were elevated in untreated EAE animals may be related to the mechanism of action of minocycline.
Asunto(s)
Proteínas del Líquido Cefalorraquídeo/líquido cefalorraquídeo , Encefalomielitis Autoinmune Experimental/líquido cefalorraquídeo , Minociclina/farmacología , Esclerosis Múltiple/líquido cefalorraquídeo , Fármacos Neuroprotectores/farmacología , Proteoma/metabolismo , Adyuvantes Inmunológicos/farmacología , Animales , Carboxipeptidasa B/líquido cefalorraquídeo , Complemento C3/líquido cefalorraquídeo , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Adyuvante de Freund/farmacología , Masculino , Minociclina/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Endogámicas Lew , Espectrometría de Masas en TándemRESUMEN
Alzheimer's disease (AD) is strongly associated with loss of synapses. The complement system has been shown to be involved in synaptic elimination. Several studies point to an association between AD and the complement system. The purpose of this study was to examine the association of cerebrospinal fluid (CSF) levels of complement components 3 and 4 (C3 and C4, respectively), and complement receptor 1 (CR1) with AD in 43 patients with AD plus dementia, 42 patients with mild cognitive impairment (MCI) who progressed to AD during follow-up (MCI-AD), 42 patients with stable MCI and 44 controls. Complement levels were also applied in a multivariate model to determine if they provided any added value to the core AD biomarkers Aß42, T-tau and P-tau. We found elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSF levels of CR1 in MCI-AD and AD when these groups were merged. These results provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Complemento C3/líquido cefalorraquídeo , Complemento C4/líquido cefalorraquídeo , Receptores de Complemento/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/líquido cefalorraquídeo , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
Representatives of the genus Pseudallescheria (anamorph: Scedosporium) are saprobes and the aetiologic agent of invasive mycosis in humans. After dissemination, the central nervous system (CNS) is one of the most affected organs. Prerequisites for the survival of Pseudallescheria/Scedosporium in the host are the ability to acquire nutrients and to evade the immune attack. The cleavage of complement compounds via the secretion of fungal proteases might meet both challenges since proteolytic degradation of proteins can provide nutrients and destroy the complement factors, a fast and effective immune weapon in the CNS. Therefore, we studied the capacity of different Pseudallescheria/Scedosporium species to degrade key elements of the complement cascade in the cerebrospinal fluid and investigated a correlation with the phylogenetic background. The majority of the Pseudallescheria apiosperma isolates tested were demonstrated to efficiently eliminate proteins like complement factors C3 and C1q, thus affecting two main components of a functional complement cascade, presumably by proteolytic degradation, and using them as nutrient source. In contrast, the tested strains of Pseudallescheria boydii have no or only weak capacity to eliminate these complement proteins. We hypothesise that the ability of Pseudallescheria/Scedosporium strains to acquire nutrients and to undermine the complement attack is at least partly phylogenetically determined.
Asunto(s)
Proteínas del Sistema Complemento/líquido cefalorraquídeo , Evasión Inmune , Pseudallescheria/clasificación , Pseudallescheria/patogenicidad , Scedosporium/clasificación , Scedosporium/patogenicidad , Encefalopatías/inmunología , Encefalopatías/microbiología , Infecciones Fúngicas del Sistema Nervioso Central/inmunología , Infecciones Fúngicas del Sistema Nervioso Central/microbiología , Complemento C1q/líquido cefalorraquídeo , Complemento C1q/inmunología , Complemento C3/líquido cefalorraquídeo , Complemento C3/inmunología , Humanos , Micosis/líquido cefalorraquídeo , Micosis/inmunología , Micosis/microbiología , Filogenia , Pseudallescheria/genética , Scedosporium/genéticaRESUMEN
Complement activation, a key component of neuroinflammation, has been reported in both Parkinson's disease (PD) and Alzheimer's disease (AD). However, it is unclear whether complement activation and neuroinflammation in general are distinctly different from each another in major neurodegenerative disorders. In the present study, cerebrospinal fluid complement 3 (C3) and factor H (FH) were measured and evaluated together with amyloid-ß(42) (Aß(42)), which in recent investigations was decreased in patients with PD, in particular those with cognitive impairment. The study included 345 participants: 126 patients with PD at various stages with or without cognitive impairment, 50 with AD, and 32 with multiple-system atrophy, and 137 healthy control individuals. In addition to changes in Aß(42) concentrations, there were clear differences in the patterns of complement profiles among neurodegenerative disorders. The C3/FH ratio demonstrated high sensitivity and specificity in differentiating patients with multiple-system atrophy from those with AD or PD and control individuals. In addition, the C3/Aß(42) and FH/Aß(42) ratios not only correlated with PD severity approximated using the Unified Parkinson's Disease Rating Scale but also with the presence of cognitive impairment or dementia in PD. Both C3 and FH correlated with the severity of impairment in AD as indicated using Mini-Mental State Examination scores.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Complemento C3/líquido cefalorraquídeo , Factor H de Complemento/líquido cefalorraquídeo , Atrofia de Múltiples Sistemas/líquido cefalorraquídeo , Enfermedad de Parkinson/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/líquido cefalorraquídeo , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Control de Calidad , Análisis de RegresiónRESUMEN
