RESUMEN
Anti-neutrophil cytoplasmic antibody vasculitis is a systemic autoimmune disease with glomerulonephritis and pulmonary haemorrhage as major clinical manifestations. The name reflects the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind to both neutrophils and monocytes. Evidence of the pathogenicity of these autoantibodies is provided by the observation that injection of anti-myeloperoxidase antibodies into mice causes a pauci-immune focal segmental necrotizing glomerulonephritis which is histologically similar to the changes seen on renal biopsy in patients. Previous studies in this model have implicated the alternative pathway of complement activation and the anaphylatoxin C5a. Despite this progress, the factors that initiate complement activation have not been defined. In addition, the relative importance of bone marrow-derived and circulating C5 is not known. This is of interest given the recently identified roles for complement within leukocytes. We induced anti-myeloperoxidase vasculitis in mice and confirmed a role for complement activation by demonstrating protection in C3-deficient mice. We showed that neither MASP-2- nor properdin-deficient mice were protected, suggesting that alternative pathway activation does not require properdin or the lectin pathway. We induced disease in bone marrow chimaeric mice and found that circulating and not bone marrow-derived C5 was required for disease. We have therefore excluded properdin and the lectin pathway as initiators of complement activation and this means that future work should be directed at other potential factors within diseased tissue. In addition, in view of our finding that circulating and not bone marrow-derived C5 mediates disease, therapies that decrease hepatic C5 secretion may be considered as an alternative to those that target C5 and C5a. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/metabolismo , Complemento C5/metabolismo , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/metabolismo , Properdina/metabolismo , Animales , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inducido químicamente , Médula Ósea/metabolismo , Complemento C3/genética , Complemento C3/metabolismo , Complemento C5/genética , Modelos Animales de Enfermedad , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Ratones , Ratones Noqueados , Peroxidasa/inmunología , Properdina/genéticaAsunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Autoanticuerpos/inmunología , Activación Neutrófila/inmunología , Neutrófilos/fisiología , Animales , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Ratones , Mieloblastina/inmunología , Peroxidasa/inmunologíaRESUMEN
The complement pathway is a central part of the innate immune system and also modulates adaptive immunity. It is implicated in the pathogenesis of glomerular disease by a number of clinical findings. These include the presence of complement components in renal biopsy samples, decreases in circulating levels indicating consumption, the presence of autoantibodies to complement proteins and the association of genetic mutations with disease either in individuals or within families. Further support and mechanistic insights comes from animal models. This review provides an overview of the role of complement in glomerular diseases and discusses the data from patients and animal models with reference to specific diseases. These include atypical haemolytic uraemic syndrome, C3 glomerulopathy, anti-neutrophil cytoplasmic antibody vasculitis, lupus nephritis and membranous nephropathy. The implications for therapy are also discussed.
Asunto(s)
Activación de Complemento/inmunología , Proteínas del Sistema Complemento/inmunología , Enfermedades Renales/inmunología , Animales , Complejo Antígeno-Anticuerpo/inmunología , Autoanticuerpos/inmunología , Activación de Complemento/genética , Proteínas del Sistema Complemento/genética , Glomerulonefritis Membranosa/tratamiento farmacológico , Glomerulonefritis Membranosa/genética , Glomerulonefritis Membranosa/inmunología , Síndrome Hemolítico-Urémico/tratamiento farmacológico , Síndrome Hemolítico-Urémico/genética , Síndrome Hemolítico-Urémico/inmunología , Humanos , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/genética , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunologíaRESUMEN
