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1.
J Proteome Res ; 19(11): 4417-4427, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-32786691

RESUMO

Over 5 million people around the world have tested positive for the beta coronavirus SARS-CoV-2 as of May 29, 2020, a third of which are in the United States alone. These infections are associated with the development of a disease known as COVID-19, which is characterized by several symptoms, including persistent dry cough, shortness of breath, chills, muscle pain, headache, loss of taste or smell, and gastrointestinal distress. COVID-19 has been characterized by elevated mortality (over 100 thousand people have already died in the US alone), mostly due to thromboinflammatory complications that impair lung perfusion and systemic oxygenation in the most severe cases. While the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) have been associated with the severity of the disease, little is known about the impact of IL-6 levels on the proteome of COVID-19 patients. The present study provides the first proteomics analysis of sera from COVID-19 patients, stratified by circulating levels of IL-6, and correlated to markers of inflammation and renal function. As a function of IL-6 levels, we identified significant dysregulation in serum levels of various coagulation factors, accompanied by increased levels of antifibrinolytic components, including several serine protease inhibitors (SERPINs). These were accompanied by up-regulation of the complement cascade and antimicrobial enzymes, especially in subjects with the highest levels of IL-6, which is consistent with an exacerbation of the acute phase response in these subjects. Although our results are observational, they highlight a clear increase in the levels of inhibitory components of the fibrinolytic cascade in severe COVID-19 disease, providing potential clues related to the etiology of coagulopathic complications in COVID-19 and paving the way for potential therapeutic interventions, such as the use of pro-fibrinolytic agents. Raw data for this study are available through ProteomeXchange with identifier PXD020601.


Assuntos
Proteínas Sanguíneas/análise , Proteínas do Sistema Complemento/análise , Infecções por Coronavirus , Interleucina-6/sangue , Pandemias , Pneumonia Viral , Proteoma/análise , Adulto , Betacoronavirus , Coagulação Sanguínea/fisiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/fisiopatologia , Feminino , Hemólise , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/sangue , Pneumonia Viral/fisiopatologia , Proteômica
2.
Virchows Arch ; 477(4): 565-572, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32300880

RESUMO

IgA nephropathy (IgAN) is common chronic glomerulonephritis with variable prognosis, ranging from minor urinary abnormalities to end-stage renal disease. The revised Oxford classification of IgAN explains that cellular/fibrocellular crescents are associated with poor renal prognosis, proposing an extension to the MEST-C score. C3 immunofluorescent staining follows a distribution similar to IgA staining. Therefore, complement activation was reported to play a pivotal role in IgAN pathogenesis. This study included 132 IgAN patients diagnosed by renal biopsies. The clinical parameters at the time of the biopsies were obtained from patient data records. We classified the patients into C ≥ 1 and C0 groups, and compared clinical, light microscopic, and immunofluorescent features. In the C ≥ 1 group, 2 (1.5%) and 31 (23.5%) patients were assigned to C2 and C1, respectively. The remaining 99 patients (75%) were classified as C0. The C ≥ 1 group had lower average age and rate of hypertension, and higher score of urinary occult blood and E score. The C ≥ 1 group had significantly higher average immunofluorescence scores for IgA, C5b-9, mannose-associated serine protease (MASP) 1/3, MASP2, properdin, factor B, and kappa. The steroid use rate was significantly higher in the C ≥ 1 group. During the follow-up period of 2.90 years on average, the rate of renal dysfunction was not significantly different between groups. Crescent formation in IgAN was associated with activation of the lectin and alternative pathways. The C ≥ 1 group had significantly increased use of steroids, which probably caused comparable renal function during the follow-up period.


Assuntos
Ativação do Complemento , Proteínas do Sistema Complemento/análise , Glomerulonefrite por IGA/imunologia , Imunoglobulina A/análise , Glomérulos Renais/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Complemento C3/análise , Fator B do Complemento/análise , Complexo de Ataque à Membrana do Sistema Complemento/análise , Feminino , Imunofluorescência , Glomerulonefrite por IGA/patologia , Humanos , Cadeias Leves de Imunoglobulina/análise , Japão , Glomérulos Renais/patologia , Masculino , Serina Proteases Associadas a Proteína de Ligação a Manose/análise , Microscopia de Fluorescência , Pessoa de Meia-Idade , Properdina/análise , Estudos Retrospectivos , Adulto Jovem
3.
F1000Res ; 92020.
Artigo em Inglês | MEDLINE | ID: mdl-32148776

RESUMO

The complement system consists of more than 30 plasma as well as cell surface proteins that together constitute a major arm of the immune system. The long-held belief is that most of the complement components are synthesized by hepatocytes in the liver and then secreted into the blood. However, there is also substantial evidence that several if not all of the complement proteins are synthesized extrahepatically by a wide range of cell types, including polymorphonuclear leukocytes, monocytes, macrophages, dendritic cells, lymphocytes, epithelial cells, fibroblasts, and neuronal cells. However, despite the proven evidence that complement proteins indeed could be synthesized non-hepatic cells and even found in unexpected places, the recent finding that certain complement proteins could be activated in intracellular spaces nonetheless has opened up a new debate. In fact, some in the field unfortunately seem to be in favor of rejecting this notion rather vehemently on the untenable and myopic grounds that complement proteins could not be found in intracellular compartments despite evidence to the contrary. Therefore, this opinion article is meant to remind colleagues in the field that new discoveries with the potential to shift established functional paradigms should be encouraged and celebrated even if, at first glance, they seem to defy the odds.


