RESUMEN
The terminal complement split product C5a has been described as an important mediator in inflammatory diseases. C5a is generated upon cleavage of C5 and earlier research suggests that, besides the known C5 convertases formed upon activation of the complement pathways, various enzymes could activate C5 directly. We demonstrate that eculizumab effectively blocks C5 activation when mediated by C5-convertase formation, but fails to block C5a generation resulting from direct enzymatic cleavage by trypsin and thrombin. C5a generated by these enzymes is shown to be fully biologically functional and can be blocked by IFX-1, a specific monoclonal anti-human C5a antibody. We further report clinical cases of atypical hemolytic uremic syndrome (aHUS) and C3 Glomerulonephritis (C3GN) patients under treatment with eculizumab presenting substantially elevated C5a levels. Thus, blocking the C5 convertase mediated activation of C5 may not be efficient to control C5a-mediated effects in human disease and that a targeted approach is warranted.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Síndrome Hemolítico Urémico Atípico/inmunología , Complemento C5a/inmunología , Glomerulonefritis/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Convertasas de Complemento C3-C5/inmunología , Glomerulonefritis/tratamiento farmacológico , Humanos , Trombina/inmunología , Tripsina/inmunología , Zimosan/farmacologíaRESUMEN
BACKGROUND: Patients infected with influenza A(H7N9) virus present with acute lung injury (ALI) that is due to severe pneumonia and systemic inflammation. It is often fatal because there are few effective treatment options. Complement activation has been implicated in the pathogenesis of virus-induced lung injury; therefore, we investigated the effect of targeted complement inhibition on ALI induced by H7N9 virus infection. METHODS: A novel neutralizing specific antihuman C5a antibody (IFX-1) was used. This antibody blocked the ability of C5a to induce granulocytes to express CD11b while not affecting the ability of C5b to form the membrane attack complex. African green monkeys were inoculated with H7N9 virus and treated intravenously with IFX-1. RESULTS: The virus infection led to intense ALI and systemic inflammatory response syndrome (SIRS) in association with excessive complement activation. Anti-C5a treatment in H7N9-infected monkeys substantially attenuated ALI: It markedly reduced the lung histopathological injury and decreased the lung infiltration of macrophages and neutrophils. Moreover, the treatment decreased the intensity of SIRS; the body temperature changes were minimal and the plasma levels of inflammatory mediators were markedly reduced. The treatments also significantly decreased the virus titers in the infected lungs. CONCLUSIONS: Antihuman C5a antibody treatment remarkably reduced the ALI and systemic inflammation induced by H7N9 virus infection. Complement inhibition may be a promising adjunctive therapy for severe viral pneumonia.
Asunto(s)
Anticuerpos Neutralizantes/uso terapéutico , Complemento C5a/antagonistas & inhibidores , Complemento C5a/inmunología , Subtipo H7N9 del Virus de la Influenza A , Gripe Humana/terapia , Neumonía Viral/terapia , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/terapia , Lesión Pulmonar Aguda/virología , Animales , Temperatura Corporal , Chlorocebus aethiops/virología , Activación de Complemento , Modelos Animales de Enfermedad , Humanos , Subtipo H7N9 del Virus de la Influenza A/aislamiento & purificación , Subtipo H7N9 del Virus de la Influenza A/patogenicidad , Gripe Humana/inmunología , Gripe Humana/patología , Gripe Humana/virología , Pulmón/patología , Pulmón/virología , Macrófagos Alveolares/inmunología , Neutrófilos/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/terapia , Infecciones por Orthomyxoviridae/virología , Neumonía Viral/inmunología , Neumonía Viral/patología , Neumonía Viral/virología , Síndrome de Respuesta Inflamatoria Sistémica/patología , Síndrome de Respuesta Inflamatoria Sistémica/terapia , Síndrome de Respuesta Inflamatoria Sistémica/virología , Resultado del Tratamiento , Carga ViralRESUMEN
Cytokine regulation possibly influences long term outcome following ankle fractures, but little is known about synovial fracture biochemistry. Eight patients with an ankle dislocation fracture were included in a prospective case series and matched with patients suffering from grade 2 osteochondritis dissecans (OCD) of the ankle. All fractures needed external fixation during which joint effusions were collected. Fluid analysis was done by ELISA measuring aggrecan, bFGF, IL-1 ß, IGF-1, and the complement components C3a, C5a, and C5b-9. The time periods between occurrence of fracture and collection of effusion were only significantly associated with synovial aggrecan and C5b-9 levels (P < 0.001). Furthermore, synovial expressions of both proteins correlated with each other (P < 0.001). Although IL-1 ß expression was relatively low, intra-articular levels correlated with C5a (P < 0.01) and serological C-reactive protein concentrations 2 days after surgery (P < 0.05). Joint effusions were initially dominated by neutrophils, but the portion of monocytes constantly increased reaching 50% at day 6 after fracture (P < 0.02). Whereas aggrecan and IL-1ß concentrations were not different in fracture and OCD patients, bFGF, IGF-1, and all complement components were significantly higher concentrated in ankle joints with fractures (P < 0.01). Complement activation and inflammatory cell infiltration characterize the joint biology following acute ankle fractures.