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1.
Sci Rep ; 11(1): 1233, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441900

RESUMO

To determine factors associated with delayed discharge of hospitalized patients with coronavirus disease (COVID-19). This retrospective cohort study included 47 patients with COVID-19 admitted to three hospitals in Quanzhou City, Fujian Province, China, between January 21, 2020 and March 6, 2020. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with delayed discharge. The median length of hospital stay was 22 days. Patients in the delayed discharge group (length of hospital stay ≥ 21 days, n = 27) were more likely to have diarrhea, anorexia, decreased white blood cell counts, increased complement C3 and C-reactive protein levels, air bronchograms, undergo thymalfasin treatment, and take significantly longer to convert to a severe acute respiratory syndrome coronavirus (SARS-CoV-2) RNA-negative status than those in the control group (length of hospital stay, < 21 days; n = 20). In multivariate logistic regression analysis, the time to SARS-CoV-2 RNA-negative conversion (odds ratio [OR]: 1.48, 95% confidence interval [CI] 1.09-2.04, P = 0.01) and complement C3 levels (OR 1.14 95% CI 1.02-1.27, P = 0.03) were the only risk factors independently associated with delayed discharge from the hospital. Dynamic monitoring of complement C3 and SARS-CoV-2 RNA levels is useful for predicting delayed discharge of patients.


Assuntos
/metabolismo , Complemento C3/metabolismo , Alta do Paciente/estatística & dados numéricos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/metabolismo
2.
J Toxicol Sci ; 45(11): 681-693, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132242

RESUMO

Trichloroethylene (TCE) as a common organic solvent in industrial production can cause occupational medicamentosa-like dermatitis (OMDT) in some exposed workers. In addition to systemic skin damage, OMDT is also accompanied by severe kidney injury. Our previous studies show that complement (C) plays an important role in immune kidney injury caused by TCE. Specifically, C3 is mainly deposited on glomeruli. Recent studies have found that intracellular complement can be activated by cathepsin L (CTSL) and exert a series of biological effects. The purpose of this study was to explore where C3 on glomeruli comes from and what role it plays. A BALB/c mouse model of skin sensitization induced by TCE in the presence or absence of CTSL inhibitor (CTSLi,10 mg/kg). In TCE sensitization-positive mice, C3 was mainly expressed on podocytes and the expression of CTSL significantly increased in podocytes. Kidney function test and related indicators showed abnormal glomerular filtration and transmission electron microscopy revealed ultrastructure damage to podocytes. These lesions were alleviated in TCE/CTSLi positive mice. These results provide the first evidence that in TCE-induced immune kidney injury, intracellular complement in podocytes can be over-activated by CTSL and aggravates podocytes injury, thereby damaging glomerular filtration function. Intracellular complement activation and cathepsin L in podocytes may be a potential target for treating immune kidney injury induced by TCE.


Assuntos
Lesão Renal Aguda/etiologia , Lesão Renal Aguda/imunologia , Ativação do Complemento/efeitos dos fármacos , Podócitos/imunologia , Solventes/efeitos adversos , Tricloroetileno/efeitos adversos , Lesão Renal Aguda/fisiopatologia , Animais , Catepsina L/efeitos adversos , Complemento C3/metabolismo , Modelos Animais de Doenças , Feminino , Taxa de Filtração Glomerular , Glomérulos Renais/imunologia , Camundongos Endogâmicos BALB C , Podócitos/patologia , Podócitos/ultraestrutura
3.
Medicine (Baltimore) ; 99(35): e21739, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871893

