RESUMO
Neurocysticercosis is caused by the establishment of Taenia solium cysts in the central nervous system. Murine cysticercosis by Taenia crassiceps is a useful model of cysticercosis in which the complement component 5 (C5) has been linked to infection resistance/permissiveness. This work aimed to study the possible relevance for human neurocysticercosis of single nucleotide polymorphisms (SNPs) in the C5-TRAF1 region (rs17611 C/T, rs992670 G/A, rs25681 G/A, rs10818488 A/G, and rs3761847 G/A) in a Mexican population and associated with clinical and radiological traits related to neurocysticercosis severity (cell count in the cerebrospinal fluid [CSF cellularity], parasite location and parasite load in the brain, parasite degenerating stage, and epilepsy). The AG genotype of the rs3761847 SNP showed a tendency to associate with multiple brain parasites, while the CT and GG genotypes of the rs17611 and rs3761847 SNPs, respectively, showed a tendency to associate with low CSF cellularity. The rs3761847 SNP was associated with epilepsy under a dominant model, whereas rs10818488 was associated with CSF cellularity and parasite load under dominant and recessive models, respectively. For haplotypes, C5- and the TRAF1-associated SNPs were, respectively, in strong linkage disequilibrium with each other; thus, these haplotypes were studied independently. For C5 SNPs, carrying the CAA haplotype increases the risk of showing high CSF cellularity 3-fold and the risk of having extraparenchymal parasites 4-fold, two conditions that are related to severe disease. For TRAF1 SNPs, the GA and AG haplotypes were associated with CSF cellularity, and the AG haplotype was associated with epilepsy. Overall, these findings support the clear participation of C5 and TRAF1 in the risk of developing severe neurocysticercosis in the Mexican population.
Assuntos
Complemento C5/genética , Epilepsia/parasitologia , Predisposição Genética para Doença/genética , Neurocisticercose/genética , Fator 1 Associado a Receptor de TNF/genética , Adolescente , Adulto , Idoso , Animais , Encéfalo/parasitologia , Líquido Cefalorraquidiano/parasitologia , Epilepsia/genética , Feminino , Haplótipos/genética , Humanos , Masculino , México , Pessoa de Meia-Idade , Neurocisticercose/parasitologia , Carga Parasitária , Polimorfismo de Nucleotídeo Único/genética , Taenia solium/patogenicidade , Adulto JovemRESUMO
METHODS: C5 rs17611 genetic variants were investigated in 494 IS patients and 330 control individuals .Ischemic stroke was classiï¬ed into subtypes and patients were assessed 90 days post-stroke with the modified Rankin Scale to determine stroke outcome. RESULTS: The presence of C5 polymorphism was associated with the incidence of large artery atherosclerosis (LAA)-subtype IS (n =2 00; p = 0.031), which even persisted after adjustment for covariates (OR = 1.518; 95%CI = 1.093-2.018; p = 0.013). However, no association was found between genotypes and the severity and outcome of stroke (p = 0.978; p = 0.296). CONCLUSIONS: The C5 polymorphism might contribute to the risk of LAA-subtype IS independently of other known risk predictors.
Assuntos
Aterosclerose/genética , Complemento C5/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , China , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
ABSTRACT The complement system has been confirmed to play an increasingly important role in ischemic stroke (IS). This study aimed to determine whether the single-nucleotide polymorphism of the complement 5 (C5) gene independently influences the occurrence, severity, and long-term outcome of IS in Chinese patients. Methods C5 rs17611 genetic variants were investigated in 494 IS patients and 330 control individuals .Ischemic stroke was classified into subtypes and patients were assessed 90 days post-stroke with the modified Rankin Scale to determine stroke outcome. Results The presence of C5 polymorphism was associated with the incidence of large artery atherosclerosis (LAA)-subtype IS (n =2 00; p = 0.031), which even persisted after adjustment for covariates (OR = 1.518; 95%CI = 1.093–2.018; p = 0.013). However, no association was found between genotypes and the severity and outcome of stroke (p = 0.978; p = 0.296). Conclusions The C5 polymorphism might contribute to the risk of LAA-subtype IS independently of other known risk predictors.