Assuntos
Proteínas do Sistema Complemento/análise , Espaço Intracelular/química , Células Dendríticas , Células Epiteliais , Fibroblastos , Humanos , Linfócitos , Macrófagos , Monócitos , Neurônios
4.
J Immunoassay Immunochem ; 41(2): 144-151, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31771421

RESUMO

Since the introduction of the most expensive drug in the world (Eculizumab) in the therapeutic arsenal of many diseases involving the alternative complement pathway (ACP) in their pathophysiology, the unmet need to perform simple ACP assays affordable for all countries has become one of the major challenges of the contemporary medicine. The assay currently used is AH50, despite it still challenging for several laboratories. This educational chapter consists of a detail protocol of standardized hemolytic assay AP100 and aims to help clinical laboratories over the world and especially those of the developing and low income countries to perform it. The procedure is essentially the same as for the timed lysis assay and dilution methods (AP50) except the concentration of ACP buffer and the chicken erythrocyte density used to make the gels. In clinical field, AP100 has at least nine applications in disease diagnosis and follow-up. AP100 has many advantages over the AH50 as it is more reliable for the Eculizumab monitoring and more practical with a purpose to be stored and transported for several weeks. AP100 is a portable and easy to use device both at the bedside and in the companion medical care.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Via Alternativa do Complemento , Nefropatias/tratamento farmacológico , Animais , Galinhas , Proteínas do Sistema Complemento/análise , Humanos , Nefropatias/sangue
6.
Ann Biol Clin (Paris) ; 77(6): 669-680, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31859644

RESUMO

Although the use of EDTA-containing collection tubes is known to stabilize the complement analytes and to make the results more reliable, no external quality assessment (EQA) scheme based on EDTA plasma samples is available to date in France. Consequently, a number of clinical laboratories currently participate to EQA program on samples whose matrix is different from their routine practice. The aim of this work was to offer a new external quality assessment scheme, as an inter-laboratory exchange (ILE). The ILE samples come from pooled EDTA plasmas of healthy subjects and are diluted to obtain distinct control levels. The protocol has been validated on CH50, C3, C4 and C1-inhibitor measurements, through: (i) a stability study of post-centrifugation storage of EDTA plasma samples at room temperature, 4̊C and -20̊C; (ii) the demonstration of the linearity of the dilution steps; and (iii) a stability study of the diluted samples. Our results demonstrate a four-weeks stability of the ILE samples prepared and stored according to our protocol. Those results are compatible with the ILE implementation constraints, and the program has been implemented in January 2018. The one-year ILE implementation experience is also presented. The newly implemented ILE will be useful for the accreditation of the complement activity of French laboratories using EDTA plasma samples.


Assuntos
Análise Química do Sangue/métodos , Coleta de Amostras Sanguíneas , Proteínas do Sistema Complemento/análise , Ácido Edético/química , Plasma/química , Análise Química do Sangue/normas , Preservação de Sangue/métodos , Preservação de Sangue/normas , Coleta de Amostras Sanguíneas/métodos , Coleta de Amostras Sanguíneas/normas , Proteínas do Sistema Complemento/efeitos dos fármacos , Proteínas do Sistema Complemento/metabolismo , Ácido Edético/farmacologia , Excipientes/química , Excipientes/farmacologia , Humanos , Ensaio de Proficiência Laboratorial , Plasma/efeitos dos fármacos , Plasma/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Garantia da Qualidade dos Cuidados de Saúde/métodos , Controle de Qualidade , Fatores de Tempo , Transportes/normas
7.
Nefrología (Madrid) ; 39(6): 664-671, nov.-dic. 2019. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-189889