RESUMO

RATIONALE: Anorexia nervosa (AN) is a serious eating disorder associated with a distorted body image. Hypercholesterolemia has been found in patients with AN but the mechanism of hyperlipidemia in AN remains little known. Ascites in patients with AN has been attributed to hypoalbuminemia and liver diseases, but massive ascites without the aforementioned etiologies has never been reported in AN. PATIENT CONCERNS: An 11-year-old girl was admitted for exclusion of organic underlying diseases due to severe body weight loss (18% within 3 weeks), poor appetite, and hypercholesterolemia (274 mg/dL). She complained of heartburn sensation, nausea, vomiting, constipation, and postprandial dull abdominal pain with fullness. DIAGNOSES: The patient's condition met with all 3 of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for diagnosing AN. On admission, her total cholesterol level was 337 mg/dL and hypocomplementemia (C3 55.5 mg/dL) was also found. Abdominal sonography and computed tomography scans showed massive ascites. However, neither proteinuria nor hypoalbuminemia was found. Upper gastroduodenal endoscopy showed chronic superficial gastritis and colonoscopy revealed negative findings. Ascites obtained by paracentesis demonstrated a transudate without bacterial infection, tuberculosis, or pancreatitis. Exploratory laparoscopy showed nonpurulent ascites. However, biopsies from the small intestine, mesentery, and liver showed chronic inflammation and fibrosis. INTERVENTIONS: The intensive nutritional therapy by increasing total energy intake stepwise with a combination of high-energy formula and her favorite foods. OUTCOMES: Her hypercholesterolemia, hypocomplementemia, and massive ascites resolved after her weight was restored. She developed binge eating with continuous weight gain after discharge. Her weight significantly increased to an obese level (body mass index [BMI] 25.9 kg/m) after loss to follow-up for 4 years until she returned to our emergency room due to suicide attempt. CONCLUSION: Diagnostic crossover between subtypes in anorexia nervosa might be a potential risk factor for illness severity and poor prognosis. AN can manifest as massive ascites with normal albumin concentrations that could possibly be due to chronic inflammation of the intestinal serosa, mesentery, and peritoneal surface of the liver.


Assuntos
Anorexia Nervosa/complicações , Anorexia Nervosa/diagnóstico , Ascite/etiologia , Hipercolesterolemia/etiologia , Adolescente , Anorexia Nervosa/sangue , Anorexia Nervosa/psicologia , Transtorno da Compulsão Alimentar/etiologia , Criança , Complemento C3/metabolismo , Feminino , Humanos , Perda de Peso
4.
Blood ; 136(18): 2080-2089, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-32877502

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein-treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.


Assuntos
Betacoronavirus , Fator D do Complemento/antagonistas & inibidores , Inativadores do Complemento/farmacologia , Via Alternativa do Complemento/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/farmacologia , Linhagem Celular , Ativação do Complemento/efeitos dos fármacos , Complemento C3/metabolismo , Complemento C5/antagonistas & inibidores , Fator H do Complemento/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Humanos , Glicoproteína da Espícula de Coronavírus/fisiologia
5.
Medicine (Baltimore) ; 99(39): e22341, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991448

RESUMO

RATIONALE: The Goodpasture syndrome is an extremely rare disease, with renal and pulmonary manifestations, and is mediated by anti-glomerular basement membrane (anti-GBM) antibodies. Renal pathological changes are mainly characterized by glomerular crescent formation and linear immunofluorescent staining for immunoglobulin G on the GBM. There are few reports on the atypical course of the syndrome involving serum-negative anti-GBM antibodies. Therefore, we present a case of Goodpasture syndrome that presented with nephrotic-range proteinuria and was seronegative for anti-GBM antibodies. PATIENT CONCERNS: A 38-year-old Chinese man presented with a lung lesion that was discovered by physical examination a month prior to presentation. The chief concern was occasional hemoptysis without fever, cough, chest pain, and edema. DIAGNOSES: Laboratory testing revealed that the urinary protein level and urine erythrocyte count were 7.4 g/24 hours and 144/high-power field (HPF), respectively. Serological testing for anti-GBM antibodies was negative. Chest computed tomography revealed multiple exudative lesions in both lungs, indicating alveolar infiltration and hemorrhage. Electronic bronchoscopy and pathological examination of the alveolar lavage fluid indicated no abnormalities. However, kidney biopsy suggested cellular crescent formation and segmental necrosis of the globuli, with linear IgG and complement C3 deposition on the GBM. These findings were consistent with the diagnosis of anti-GBM antibody nephritis. INTERVENTIONS: The patient underwent 7 sessions of double filtration plasmapheresis. He was also administered with intravenous methylprednisolone and cyclophosphamide. After renal function stabilization, he was discharged under an immunosuppressive regimen comprising of glucocorticoids and cyclophosphamides. OUTCOMES: Three months later, follow-up examination revealed that the 24-hour urine protein had increased to 13 g. Furthermore, the urine erythrocyte count was 243/HPF. After a 6-month follow-up, the patient achieved partial remission, with a proteinuria level of 3.9 g/24 hours and a urine erythrocyte count of 187/HPF. LESSONS: This extremely rare case of Goodpasture syndrome manifested with seronegativity for anti-GBM antibodies and nephrotic-range proteinuria. Our findings emphasize the importance of renal biopsy for the clinical diagnosis of atypical cases. Furthermore, because renal involvement achieved only partial remission despite therapy, early detection and active treatment of the Goodpasture syndrome is necessary to improve the prognosis of patients.