RESUMO Já se confirmou que o sistema do complemento exerce um papel cada vez mais importante nos acidentes vasculares cerebrais isquêmicos. Este estudo teve o objetivo de determinar se o polimorfismo de nucleotídeo único (SNP) do gene codificador do componente 5 (C5) influencia de forma independente a ocorrência, a severidade e o desfecho em longo prazo do acidente vascular cerebral isquêmico (AVCI) em pacientes chineses. Métodos Variantes genéticas rs17611 do C5 foram investigadas em 494 pacientes com AVCI e em 330 indivíduos controles. O AVCI foi classificado em subtipos e os pacientes foram avaliados 90 dias após o acidente vascular, através da Escala Modificada de Rankin (mRS), para determinação do desfecho do acidente. Resultados A presença de polimorfismo do C5 foi associada à incidência de AVCI do subtipo com aterosclerose de grandes artérias (AGA) (n = 200; p = 0,031), que persistiu mesmo após os ajustes de covariáveis (RP = 1,518; 95% IC = 1,093–2,018; p = 0,013). Entretanto, nenhuma associação foi observada entre os genótipos e a severidade ou o desfecho do acidente vascular (p = 0,978; p = 0,296). Conclusões O polimorfismo do C5 pode contribuir para o risco de AVCI do tipo com AGA, independentemente de outros riscos preditores conhecidos.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Complemento C5/genética , Acidente Vascular Cerebral/genética , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , China , Predisposição Genética para Doença/genética , Povo Asiático/genética , Aterosclerose/genética , Estudos de Associação GenéticaRESUMO
Innate immunity contributes effectively to the development of alcoholic liver disease (ALD). In special, the activation of the complement system is involved in the pathogenesis of this disease. Here we investigated the contribution of complement C5 protein to the establishment and maintenance of ALD. Eight- to ten-week-old B6C5(+) and B6C5(-) male mice were fed with high fat diet (HFD) only or the same diet containing equicaloric supplements of ethanol (HFDE) or maltodextrin (HFDM) for 10 weeks. Serum parameters of liver function as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), albumin, glucose, triglycerides (TG) and cholesterol were evaluated. Liver tissue samples were collected for histopathological analysis, lipid extraction (TG and cholesterol), cytokines (TNF-α, IL-6, IL-1ß, IL-10, IL-12, IL-17, IFN-γ, TGF-ß) measurement and NO production. We observed that B6C5(-) mice HFDE-fed accumulated more liver cholesterol and TG, increased liver IL-17 and IL-10 levels and reduced liver TGF-ß levels when compared to HFD-fed mice. We also observed that serum AST, AP and albumin were increased in B6C5(-) mice. Liver IL-1ß, IL-6, IL-12 and IFN-γ were decreased in B6C5(-) mice independently of diet. We conclude that C5 acts in the control of serum TG and cholesterol, liver cholesterol deposition, liver homeostasis and C5 promotes a pro-inflammatory liver environment in our mouse model of ALD.
Assuntos
Complemento C5/metabolismo , Hepatopatias Alcoólicas/imunologia , Fígado/fisiologia , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Aspartato Aminotransferases/sangue , Células Cultivadas , Colesterol/metabolismo , Complemento C5/genética , Citocinas/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Etanol , Humanos , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Triglicerídeos/metabolismoRESUMO
To investigate the in vivo role of complement component C5 it is common to compare the inflammatory response between C5-normal and C5-deficient inbred mice strains. Nevertheless, it should be expected that differences in the genetic backgrounds between those strains may affect several physiological parameters, complicating the correct interpretation of results. The use of congenic mice, developed by backcrossing, is therefore preferred. Still, several physiological parameters may be distinctive in the normal and deficient strains and therefore require careful analysis before animals are selected for investigation. We generated two congenic mouse strains: C57BL/6 (B6) C5(-), derived from the parental B6 C5(+) strain and A/J C5(+) mice derived from the parental A/J C5(-) strain. After confirmation by nucleotide sequencing, immunodiffusion and hemolytic activity analysis, several basal physiological parameters were analyzed in the congenic and parental strains before antigen exposition. Serum levels of liver alanine aminotransferase, alkaline phosphatase, albumin, triglycerides, cholesterol and uric acid were found to be different in C5-sufficient and C5-deficient mice from one or both genetic backgrounds (B6 and/or A/J). On the other hand, serum levels of liver aspartate aminotransferase, glucose and urea were not affected by the presence of C5 in either strain. Furthermore, in some cases, C5-dependent variations in these parameters were more evident in mice of the same gender. We conclude here that C5-deficient mice strains may present distinct systemic behaviors which should be taken in consideration before differences in the immune responses are attributed solely to the lack of circulating C5.
