RESUMO
Resumen El sistema del complemento juega un papel central en la inmunidad innata, es una línea de defensa contra patógenos y participa en la homeostasis. La activación anormal del complemento contribuye al desarrollo de patologías de variable severidad, tanto inmunológicas y hematológicas como renales. Entre ellas, las microangiopatías trombóticas (MAT) representan un grupo de enfermedades raras con manifestaciones clínicas comunes caracterizadas por anemia hemolítica no inmune, trombocitopenia y daño de órgano(s) blanco. Si bien la clasificación de las MAT sigue siendo desafiante y no ha sido internacionalmente estandarizada, la descripción de entidades asociadas a anomalías del complemento fue comprobada con la eficiencia de la terapia anticomplemento en los pacientes. Las herramientas de diagnóstico desarrolladas en las últimas décadas son esenciales actualmente para diferenciar las MAT más características del grupo; esto es, la púrpura trombótica trombocitopénica (PTT) y el síndrome urémico hemolítico (SUH). En el presente trabajo se presenta una revisión del funcionamiento del sistema del complemento en condiciones fisiológicas, para poder explicar luego cuáles son las alteraciones del sistema implicadas en el desarrollo de las MAT y describir las herramientas disponibles para detectarlas en el laboratorio.
Abstract The complement system plays a crucial role in the innate immune response, being the first-line defense against pathogens and regulating homeostasis. Uncontrolled complement activation can cause immunologic, hematologic as well as renal syndromes of variable severity. Among them, thrombotic microangiopathies (TMA) represent a group of rare diseases characterised by similar clinical manifestations such as microangiopathic hemolytic anemia (MAHA), peripheral thrombocytopenia and organ injury. Although TMA classification is still challenging and no international consensus has been reached, complement-associated disorders have been described thanks to the efficiency of anti-complement therapy in patients. Diagnostic tools developed in the last decades are essential to differentiate the two most well characterized TMA: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). This review will describe how the complement system works in physiological conditions in order to explain how complement abnormalities are involved in TMA, and finally how to detect those anomalies using laboratory tests.
Resumo O sistema do complemento desempenha um papel central na imunidade inata, sendo uma linha de defesa contra patógenos e participando da homeostase. A ativação anormal do complemento contribui para o desenvolvimento de patologias de gravidade variável, como imunológicas, hematológicas e renais. Entre elas, as microangiopatias trombóticas (MAT) representam um grupo de doenças raras com manifestações clínicas comuns caracterizadas por anemia hemolítica não imune, trombocitopenia e lesão de órgão(s) alvo. Embora a classificação das MAT continue sendo desafiadora e não tenha sido padronizada internacionalmente, a descrição de entidades associadas a anomalias do complemento foi comprovada com a eficiência da terapia anticomplemento nos pacientes. As ferramentas de diagnóstico desenvolvidas nas últimas décadas são atualmente essenciais para diferenciar as MAT mais características do grupo, que são a púrpura trombocitopênica trombótica (PTT) e a síndrome hemolítica urêmica atípica (SHU). Neste trabalho, é apresentada uma revisão do funcionamento do sistema de complemento em condições fisiológicas, a fim de explicar posteriormente quais são as alterações do sistema compreendidas no desenvolvimento das MAT, e descrever as ferramentas disponíveis para detectá-las em laboratório.
Assuntos
Humanos , Biomarcadores/análise , Ativação do Complemento/fisiologia , Microangiopatias Trombóticas/diagnóstico , Trombocitopenia/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Homeostase , Anemia Hemolítica/diagnósticoRESUMO
Synapses are well known as the main structures responsible for transmitting information through the release and recognition of neurotransmitters by pre- and post-synaptic neurons. These structures are widely formed and eliminated throughout the whole lifespan via processes termed synaptogenesis and synaptic pruning, respectively. Whilst the first process is needed for ensuring proper connectivity between brain regions and also with the periphery, the second phenomenon is important for their refinement by eliminating weaker and unnecessary synapses and, at the same time, maintaining and favoring the stronger ones, thus ensuring proper synaptic transmission. It is well-known that synaptic elimination is modulated by neuronal activity. However, only recently the role of the classical complement cascade in promoting this phenomenon has been demonstrated. Specifically, microglial cells recognize activated complement component 3 (C3) bound to synapses targeted for elimination, triggering their engulfment. As this is a highly relevant process for adequate neuronal functioning, disruptions or exacerbations in synaptic pruning could lead to severe circuitry alterations that could underlie neuropathological alterations typical of neurological and neuropsychiatric disorders. In this review, we focus on discussing the possible involvement of excessive synaptic elimination in Alzheimer's disease, as it has already been reported dendritic spine loss in post-synaptic neurons, increased association of complement proteins with its synapses and, hence, augmented microglia-mediated pruning in animal models of this disorder. In addition, we briefly discuss how this phenomenon could be related to other neurological disorders, including multiple sclerosis and schizophrenia.