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease with an average survival of 3 years from symptom onset. Rapid and conclusive early diagnosis is essential if interventions with disease-modifying therapies are to be successful. Cytoskeletal modification and inflammation are known to occur during the pathogenesis of ALS. We measured levels of cytoskeletal proteins and inflammatory markers in the CSF of ALS, disease controls and healthy subjects. We determined threshold values for each protein that provided the optimal sensitivity and specificity for ALS within a training set, as determined by receiver operating characteristic analysis. Interestingly, the optimal assay was a ratio of the levels for phosphorylated neurofilament heavy chain and complement C3 (pNFH/C3). We next applied this assay to a separate test set of CSF samples to verify our results. Overall, the predictive pNFH/C3 ratio identified ALS with 87.3% sensitivity and 94.6% specificity in a total of 71 ALS subjects, 52 disease control subjects and 40 healthy subjects. In addition, the level of CSF pNFH correlated with survival of ALS patients. We also detected increased pNFH in the plasma of ALS patients and observed a correlation between CSF and plasma pNFH levels within the same subjects. These findings support large-scale prospective biomarker studies to determine the clinical utility of diagnostic and prognostic signatures in ALS.
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Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Complemento C3/líquido cefalorraquídeo , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Adulto , Anciano , Esclerosis Amiotrófica Lateral/mortalidad , Análisis de Varianza , Biomarcadores/líquido cefalorraquídeo , Proteína C-Reactiva/líquido cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neurofilamentos/sangre , Curva ROC , Estadística como Asunto , Proteínas tau/líquido cefalorraquídeoRESUMEN
INTRODUCTION: Eosinophilic meningoencephalitis due to Angiostrongylus cantonensis is an emergent infectious disease in our area. The objective of the present paper is to determine if the activation of the complement system was taken placed with the C3c production in cerebrospinal fluid. PATIENTS AND METHODS: 14 patients with an average age 4.5 years were studied. In such patients a lumbar punction was performed. C3c was quantified in serum and cerebrospinal fluid by radial immunodiffusion. RESULTS: Median cell number was 396 x 10(-6)/L with an average of 8.8% of eosinophils. Main symptoms were headache, vomiting and fever. Meningeal signs were present in 50% of the patients. C3c intrathecal synthesis occurred in 13 patients (92.8%). CONCLUSION: It was demonstrated the participation of complement system in third-stage larvae destruction in cerebrospinal fluid.
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Angiostrongylus cantonensis , Helmintiasis del Sistema Nervioso Central/inmunología , Complemento C3/líquido cefalorraquídeo , Complemento C3/fisiología , Eosinofilia/inmunología , Eosinofilia/parasitología , Meningoencefalitis/inmunología , Meningoencefalitis/parasitología , Infecciones por Strongylida/inmunología , Animales , Preescolar , Complemento C3/biosíntesis , HumanosRESUMEN
A strong initial inflammatory response is important in neuroborreliosis. Since complement is a main player in early inflammation, we monitored the concentration and activation of complement in plasma and cerebrospinal fluid from 298 patients, of whom 23 were diagnosed with neuroborreliosis. Using sandwich ELISAs, we found significantly elevated levels of C1q, C4, C3, and C3a in cerebrospinal fluid, but not in plasma, in patients with neuroborreliosis. This finding indicates that complement plays a role in the human immune response in neuroborreliosis, that the immunologic process is compartmentalized to the CNS, and that complement activation may occur via the classical pathway.
Asunto(s)
Sistema Nervioso Central/inmunología , Activación de Complemento , Complemento C1q/líquido cefalorraquídeo , Complemento C3/líquido cefalorraquídeo , Neuroborreliosis de Lyme/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/patología , Masculino , Persona de Mediana Edad , Estadísticas no ParamétricasRESUMEN
beta-Amyloid protein (betaA) has been implicated in the pathogenesis of Alzheimer's disease (AD) because of its neurotoxicity and ability to trigger a local inflammatory response. Although assembly of betaA in particular aggregates seems to be crucial event in AD pathogenesis, soluble, non-fibrillar betaA may also be involved. Non-fibrillar betaA1-42, and truncated peptide 1-28, induced dose-dependent activation of C4 sparing C3. The mechanism of C4 activation was not dependent on C1q, because non-fibrillar betaA can still activate C4 in plasma genetically deficient in C1q. A C1q independent mechanism of complement classical pathway activation could be via the activation of contact/kinin system. The possible involvement of contact system in AD is suggested by the finding that this system is massively activated in CSF of AD patients. The mechanism of activation of contact system could be the result of an anionic interaction of residues within the region 1-11 of betaA1-42 with factor XII, and of kallikrein generation. Concomitant incubation of a small cationic peptide (lysine4) with betaA abrogated its ability to trigger the cleavage of high molecular weight kininogen. In vivo, prevention of contact system activation beside the reduction of kallikrein generation, can also decrease the activation of complement system and the release of interleukin-6, both factors being considered to play an important role in the inflammatory reactions in AD brain.