Assuntos
Doença Antimembrana Basal Glomerular/complicações , Doença Antimembrana Basal Glomerular/imunologia , Autoanticorpos/sangue , Proteinúria/etiologia , Administração Intravenosa , Adulto , Assistência ao Convalescente , Doença Antimembrana Basal Glomerular/diagnóstico , Doença Antimembrana Basal Glomerular/terapia , Grupo com Ancestrais do Continente Asiático/etnologia , Complemento C3/metabolismo , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Hemoptise/diagnóstico , Hemorragia/etiologia , Hemorragia/patologia , Humanos , Imunoglobulina G/metabolismo , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Rim/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/uso terapêutico , Nefrite/diagnóstico , Nefrite/imunologia , Plasmaferese/métodos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
6.
PLoS One ; 15(8): e0236968, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745140

RESUMO

Many circumstantial evidences from human and animal studies suggest that complement cascade dysregulation may play an important role in pregnancy associated complications including preeclampsia. Deletion of rodent specific complement inhibitor gene, Complement Receptor 1-related Gene/Protein y (Crry) produces embryonic lethal phenotype due to complement activation. It is not clear if decreased expression of Crry during pregnancy produces hypertensive phenotype. We downregulated Crry in placenta by injecting inducible lentivialshRNA vectors into uterine horn of pregnant C57BL/6 mice at the time of blastocyst hatching. Placenta specific downregulation of Crry without significant loss of embryos was achieved upon induction of shRNA using an optimal doxycycline dose at mid gestation. Crry downregulation resulted in placental complement deposition. Late-gestation measurements showed that fetal weights were reduced and blood pressure increased in pregnant mice upon downregulation of Crry suggesting a critical role for Crry in fetal growth and blood pressure regulation.


Assuntos
Desenvolvimento Fetal/fisiologia , Placenta/metabolismo , Receptores de Complemento 3b/genética , Animais , Pressão Sanguínea/genética , Ativação do Complemento/genética , Complemento C3/metabolismo , Inativadores do Complemento/farmacologia , Feminino , Desenvolvimento Fetal/genética , Regulação da Expressão Gênica/genética , Camundongos , Camundongos Endogâmicos C57BL , Placenta/fisiologia , Pré-Eclâmpsia/genética , Gravidez , RNA Interferente Pequeno/genética , Receptores de Complemento/genética , Receptores de Complemento 3b/metabolismo
7.
Cell Prolif ; 53(10): e12886, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32794619

RESUMO

OBJECTIVES: Diabetes aggravates the risk and severity of periodontitis, but the specific mechanism remains confused. Complement 3 (C3) is closely related to complications of type 2 diabetes (T2DM). In the present study, we concentrated on whether C3 mediates the development of periodontitis in T2DM. MATERIALS AND METHODS: Levels of C3 in blood and gingival crevicular fluid (GCF) of patients were measured first. A C3-knockout diabetic mouse model was established, real-time PCR, Western blotting and histological investigation were performed to evaluate the progress of periodontitis. Microcomputed tomography (micro-CT) and TRAP staining were performed to detect alveolar bone resorption. Immunofluorescence was performed to detect polarization of macrophages. RESULTS: Our data showed that C3 levels were elevated in the blood and GCF of T2DM patients compared with non-diabetic individuals. Increased C3 was closely related to the upregulation of inflammatory cytokines including interleukin (IL)-1, IL-6 and tumour necrosis factor-alpha (TNF-α), as well as the decline of the bone volume density (BMD) and bone volume over total volume (BV/TV) of the alveolar bones in diabetic mice. The deletion of C3 inhibited inflammatory cytokines and rescued the decreased BMD and BV/TV of the alveolar bones. C3-mediated polarization of macrophages was responsible for the damage. CONCLUSION: T2DM-related upregulation of C3 contributes to the development of periodontitis by promoting macrophages M1 polarization and inhibiting M2 polarization, triggering a pro-inflammatory effect on periodontal tissues.