Assuntos
Doença de Alzheimer/fisiopatologia , Ativação do Complemento/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Humanos , Esclerose Múltipla/fisiopatologia , Esquizofrenia/fisiopatologiaRESUMO
OBJECTIVES: Many authors recommend posterior cruciate ligament-retaining arthroplasty with the intention to maintain the proprioception properties of this ligament. Preservation of the neuroreceptors and nervous fibers may be essential for retaining the proprioception function of the posterior cruciate ligament. The present study was thus developed to evaluate the presence of neural structures in the posterior cruciate ligament resected during posterior stabilized arthroplasty in osteoarthritis patients. In particular, clinical, radiographic and histological parameters were correlated with the presence or absence of neural structures in the posterior cruciate ligament. METHODS: In total, 34 posterior cruciate ligament specimens were stained with hematoxylin-eosin and Gomori trichrome. An immunohistochemical analysis using antibodies against the S100 protein and neurofilaments was also performed. The presence of neural structures was correlated with parameters such as tibiofemoral angulation, histological degeneration of the posterior cruciate ligament, Ahlbäck radiological classification, age, gender and the histologic pattern of the synovial neurovascular bundle around the posterior cruciate ligament. RESULTS: In total, 67.5% of the cases presented neural structures in the posterior cruciate ligament. In 65% of the cases, the neurovascular bundle was degenerated. Nervous structures were more commonly detected in varus knees than in valgus knees (77% versus 50%). Additionally, severe histologic degeneration of the posterior cruciate ligament was related to neurovascular bundle degeneration. CONCLUSIONS: Severe posterior cruciate ligament degeneration was related to neurovascular bundle compromise. Neural structures were more commonly detected in varus knees. Intrinsic neural structures were detected in the majority of the posterior cruciate ligaments of patients submitted to knee arthroplasty for osteoarthritis. .
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Queimaduras/sangue , Queimaduras/patologia , Ativação do Complemento/fisiologia , /metabolismo , /sangue , Biomarcadores/sangue , Queimaduras/metabolismo , Ensaio de Imunoadsorção Enzimática , PrognósticoRESUMO
Acute kidney injury is a common and severe clinical problem. Patients who develop acute kidney injury are at increased risk of death despite supportive measures such as hemodialysis. Research in recent years has shown that tissue inflammation is central to the pathogenesis of renal injury, even after nonimmune insults such as ischemia/reperfusion and toxins. Examination of clinical samples and preclinical models has shown that activation of the complement system is a critical cause of acute kidney injury. Furthermore, complement activation within the injured kidney is a proximal trigger of many downstream inflammatory events within the renal parenchyma that exacerbate injury to the kidney. Complement activation also may account for the systemic inflammatory events that contribute to remote organ injury and patient mortality. Complement inhibitory drugs have now entered clinical use and may provide an important new therapeutic approach for patients suffering from, or at high risk of developing, acute kidney injury.
Assuntos
Injúria Renal Aguda/fisiopatologia , Inativadores do Complemento/uso terapêutico , Proteínas do Sistema Complemento/fisiologia , Rim/imunologia , Traumatismo por Reperfusão/imunologia , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Ativação do Complemento/fisiologia , Humanos , Inflamação/patologia , Isquemia/patologia , Rim/fisiopatologia , Traumatismo por Reperfusão/patologiaRESUMO
We identified a 4-year-old Brazilian boy from a family of Japanese descent and history of consanguinity, who suffered from severe recurrent pneumonia. He carries factor H (FH) deficiency associated with reduced levels of component C9 and low serum levels of C3 and factor B. His mother also presented low levels of these proteins and factor I, while his father and sister had only lower levels of FH. Western blot assays confirmed the complete absence of FH and FHL-1 polypeptides in this patient. Sequencing of the proband's FH cDNA revealed a homozygous G453A substitution, encoding an Arg(127)His change. His mother, father and sister are heterozygous for this substitution. Despite the absence of FH in the plasma, this protein was detected in the patient's fibroblasts, suggesting that Arg(127) may be important for FH secretion. Low concentrations of C9 were detected in the proband serum but no mutations in the patient's C9 gene or promoter have been identified, suggesting that this is a consequence of uncontrolled complement activation and high C9 consumption.