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Enfermedad de Alzheimer/inmunología , Precursor de Proteína beta-Amiloide/inmunología , Activación de Complemento , Complemento C4/inmunología , Factor XII/inmunología , Calicreínas/antagonistas & inhibidores , Enfermedad de Alzheimer/líquido cefalorraquídeo , Secuencia de Aminoácidos , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/farmacología , Precursor de Proteína beta-Amiloide/farmacología , Complemento C3/líquido cefalorraquídeo , Complemento C3/inmunología , Complemento C4/líquido cefalorraquídeo , Factor B del Complemento/líquido cefalorraquídeo , Factor B del Complemento/inmunología , Factor XII/genética , Femenino , Humanos , Calicreínas/inmunología , Quininógenos/sangre , Quininógenos/inmunología , Masculino , Datos de Secuencia Molecular , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/farmacologíaRESUMEN
OBJECTIVES: Validation of cerebrospinal fluid (CSF) indexes as a measure for intrathecal C3 and C4 production. Examination of their role in differential diagnosis of immunological disorders of the central nervous system (CNS). MATERIAL AND METHODS: Correlative study in controls (low back pain without disk herniation) between the CSF/serum ratio (Q) for albumin, and Q C3 and Q C4. Comparative study of C3 and C4 indexes in patients with CNS dysfunction due to relapsing-remitting (RR) multiple sclerosis (MS), secondary progressive (SP) MS, systemic lupus erythematosus (SLE), and human immunodeficiency virus (HIV) infection. RESULTS: Strong and statistically highly significant correlations between Q albumin and Q C3 (r=0.89, P=0.0001), and Q C4 (r=0.68, P= 0.0001). In MS patients decreased mean values for serum (RR, SP) and CSF (RR) C3, and increased C3 index mean value (RR, SP). In CNS SLE increase of mean C3 and C4 index values. In CNS HIV increase of mean C3 and C4 index values, and CSF C3 and C4 concentrations. Most individual index values were within the reference range. CONCLUSION: CSF index is a valid tool to detect intrathecal C3 or C4 production. C3 or C4 index contributes little to the differential diagnosis of immunological CNS disorders. C3 might play a pathogenic role in various immunological CNS disorders.
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Complejo SIDA Demencia/líquido cefalorraquídeo , Complemento C3/líquido cefalorraquídeo , Complemento C4/líquido cefalorraquídeo , Lupus Eritematoso Sistémico/líquido cefalorraquídeo , Esclerosis Múltiple Crónica Progresiva/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Complejo SIDA Demencia/sangre , Complejo SIDA Demencia/diagnóstico , Albúminas/líquido cefalorraquídeo , Enfermedades Autoinmunes , Barrera Hematoencefálica , Estudios de Casos y Controles , Diagnóstico Diferencial , Femenino , Humanos , Inmunoglobulina G/análisis , Inmunoglobulina M/análisis , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/diagnóstico , Masculino , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Crónica Progresiva/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Valores de Referencia , Albúmina Sérica/análisis , Estadísticas no ParamétricasRESUMEN
Complement has been shown to contribute to intrathecal inflammation in bacterial meningitis. However, the cellular source of complement in the infected central nervous system has not been determined. In this study, we analyzed protein and mRNA expression of two alternative pathway complement activation proteins, C3 and factor B, in the brains of mice with Listeria monocytogenes meningitis. Complement protein levels were found elevated in the cerebrospinal fluid of infected mice, compared with mock-infected animals. In the course of the disease, enhanced C3 and factor B mRNA expression was detected on pyramidal neurons and Purkinje cells within 6 hours, peaking at 12 hours and then gradually decreasing by 72 hours after infection. In addition, leukocytes infiltrating the subarachnoid space, within 12 to 24 hours, expressed mRNA for C3 and factor B. The cellular infiltration increased dramatically up to 72 hours. Intraperitoneal injection of tumor necrosis factor (TNF)-alpha up-regulated C3 and factor B mRNA expression on neurons in normal mice, suggesting that TNF-alpha may represent one cytokine regulating complement expression in this model of bacterial meningitis. However, additional mediators may be involved in regulation of intrathecal complement expression, as infected mice deficient of TNF/lymphotoxin-alpha genes did not demonstrate attenuated complement expression in the brain.