Assuntos
Complemento C3/metabolismo , Diabetes Mellitus Tipo 2/patologia , Macrófagos/imunologia , Periodontite/diagnóstico , Adulto , Processo Alveolar/diagnóstico por imagem , Processo Alveolar/patologia , Processo Alveolar/fisiologia , Animais , Densidade Óssea , Complemento C3/análise , Complemento C3/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/complicações , Feminino , Líquido do Sulco Gengival/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Periodontite/etiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
8.
J Mol Model ; 26(9): 231, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32789582

RESUMO

The complement system plays a major role in human immunity, but its abnormal activation can have severe pathological impacts. By mimicking a natural mechanism of complement regulation, the small peptide compstatin has proven to be a very promising complement inhibitor. Over the years, several compstatin analogs have been created, with improved inhibitory potency. A recent analog is being developed as a candidate drug against several pathological conditions, including COVID-19. However, the reasons behind its higher potency and increased binding affinity to complement proteins are not fully clear. This computational study highlights the mechanistic properties of several compstatin analogs, thus complementing previous experimental studies. We perform molecular dynamics simulations involving six analogs alone in solution and two complexes with compstatin bound to complement component 3. These simulations reveal that all the analogs we consider, except the original compstatin, naturally adopt a pre-bound conformation in solution. Interestingly, this set of analogs adopting a pre-bound conformation includes analogs that were not known to benefit from this behavior. We also show that the most recent compstatin analog (among those we consider) forms a stronger hydrogen bond network with its complement receptor than an earlier analog.


Assuntos
Antivirais/química , Complemento C3/antagonistas & inibidores , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Antivirais/metabolismo , Complemento C3/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Humanos , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Relação Estrutura-Atividade
9.
Nat Commun ; 11(1): 3753, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719333

RESUMO

Reactive astrocytes have been implicated in the pathogenesis of neurodegenerative diseases, including a non-cell autonomous effect on motor neuron survival in ALS. We previously defined a mechanism by which microglia release three factors, IL-1α, TNFα, and C1q, to induce neurotoxic astrocytes. Here we report that knocking out these three factors markedly extends survival in the SOD1G93A ALS mouse model, providing evidence for gliosis as a potential ALS therapeutic target.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Astrócitos/metabolismo , Complemento C1q/metabolismo , Progressão da Doença , Interleucina-1alfa/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Complemento C3/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia , Superóxido Dismutase-1/metabolismo
10.
Proc Natl Acad Sci U S A ; 117(27): 15818-15826, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541024

RESUMO

Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Clonagem Molecular , Ativação do Complemento , Miócitos de Músculo Liso/metabolismo , Fagocitose/fisiologia , Animais , Antígeno CD47/metabolismo , Linhagem da Célula , Proliferação de Células , Complemento C3/genética , Complemento C3/metabolismo , Feminino , Humanos , Inflamação , Macrófagos/metabolismo , Masculino , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/citologia , Placa Aterosclerótica/metabolismo , Análise de Sequência de RNA , Regulação para Cima
11.
Invest Ophthalmol Vis Sci ; 61(5): 19, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32407521

RESUMO

Purpose: The 32W and 32Q variants of complement factor B (CFB) are associated with reduced risk of developing neovascular age-related macular degeneration (AMD) compared with the common 32R allele. The objective of this study was to determine if the most protective R32Q variant affects the neovascular process in a manner consistent with the reported reduced disease association. Methods: The 32R, 32W, and 32Q human CFB variants were expressed in human embryonic kidney 293T cells and purified from culture supernatant. The ex vivo mouse fetal metatarsal explant model was used to investigate the effect of these three human CFB variants on angiogenesis. Metatarsal bones were isolated from mouse embryos and cultured in the presence of the three CFB variants, and angiogenesis was measured following immunostaining of fixed samples. ELISAs were used to quantify C3 and VEGF protein levels in metatarsal culture and quantitative PCR to measure Cfb, C3, and Vegf expression. Results: We show here that the three CFB variants have different biological activities in the mouse metatarsal assay, with CFBR32 exhibiting significantly greater angiogenic activity than CFBQ32 or CFBW32, which were broadly similar. We also observed differences in macrophage phenotype with these two variants that may contribute to their activities in this experimental model. Conclusions: We have demonstrated that the biological activities of CFBR32, CFBW32, and CFBQ32 are consistent with their AMD risk association, and we provide functional evidence of roles for these variants in angiogenesis that may be relevant to the pathogenesis of the neovascular form of AMD.