Assuntos
Transtornos Herdados da Coagulação Sanguínea/sangue , Transtornos Herdados da Coagulação Sanguínea/genética , Complemento C9/análise , Fator H do Complemento/deficiência , Fator H do Complemento/genética , Sequência de Bases , Transtornos Herdados da Coagulação Sanguínea/fisiopatologia , Western Blotting , Pré-Escolar , Ativação do Complemento/fisiologia , Proteínas Inativadoras do Complemento C3b , Complemento C9/genética , Proteínas do Sistema Complemento/análise , Consanguinidade , Ensaio de Imunoadsorção Enzimática , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Microscopia Confocal , Mutação , Linhagem , Pneumonia/etiologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
In this work we studied the evolution of early inflammation, complement activation and parasite survival/death along the establishment phase of Echinococcus granulosus metacestode. Using a chamber model of infection in mice, we examined cell infiltration and C3 deposition on individual parasites during their development from protoscoleces to cystic forms. We found that the intensity of the initial inflammation decreased around undamaged but not around damaged parasites: at 43dpi undamaged parasites were mostly associated with poor/mild inflammation while damaged parasites with a strong inflammation. In addition, whereas complement activation participated in the induction of early inflammation, the deposition of C3 on undamaged parasites progressively diminished. Interestingly, we observed some parasites in pre-cystic stage with no/poor C3 deposition at 3dpi. Overall, these results indicated that the establishment and survival of the hydatid cyst is associated with the control of complement and, consequently, of local inflammation at the initial phases of infection.
Assuntos
Ativação do Complemento/fisiologia , Complemento C3/imunologia , Equinococose/imunologia , Echinococcus granulosus/imunologia , Animais , Bovinos , Complemento C3/análise , Cultura em Câmaras de Difusão , Modelos Animais de Doenças , Regulação para Baixo , Equinococose/parasitologia , Equinococose/patologia , Echinococcus granulosus/crescimento & desenvolvimento , Feminino , Imunoglobulina G/metabolismo , Imunoglobulina M/metabolismo , Imuno-Histoquímica , Inflamação/imunologia , Inflamação/parasitologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Since there are no studies evaluating the participation of the complement system (CS) in Jorge Lobo's disease and its activity on the fungus Lacazia loboi, we carried out the present investigation. Fungal cells with a viability index of 48% were obtained from the footpads of BALB/c mice and incubated with a pool of inactivated serum from patients with the mycosis or with sterile saline for 30 min at 37 masculineC. Next, the tubes were incubated for 2 h with a pool of noninactivated AB+ serum, inactivated serum, serum diluted in EGTA-MgCl2, and serum diluted in EDTA. The viability of L. loboi was evaluated and the fungal suspension was cytocentrifuged. The slides were submitted to immunofluorescence staining using human anti-C3 antibody. The results revealed that 98% of the fungi activated the CS by the alternative pathway and no significant difference in L. loboi viability was observed after CS activation. In parallel, frozen histological sections from 11 patients were analyzed regarding the presence of C3 and IgG by immunofluorescence staining. C3 and IgG deposits were observed in the fungal wall of 100% and 91% of the lesions evaluated, respectively. The results suggest that the CS and immunoglobulins may contribute to the defense mechanisms of the host against L. loboi.
Assuntos
Ativação do Complemento/fisiologia , Proteínas do Sistema Complemento/fisiologia , Imunoglobulinas/imunologia , Paracoccidioides/fisiologia , Animais , Ativação do Complemento/imunologia , Complemento C3/imunologia , Complemento C3/fisiologia , Proteínas do Sistema Complemento/imunologia , Imunofluorescência , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Paracoccidioides/imunologiaRESUMO
Since there are no studies evaluating the participation of the complement system (CS) in Jorge Lobo's disease and its activity on the fungus Lacazia loboi, we carried out the present investigation. Fungal cells with a viability index of 48 percent were obtained from the footpads of BALB/c mice and incubated with a pool of inactivated serum from patients with the mycosis or with sterile saline for 30 min at 37 °C. Next, the tubes were incubated for 2 h with a pool of noninactivated AB+ serum, inactivated serum, serum diluted in EGTA-MgCl2, and serum diluted in EDTA. The viability of L. loboi was evaluated and the fungal suspension was cytocentrifuged. The slides were submitted to immunofluorescence staining using human anti-C3 antibody. The results revealed that 98 percent of the fungi activated the CS by the alternative pathway and no significant difference in L. loboi viability was observed after CS activation. In parallel, frozen histological sections from 11 patients were analyzed regarding the presence of C3 and IgG by immunofluorescence staining. C3 and IgG deposits were observed in the fungal wall of 100 percent and 91 percent of the lesions evaluated, respectively. The results suggest that the CS and immunoglobulins may contribute to the defense mechanisms of the host against L. loboi.