Assuntos
Complemento C5/genética , Camundongos Congênicos/fisiologia , Camundongos Endogâmicos C57BL/fisiologia , Alanina Transaminase/metabolismo , Albuminas/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Sequência de Bases , Colesterol/metabolismo , Complemento C5/deficiência , Complemento C5/imunologia , Cruzamentos Genéticos , Feminino , Expressão Gênica , Heterogeneidade Genética , Loci Gênicos , Fígado/enzimologia , Masculino , Camundongos , Especificidade da Espécie , Triglicerídeos/metabolismo , Ácido Úrico/metabolismoRESUMO
The deficiency of complement C5 is rare and frequently associated with severe and recurrent infections, especially caused by Neisseria spp. We observed the absence of component C5 in the serum of 3 siblings from a Brazilian family with history of consanguinity. The patients had suffered from recurrent episodes of meningitis and other less severe infections. Sera from these patients were unable to mediate hemolytic activity either by the classical or alternative pathways and presented extremely low levels of C5 protein (1.3, 0.9 and 1.0 microg/ml-normal range: 45-190 microg/ml). Hemolytic activity could be restored by the addition of purified C5 to deficient serum. Sequencing of sibling C5 cDNA revealed a homozygous 153 bp deletion that corresponds precisely to exon 30. The parents carried the same deletion but only in one allele. Sequencing of the corresponding region in the genomic DNA revealed a C to G substitution within intron 30 and, most significantly, the substitution of GAG(4028) for GAA(4028) at the 3' end of exon 30 which is most likely responsible for skipping of exon 30. The resulting in-frame deletion in the C5 mRNA codes for a mutant C5 protein lacking residues 1289-1339. These residues map to the CUB and C5d domains of the C5 alpha chain. This deletion is expected to produce a non-functional and unstable C5 protein which is more susceptible to degradation.
Assuntos
Complemento C5/química , Complemento C5/genética , Éxons/genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Adolescente , Adulto , Indígena Americano ou Nativo do Alasca/genética , Sequência de Bases , Western Blotting , Brasil , Criança , Análise Mutacional de DNA , DNA Complementar/genética , Feminino , Hemólise , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Estabilidade Proteica , Estrutura Terciária de ProteínaRESUMO
OBJECTIVE: Mice selected for a strong (AIRmax) or weak (AIRmin) acute inflammatory response present different susceptibilities to bacterial infections, autoimmune diseases and carcinogenesis. Variations in these phenotypes have been also detected in AIRmax and AIRmin mice rendered homozygous for Slc11a1 resistant (R) and susceptible (S) alleles. Our aim was to investigate if the phenotypic differences observed in these mice was related to the complement system. MATERIAL: AIRmax and AIRmin mice and AIRmax and AIRmin groups homozygous for the resistance (R) or susceptibility (S) alleles of the solute carrier family 11a1 member (Slc11a1) gene, formerly designated Nramp-1. METHODS AND RESULTS: While no difference in complement activity was detected in sera from AIRmax and AIRmin strains, all sera from AIRmax Slc11a1 resistant mice (AIRmax(RR)) presented no complement-dependent hemolytic activity. Furthermore, C5 was not found in their sera by immunodiffusion and, polymerase chain reaction and DNA sequencing of its gene demonstrated that AIRmax(RR) mice are homozygous for the C5 deficient (D) mutation previously described in A/J. Therefore, the C5D allele was fixed in homozygosis in AIRmax(RR) line. CONCLUSIONS: The AIRmax(RR) line is a new experimental mouse model in which a strong inflammatory response can be triggered in vivo in the absence of C5.