Assuntos
Fator B do Complemento/genética , Degeneração Macular/genética , Animais , Neovascularização de Coroide , Ativação do Complemento , Complemento C3/genética , Complemento C3/metabolismo , Fator B do Complemento/metabolismo , Modelos Animais de Doenças , Variação Genética , Macrófagos/metabolismo , Camundongos , Polimorfismo Genético , RNA Mensageiro/metabolismo , Proteínas Recombinantes , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Sci Rep ; 10(1): 6930, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332767

RESUMO

Normothermic machine perfusion (NMP) is an emerging modality for kidney preservation prior to transplantation. NMP may allow directed pharmacomodulation of renal ischemia-reperfusion injury (IRI) without the need for systemic donor/recipient therapies. Three proven anti-IRI agents not in widespread clinical use, CD47-blocking antibody (αCD47Ab), soluble complement receptor 1 (sCR1), and recombinant thrombomodulin (rTM), were compared in a murine model of kidney IRI. The most effective agent was then utilized in a custom NMP circuit for the treatment of isolated porcine kidneys, ascertaining the impact of the drug on perfusion and IRI-related parameters. αCD47Ab conferred the greatest protection against IRI in mice after 24 hours. αCD47Ab was therefore chosen as the candidate agent for addition to the NMP circuit. CD47 receptor binding was demonstrated by immunofluorescence. Renal perfusion/flow improved with CD47 blockade, with a corresponding reduction in oxidative stress and histologic damage compared to untreated NMP kidneys. Tubular and glomerular functional parameters were not significantly impacted by αCD47Ab treatment during NMP. In a murine renal IRI model, αCD47Ab was confirmed as a superior anti-IRI agent compared to therapies targeting other pathways. NMP enabled effective, direct delivery of this drug to porcine kidneys, although further efficacy needs to be proven in the transplantation setting.


Assuntos
Anticorpos/farmacologia , Rim/patologia , Perfusão , Traumatismo por Reperfusão/patologia , Temperatura , Animais , Nitrogênio da Ureia Sanguínea , Antígeno CD47/imunologia , Quimiocinas/genética , Quimiocinas/metabolismo , Complemento C3/metabolismo , Complemento C9/metabolismo , Creatinina/sangue , Sistemas de Liberação de Medicamentos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Receptor Celular 1 do Vírus da Hepatite A/genética , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Peróxido de Hidrogênio/metabolismo , Mediadores da Inflamação/metabolismo , Túbulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Complemento/metabolismo , Traumatismo por Reperfusão/sangue , Suínos
13.
Sci Rep ; 10(1): 6391, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286427

RESUMO

Gout is caused by crystallization of uric acid in the form of monosodium urate (MSU) crystals, which induce a sterile inflammatory response that is hardly distinguishable from microbe-induced inflammatory responses. It is unclear, if MSU crystals (like microbes) are recognized by specific pattern recognition receptors. To identify possible soluble pattern recognition molecules for MSU crystals, we purified MSU-binding proteins from human body fluids. We identified C-reactive protein (CRP) as a major MSU-binding protein. Binding of CRP was strong enough to specifically deplete CRP from human serum. We found that CRP was required for fixation of complement components C1q, C1r, C1s and MASP1. Thus, we have identified a pattern recognition molecule for MSU crystals that links to the activation of complement. Notably, CRP does not show an even binding to the complete surface of the crystals. It rather binds to edges or distinct faces of the crystals.


Assuntos
Proteína C-Reativa/metabolismo , Endopeptidases/metabolismo , Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo , Ácido Úrico/metabolismo , Líquidos Corporais/metabolismo , Complemento C3/metabolismo , Cristalização , Feminino , Humanos , Masculino , Ligação Proteica
14.
Immunity ; 52(3): 513-527.e8, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32187519

RESUMO

Intrinsic complement C3 activity is integral to human T helper type 1 (Th1) and cytotoxic T cell responses. Increased or decreased intracellular C3 results in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression remain undefined. We identified complement, including C3, as among the most significantly enriched biological pathway in tissue-occupying cells. We generated C3-reporter mice and confirmed that C3 expression was a defining feature of tissue-immune cells, including T cells and monocytes, occurred during transendothelial diapedesis, and depended on integrin lymphocyte-function-associated antigen 1 (LFA-1) signals. Immune cells from patients with leukocyte adhesion deficiency type 1 (LAD-1) had reduced C3 transcripts and diminished effector activities, which could be rescued proportionally by intracellular C3 provision. Conversely, increased C3 expression by T cells from arthritis patients correlated with disease severity. Our study defines integrins as key controllers of intracellular complement, demonstrates that perturbations in the LFA-1-C3-axis contribute to primary immunodeficiency, and identifies intracellular C3 as biomarker of severity in autoimmunity.