OBJECTIVES: Granulocyte colony stimulating factor (GCSF) is important in mobilising neutrophils from the bone marrow but also has a range of proinflammatory effects. We therefore decided to investigate the role of GCSF in antineutrophil cytoplasmic antibody (ANCA) vasculitis. METHODS: We measured GCSF levels in the serum of 38 patients with active ANCA vasculitis compared with 31 age-matched controls, and assessed the effect of GCSF priming on the response of human neutrophils to ANCA. We also examined the effect of exogenous GCSF administration in a murine model of antimyeloperoxidase (anti-MPO) vasculitis, and the effect of GCSF on murine neutrophil activation. RESULTS: The serum levels of GCSF in patients with active ANCA vasculitis were significantly higher than those of age matched healthy controls (mean 38.04 vs 18.35 pg/ml, p<0.001). Furthermore, we demonstrated that GCSF primed human neutrophils in vitro for a respiratory burst in response to anti-MPO ANCA. In an anti-MPO antibody transfer model, mice given GCSF had more crescents (mean 29.1% vs 5.8% per glomerular cross section, p<0.05), more macrophages (mean 3.2 vs 1.2 per glomerular cross-section, p<0.01), higher serum creatines (mean 13.6 vs 8.3 µmol/l, p<0.05) and more haematuria (p<0.05) compared with controls. In vivo administration of GCSF with lipopolysaccharide (LPS), but not LPS alone, led to upregulation of CD11c on murine neutrophils. CONCLUSIONS: These data suggest that GCSF, which is raised in patient serum, may play an important role in exacerbating disease in ANCA vasculitis. In addition, GCSF therapy for neutropenia should be used with caution in these patients.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Factor Estimulante de Colonias de Granulocitos/inmunología , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Anciano , Animales , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Glomerulonefritis/inducido químicamente , Glomerulonefritis/inmunología , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Masculino , Ratones , Activación Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Peroxidasa/inmunologíaRESUMEN
Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is characterized by the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind monocytes in addition to neutrophils. While a pathological effect on neutrophils is acknowledged, the impact of ANCA on monocyte function is less well understood. Using IgG from patients we investigated the effect of these autoantibodies on monocytes and found that anti-myeloperoxidase antibodies (MPO-ANCA) reduced both IL-10 and IL-6 secretion in response to LPS. This reduction in IL-10 and IL-6 depended on Fc receptors and enzymatic myeloperoxidase and was accompanied by a significant reduction in TLR-driven signaling pathways. Aligning with changes in TLR signals, oxidized phospholipids, which function as TLR4 antagonists, were increased in monocytes in the presence of MPO-ANCA. We further observed that MPO-ANCA increased monocyte survival and differentiation to macrophages by stimulating CSF-1 production. However, this was independent of myeloperoxidase enzymatic activity and TLR signaling. Macrophages differentiated in the presence of MPO-ANCA secreted more TGF-ß and further promoted the development of IL-10- and TGF-ß-secreting CD4+ T cells. Thus, MPO-ANCA may promote inflammation by reducing the secretion of antiinflammatory IL-10 from monocytes, and MPO-ANCA can alter the development of macrophages and T cells to potentially promote fibrosis.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Autoanticuerpos/inmunología , Inmunoglobulina G/inmunología , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Peroxidasa/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/metabolismo , Anticuerpos Anticitoplasma de Neutrófilos , Linfocitos T CD4-Positivos/inmunología , Supervivencia Celular , Células Cultivadas , Femenino , Humanos , Interleucina-10/inmunología , Interleucina-10/metabolismo , Interleucina-6/inmunología , Interleucina-6/metabolismo , Linfopoyesis , Factor Estimulante de Colonias de Macrófagos/inmunología , Factor Estimulante de Colonias de Macrófagos/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Oxidación-Reducción , Peroxidasa/metabolismo , Fosfolípidos/metabolismo , Receptores Fc , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo , Factor de Crecimiento Transformador beta/inmunología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Systemic lupus erythematosus is an autoimmune disease with a high morbidity and nephritis is a common manifestation. Previous studies in murine lupus models have suggest a role for Toll-like receptor 2 and 4. We examined the role of these molecules in MRL lpr mice which is one of the most established and robust murine models. We compared disease parameters in Toll-like receptor 2 or Toll-like receptor 4 deficient mice with their littermate controls. We found no difference in the severity of glomerulonephritis as assessed by histology, serum creatinine and albuminuria when Toll-like receptor 2 or Toll-like receptor 4 deficient MRLlpr mice were compared with Toll-like receptor sufficient controls. We also found similar levels of anti-dsDNA and anti-ssDNA antibodies. These results show that Toll-like receptor 2 and Toll-like receptor 4 do not play a significant role in MRLlpr mice, and therefore they may not be important in human lupus.