Considerando que não existe nenhum estudo avaliando a participação do sistema complemento (SC) na doença de Jorge Lobo e sua atividade sobre o fungo Lacazia loboi, realizamos o presente trabalho. Os fungos foram obtidos dos coxins plantares de camundongos BALB/c com índice de viabilidade de 48 por cento e, em seguida, foram incubados com pool de soro inativado de pacientes ou com solução salina estéril (SSE) por 30 min, a 37 °C. Os tubos foram incubados, por 2 h, com pool de soro AB+ sem inativar, inativado, diluído em EGTA-MgCl2 e EDTA. A viabilidade do L. loboi foi avaliada e a suspensão fúngica foi citocentrifugada. As lâminas foram submetidas à técnica de imunofluorescência empregando o anticorpo anti-C3 humano. Os resultados revelaram que 98 por cento dos fungos ativaram o SC pela via alternativa e que não houve diferença significante na viabilidade do L. loboi após ativação do SC. Em paralelo, cortes histológicos congelados de 11 pacientes foram avaliados quanto à presença de C3 e IgG, pela técnica de imunofluorescência. Foram encontrados depósitos de C3 e de IgG na parede dos fungos em 100 por cento e 91 por cento das lesões avaliadas, respectivamente. Os resultados sugerem que o SC e as imunoglobulinas poderiam contribuir nos mecanismos de defesa do hospedeiro contra o L. loboi.
Assuntos
Humanos , Animais , Camundongos , Ativação do Complemento/fisiologia , Proteínas do Sistema Complemento/fisiologia , Imunoglobulinas/imunologia , Paracoccidioides/fisiologia , Ativação do Complemento/imunologia , /imunologia , /fisiologia , Proteínas do Sistema Complemento/imunologia , Imunofluorescência , Camundongos Endogâmicos BALB C , Paracoccidioides/imunologiaRESUMO
Since there are no studies evaluating the participation of the complement system (CS) in Jorge Lobo's disease and its activity on the fungus Lacazia loboi, we carried out the present investigation. Fungal cells with a viability index of 48% were obtained from the footpads of BALB/c mice and incubated with a pool of inactivated serum from patients with the mycosis or with sterile saline for 30 min at 37 ºC. Next, the tubes were incubated for 2 h with a pool of noninactivated AB+ serum, inactivated serum, serum diluted in EGTA-MgCl2, and serum diluted in EDTA. The viability of L. loboi was evaluated and the fungal suspension was cytocentrifuged. The slides were submitted to immunofluorescence staining using human anti-C3 antibody. The results revealed that 98% of the fungi activated the CS by the alternative pathway and no significant difference in L. loboi viability was observed after CS activation. In parallel, frozen histological sections from 11 patients were analyzed regarding the presence of C3 and IgG by immunofluorescence staining. C3 and IgG deposits were observed in the fungal wall of 100% and 91% of the lesions evaluated, respectively. The results suggest that the CS and immunoglobulins may contribute to the defense mechanisms of the host against L. loboi
Considerando que não existe nenhum estudo avaliando a participação do sistema complemento (SC) na doença de Jorge Lobo e sua atividade sobre o fungo Lacazia loboi, realizamos o presente trabalho. Os fungos foram obtidos dos coxins plantares de camundongos BALB/c com índice de viabilidade de 48% e, em seguida, foram incubados com pool de soro inativado de pacientes ou com solução salina estéril (SSE) por 30 min, a 37 ºC. Os tubos foram incubados, por 2 h, com pool de soro AB+ sem inativar, inativado, diluído em EGTA-MgCl2 e EDTA. A viabilidade do L. loboi foi avaliada e a suspensão fúngica foi citocentrifugada. As lâminas foram submetidas à técnica de imunofluorescência empregando o anticorpo anti-C3 humano. Os resultados revelaram que 98% dos fungos ativaram o SC pela via alternativa e que não houve diferença significante na viabilidade do L. loboi após ativação do SC. Em paralelo, cortes histológicos congelados de 11 pacientes foram avaliados quanto à presença de C3 e IgG, pela técnica de imunofluorescência. Foram encontrados depósitos de C3 e de IgG na parede dos fungos em 100% e 91% das lesões avaliadas, respectivamente. Os resultados sugerem que o SC e as imunoglobulinas poderiam contribuir nos mecanismos de defesa do hospedeiro contra o L. loboi