Assuntos
Complemento C3/imunologia , Integrinas/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Linfócitos/imunologia , Monócitos/imunologia , Migração Transendotelial e Transepitelial/imunologia , Adulto , Idoso , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Criança , Pré-Escolar , Complemento C3/genética , Complemento C3/metabolismo , Feminino , Humanos , Integrinas/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Linfócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Transdução de Sinais/imunologia
15.
J Am Soc Nephrol ; 31(4): 829-840, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32034108

RESUMO

BACKGROUND: The pathophysiology of the leading cause of pediatric acute nephritis, acute postinfectious GN, including mechanisms of the pathognomonic transient complement activation, remains uncertain. It shares clinicopathologic features with C3 glomerulopathy, a complement-mediated glomerulopathy that, unlike acute postinfectious GN, has a poor prognosis. METHODS: This retrospective study investigated mechanisms of complement activation in 34 children with acute postinfectious GN and low C3 level at onset. We screened a panel of anticomplement protein autoantibodies, carried out related functional characterization, and compared results with those of 60 children from the National French Registry who had C3 glomerulopathy and persistent hypocomplementemia. RESULTS: All children with acute postinfectious GN had activation of the alternative pathway of the complement system. At onset, autoantibodies targeting factor B (a component of the alternative pathway C3 convertase) were found in a significantly higher proportion of children with the disorder versus children with hypocomplementemic C3 glomerulopathy (31 of 34 [91%] versus 4 of 28 [14%], respectively). In acute postinfectious GN, anti-factor B autoantibodies were transient and correlated with plasma C3 and soluble C5b-9 levels. We demonstrated that anti-factor B antibodies enhance alternative pathway convertase activity in vitro, confirming their pathogenic effect. We also identified crucial antibody binding sites on factor B, including one correlated to disease severity. CONCLUSIONS: These findings elucidate the pathophysiologic mechanisms underlying acute postinfectious GN by identifying anti-factor B autoantibodies as contributing factors in alternative complement pathway activation. At onset of a nephritic syndrome with low C3 level, screening for anti-factor B antibodies might help guide indications for kidney biopsy to avoid misdiagnosed chronic glomerulopathy, such as C3 glomerulopathy, and to help determine therapy.


Assuntos
Autoanticorpos/sangue , Ativação do Complemento/fisiologia , Complemento C3/metabolismo , Fator B do Complemento/imunologia , Glomerulonefrite/sangue , Glomerulonefrite/diagnóstico , Criança , Pré-Escolar , Fator Nefrítico do Complemento 3/metabolismo , Feminino , França , Humanos , Masculino , Estudos Retrospectivos
16.
BMC Pregnancy Childbirth ; 20(1): 131, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32106828

RESUMO

BACKGROUND: Currently, there are many studies researched the associations between maternal serum inflammatory indicators (i.e. ferritin, C-reactive protein [CRP], C3 and C4) and preterm birth (PTB). The results, however, are inconsistent. Therefore, the aim of this study was to estimate the relationship between maternal serum inflammatory indicators and PTB in a nested case-control (NCC)study. METHODS: A NCC study was conducted by Guangxi Birth Cohort Study which enrolled a total of 6203 pregnant women between 50/7 and 346/7 weeks of gestational age (wGA) from six cities in China between 2015 and 2016. There were 206women who delivered preterm (< 370/7 wGA), and 412 women who delivered term birth, those women were matched by maternal age, birth place, gender of infants, and wGA at blood collection. The inflammatory indicators were quantified by immunoturbidimetric methods. RESULTS: Highest quartile concentrations of all inflammatory indicators were determined versus median. After adjusting for maternal age, high levels of CRP (CRP > 16.60 mg/L) are related to the risk of PTB (OR = 2.16, 95% CI: 1.02-4.56, p = 0.044) in the first trimester. The association of C3 was extremely related to those who delivered PTB (OR = 2.53, 95% CI: 1.14-5.64, p = 0.023) in the first trimester. Moreover, no significant associations were found in C4 (p = 0.079) and ferritin (p = 0.067) between PTB. CONCLUSIONS: Elevated concentrations of CRP and C3 in the first trimester were associated with increased risk of PTB. Inflammatory indicators may act a pivotal part in early diagnosis and prognosis of PTB.