Asunto(s)
Lupus Eritematoso Sistémico/fisiopatología , Receptor Toll-Like 2/fisiología , Receptor Toll-Like 4/fisiología , Animales , Secuencia de Bases , Cartilla de ADN , Ratones , Reacción en Cadena de la Polimerasa , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/genéticaRESUMEN
In this study, we have investigated the effects of artemin (ARTN), one of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, on C-fibres following nerve injury in the adult rat. GDNF family receptor alpha (GFRalpha) 3, the ligand binding domain of the ARTN receptor, is expressed in 34% of dorsal root ganglion (DRG) cells, predominantly in the peptidergic population of C-fibres and in a proportion of the isolectin B4 (IB4)-binding population. Interestingly, only 30% of GFRalpha3-expressing DRG cells co-expressed RET (the signal transducing domain). In agreement with previous studies, treatment with ARTN prevented many of the nerve injury-induced changes in the histochemistry of both the peptidergic and the IB4-binding populations of small, but not large, diameter DRG cells. In addition, ARTN treatment maintained C-fibre conduction velocity, and C-fibre evoked substance P release within the dorsal horn following nerve injury. ARTN was also protective following capsaicin treatment, which produces selective C-fibre injury. Given the potent neurotrophic actions of ARTN on C-fibres, it may therefore provide potential for the treatment of nerve injury, particularly in the maintenance of small fibre function.
Asunto(s)
Proteínas del Tejido Nervioso/farmacología , Neuronas Aferentes/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Axotomía , Células Cultivadas , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/lesiones , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Hibridación in Situ , Ratones , Regeneración Nerviosa/efectos de los fármacos , Conducción Nerviosa/efectos de los fármacos , Neuronas Aferentes/patología , Ratas , Proteínas Recombinantes/farmacología , Sustancia P/efectos de los fármacos , Sustancia P/metabolismoRESUMEN
The inability of axons to regenerate after a spinal cord injury in the adult mammalian central nervous system (CNS) can lead to permanent paralysis. At sites of CNS injury, a glial scar develops, containing extracellular matrix molecules including chondroitin sulphate proteoglycans (CSPGs). CSPGs are inhibitory to axon growth in vitro, and regenerating axons stop at CSPG-rich regions in vivo. Removing CSPG glycosaminoglycan (GAG) chains attenuates CSPG inhibitory activity. To test the functional effects of degrading chondroitin sulphate (CS)-GAG after spinal cord injury, we delivered chondroitinase ABC (ChABC) to the lesioned dorsal columns of adult rats. We show that intrathecal treatment with ChABC degraded CS-GAG at the injury site, upregulated a regeneration-associated protein in injured neurons, and promoted regeneration of both ascending sensory projections and descending corticospinal tract axons. ChABC treatment also restored post-synaptic activity below the lesion after electrical stimulation of corticospinal neurons, and promoted functional recovery of locomotor and proprioceptive behaviours. Our results demonstrate that CSPGs are important inhibitory molecules in vivo and suggest that their manipulation will be useful for treatment of human spinal injuries.
Asunto(s)
Condroitina ABC Liasa/metabolismo , Condroitina ABC Liasa/uso terapéutico , Regeneración Nerviosa/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Animales , Axones/metabolismo , Axones/patología , Electrofisiología , Proteína GAP-43/metabolismo , Ganglios Espinales/lesiones , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Humanos , Isoenzimas/metabolismo , Masculino , Actividad Motora , Compresión Nerviosa , Neuronas/metabolismo , Neuronas/patología , Proteína Quinasa C/metabolismo , Desempeño Psicomotor , Ratas , Ratas Wistar , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Regulación hacia ArribaRESUMEN
BACKGROUND: Metastatic breast cancer is generally believed to be associated with a poor prognosis. Therapeutic advances over the past two decades, however, have resulted in improved outcomes for selected patients with limited metastatic disease. METHODS: Between March 1991 and October 2002, 31 patients had hepatic resection for breast cancer metastases limited to the liver. Clinical and pathologic data were collected prospectively from breast and hepatobiliary databases. RESULTS: Median age of patients was 46 years (range, 31 to 70). Liver metastases were solitary in 20 patients and multiple in 11 patients. Median size of the largest liver metastasis was 2.9 cm (range, 1 to 8). Major liver resections (three or more segments resected) were performed in 14 patients, whereas minor resections (fewer than three segments resected) with or without radiofrequency ablation (RFA) were performed in 17 patients. No postoperative mortality occurred. Of the 31 patients, 27 (87%) received either preoperative or postoperative systemic therapy as treatment for metastatic disease. The median survival was 63 months; a single patient died within 12 months of hepatic resection. The overall 2- and 5-year survival rates were 86% and 61%, respectively, whereas the 2- and 5-year disease-free survival rates were 39% and 31%, respectively. No treatment- or patient-specific variables were found to correlate with survival rates. CONCLUSIONS: In selected patients with liver metastases from breast cancer, an aggressive surgical approach is associated with favorable long-term survival. Hepatic resection should be considered a component of multimodality treatment of breast cancer in these patients.