Assuntos
Proteína C-Reativa/metabolismo , Complemento C3/metabolismo , Nascimento Prematuro/sangue , Adolescente , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , China , Estudos de Coortes , Complemento C4/metabolismo , Feminino , Ferritinas/metabolismo , Idade Gestacional , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Gravidez , Primeiro Trimestre da Gravidez , Fatores de Risco , Adulto Jovem
17.
Transplant Proc ; 52(2): 614-618, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32057496

RESUMO

Renal transplantation is an ever-growing therapeutic option for patients with end-stage renal disease due to lupus nephritis. Outcomes for these patients are comparable to those of patients receiving renal transplantation for other causes. A known complication for these patients is recurrence of lupus nephritis in the renal graft (recurrent lupus nephritis [RLN]). Although disease severity at the time of recurrence is usually milder, a small number of cases have been reported to progress to allograft failure. There is a trend toward preemptive renal transplantation in patients with lupus nephritis, as more favorable outcomes have been observed with this treatment modality. While clinicians usually seek clinical remission of lupus prior to proceeding with renal transplantation, no guidelines are established regarding how often to check for serologic activity of lupus in patients with end-stage renal disease due to lupus nephritis and whether these serologic markers should be taken into account when deciding on the timing of transplantation. We present a case of early RLN co-occurring with acute cellular rejection 15 days after renal transplantation. The patient had been in clinical remission for more than 5 months prior to transplantation but had a rise in anti-double-stranded DNA antibody titers and a decrease in complement C3 level at the time of surgery. Although additional studies are needed to establish the extent to which serologic markers of lupus correlate with renal graft dysfunction, this case suggests hypocomplementemia and high double-stranded DNA antibody titers may be a risk factor for early RLN.


Assuntos
Anticorpos Antinucleares/sangue , Complemento C3/metabolismo , Transplante de Rim , Nefrite Lúpica/imunologia , Nefrite Lúpica/cirurgia , Rejeição de Enxerto , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Nefrite Lúpica/patologia , Masculino , Recidiva , Fatores de Risco , Transplante Homólogo , Adulto Jovem
18.
Ann Hematol ; 99(4): 703-714, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32103323

RESUMO

Monoclonal gammopathy of renal significance (MGRS) is characterized by the nephrotoxic monoclonal immunoglobulin secreted by an otherwise asymptomatic or indolent B cell or plasma cell clone, without hematologic criteria for treatment. These MGRS-associated diseases can involve one or more renal compartments, including glomeruli, tubules, and vessels. Hydrophobic residue replacement, N-glycosylated, increase in isoelectric point in monoclonal immunoglobulin (MIg) causes it to transform from soluble form to tissue deposition, and consequently resulting in glomerular damage. In addition to MIg deposition, complement deposition is also found in C3 glomerulopathy with monoclonal glomerulopathy, which is caused by an abnormality of the alternative pathway and may involve multiple factors including complement component 3 nephritic factor, anti-complement factor auto-antibodies, or MIg which directly cleaves C3. Furthermore, inflammatory factors, growth factors, and virus infection may also participate in the development of the diseases. In this review, for the first time, we discussed current highlights in the mechanism of MGRS-related lesions.


Assuntos
Anticorpos Monoclonais/metabolismo , Nefropatias/etiologia , Paraproteinemias/etiologia , Paraproteínas/metabolismo , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Complemento C3/metabolismo , Fator Nefrítico do Complemento 3/metabolismo , Convertases de Complemento C3-C5/antagonistas & inibidores , Convertases de Complemento C3-C5/metabolismo , Via Alternativa do Complemento , Crioglobulinemia/etiologia , Crioglobulinemia/metabolismo , Glicosilação , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/etiologia , Amiloidose de Cadeia Leve de Imunoglobulina/metabolismo , Mediadores da Inflamação/metabolismo , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Proteínas de Neoplasias/metabolismo , Paraproteinemias/complicações , Paraproteinemias/genética , Paraproteinemias/metabolismo , Processamento de Proteína Pós-Traducional , Fator de Crescimento Transformador beta/metabolismo
19.
J Exp Clin Cancer Res ; 39(1): 9, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31928530

RESUMO

BACKGROUND: Localized C3 deposition is a well-known factor of inflammation. However, its role in oncoprogression of gastric cancer (GC) remains obscured. This study aims to explore the prognostic value of C3 deposition and to elucidate the mechanism of C3-related oncoprogression for GC. METHODS: From August to December 2013, 106 GC patients were prospectively included. The regional expression of C3 and other effectors in gastric tissues were detected by WB, IHC, qRT-PCR and other tests. The correlation of localized C3 deposition and oncologic outcomes was determined by 5-year survival significance. Human GC and normal epithelial cell lines were employed to detect a relationship between C3 and STAT3 signaling pathway in vitro experiments. RESULTS: C3 and C3a expression were markedly enhanced in GC tissues at both mRNA and protein levels compared with those in paired nontumorous tissues. According to IHC C3 score, 65 (61.3%) and 41 (38.7%) patients had high and low C3 deposition, respectively. C3 deposition was negatively correlated with plasma levels of C3 and C3a (both P < 0.001) and positively correlated with pathological T and TNM stages (both P < 0.001). High C3 deposition was identified as an independent prognostic factor of poor 5-year overall survival (P = 0.045). In vitro C3 administration remarkably enhanced p-JAK2/p-STAT3 expression in GC cell lines but caused a reduction of such activation when pre-incubated with a C3 blocker. Importantly, C3 failed to activate such signaling in cells pre-treated with a JAK2 inhibitor. CONCLUSIONS: Localized C3 deposition in the tumor microenvironment is a relevant immune signature for predicting prognosis of GC. It may aberrantly activate JAK2/STAT3 pathway allowing oncoprogression. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02425930, Registered 1st August 2013.


Assuntos
Complemento C3/genética , Complemento C3/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologia , Regulação para Cima , Adulto , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Análise de Sobrevida , Microambiente Tumoral
20.
Thorax ; 75(4): 321-330, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31959730

RESUMO

INTRODUCTION: Alpha-1 antitrypsin (AAT) deficiency (AATD) is associated with early onset emphysema. The aim of this study was to investigate whether AAT binding to plasma constituents could regulate their activation, and in AATD, exploit this binding event to better understand the condition and uncover novel biomarkers of therapeutic efficacy. METHODS: To isolate AAT linker proteins, plasma samples were separated by size exclusion chromatography, followed by co-immunoprecipitation. AAT binding proteins were identified by mass spectrometry. Complement turnover and activation was determined by ELISA measurement of C3, C3a and C3d levels in plasma of healthy controls (n=15), AATD (n=51), non-AATD patients with obstructive airway disease (n=10) and AATD patients post AAT augmentation therapy (n=5). RESULTS: Direct binding of complement C3 to AAT was identified in vivo and in vitro. Compared with healthy controls, a breakdown product of C3, C3d, was increased in AATD (0.04 µg/mL vs 1.96 µg/mL, p=0.0002), with a significant correlation between radiographic pulmonary emphysema and plasma levels of C3d (R2=0.37, p=0.001). In vivo, AAT augmentation therapy significantly reduced plasma levels of C3d in comparison to patients not receiving AAT therapy (0.15 µg/mL vs 2.18 µg/mL, respectively, p=0.001). DISCUSSION: Results highlight the immune-modulatory impact of AAT on the complement system, involving an important potential role for complement activation in disease pathogenesis in AATD. The association between plasma C3d levels and pulmonary disease severity, that decrease in response to AAT augmentation therapy, supports the exploration of C3d as a candidate biomarker of therapeutic efficacy in AATD.


Assuntos
Complemento C3/metabolismo , Enfisema Pulmonar/epidemiologia , Transtornos Respiratórios/epidemiologia , Deficiência de alfa 1-Antitripsina/epidemiologia , Deficiência de alfa 1-Antitripsina/terapia , alfa 1-Antitripsina/uso terapêutico , Idoso , Análise de Variância , Biomarcadores/sangue , Western Blotting , Estudos de Casos e Controles , Comorbidade , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Enfisema Pulmonar/sangue , Enfisema Pulmonar/diagnóstico , Valores de Referência , Transtornos Respiratórios/sangue , Transtornos Respiratórios/diagnóstico , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Resultado do Tratamento , Deficiência de alfa 1-Antitripsina/diagnóstico
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