RESUMO

BACKGROUND: C3 glomerulonephritis is a rare, chronic disease characterized by C3c-dominant staining on renal biopsy and is caused by inherited or acquired alternative complement pathway dysregulation. Case presentation: Here, we reported a 36-year-old man presenting with nephritic syndrome and normal renal function. Secondary causes were excluded by detailed clinical history and laboratory tests. His renal biopsy was consistent with C3 glomerulonephritis with a membranoproliferative glomerulonephritis pattern. To identify the etiology, we carried out genetic and autoantibody screening tests. The results showed he was negative for autoantibodies, while the next-generation sequencing revealed common variants of complement factor H (c.1204T > C; p.Tyr402His), (c.184G > A; p.Val62Ile) and thrombomodulin (c.1418C > T; p.Ala473Val), which have previously been reported to increase susceptibility to complement-mediated diseases. He also carried complement factor H (c.2808G > T; p.Glu936Asp) and mannose-binding lectin (c.161G > A; p.Gly54Asp), putting the patient at an increased risk of infections, which was an important trigger for C3 glomerulonephritis. A novel variant of complement 2 (c.53A > G; p.His18Arg) that might contribute to the occurrence of C3 glomerulonephritis when combined with these susceptibility variants was further identified. The patient was treated with ramipril and regular fresh frozen plasma infusion. He had a good response to treatment with well-controlled proteinuria, stable renal function and an increasing serum C3 level. CONCLUSIONS: This case adds insight into the pathogenesis of C3 glomerulopathy by showing that a combination of susceptibility variants, genetic mutations and triggers might be responsible for the clinical and pathological phenotypes


ANTECEDENTES: La glomerulonefritis C3 es una enfermedad rara y crónica caracterizada por tinción dominante en C3c en la biopsia renal y es causada por una desregulación de la ruta alternativa del complemento heredada o adquirida. Presentación del caso: Informamos sobre un varón de 36 años que presenta síndrome nefrítico y función renal normal. Las causas secundarias fueron excluidas por la historia clínica detallada y las pruebas de laboratorio. Su biopsia renal fue consistente con glomerulonefritis C3, con un patrón de glomerulonefritis membranoproliferativa. Para identificar la etiología realizamos pruebas de cribado genéticas y de autoanticuerpos. Los resultados mostraron que era negativo para autoanticuerpos, mientras que la secuenciación de próxima generación reveló variantes comunes del factor del complemento H (c.1204T > C; p.Tyr402His), (c.184G >A; p.Val62Ile) y trombomodulina (c.1418C > T; p.Ala473Val), que previamente se había informado que aumentaban la susceptibilidad a las enfermedades mediadas por el complemento. También tuvo factor del complemento H (c.2808G>T; p.Glu936Asp) y lectina de unión a manosa (c.161G > A; p.Gly54Asp), que aumentaba el riesgo de infección para el paciente, y que fue un desencadenante importante para glomerulonefritis C3. Una nueva variante del complemento 2 (c.53ª >G; p.His18Arg) que podría contribuir a la aparición de glomerulonefritis C3 cuando se combina con estas variantes de susceptibilidad fue identificado. El paciente fue tratado con ramipril e infusión regular de plasma fresco congelado. Tuvo una buena reacción al tratamiento con proteinuria bien controlada, función renal estable y un aumento de suero del nivel C3. CONCLUSIONES: Este caso agrega una idea de la patogénesis de la glomerulopatía C3 al mostrar que una combinación de variantes de susceptibilidad, mutaciones genéticas y desencadenantes podría ser responsable de los fenotipos clínicos y patológicos


Assuntos
Humanos , Masculino , Adulto , Glomerulonefrite/genética , Complemento C2/deficiência , Glomerulonefrite Membranoproliferativa/genética , Glomerulonefrite/imunologia , Complemento C2/genética , Proteínas do Sistema Complemento/análise , Biópsia
8.
Transfus Med Rev ; 33(4): 207-216, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31672339

RESUMO

The complement system plays an important role in varying types of disease, ranging from inflammatory and autoimmune disorders to immune deficiency states. In addition, new settings have emerged where complement analysis is of interest to monitor complement-directed therapy and aid identification of transplant complications. Therefore, it is critical that clinical laboratories offer optimized and timely complement analysis. This review presents a comprehensive overview of the most important complement analysis methods that are currently used. It also points to some areas within complement diagnostics where development is needed, for example, regarding certain analytes for which practical methods suitable for the routine laboratory are lacking. Furthermore, it contains a more detailed discussion on complement autoantibody assessment. The list of analyses providing clinically valuable information includes analysis of complement function, quantification of individual complement components and complement activation fragments, identification of autoantibodies to complement, as well as genetic complement analyses. There is still a shortage of commercially available methods suitable for high-throughput screening of complement deficiency and for assessment of complement activation, but development is under way. There is also ongoing work within the complement community to improve standardization of measurements, and recently, an extensive quality assurance program has been initiated.


Assuntos
Técnicas de Laboratório Clínico , Proteínas do Sistema Complemento/análise , Autoanticorpos/análise , Técnicas de Laboratório Clínico/métodos , Técnicas de Laboratório Clínico/normas , Ativação do Complemento , Inativadores do Complemento , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Ensaios de Triagem em Larga Escala , Humanos , Indicadores e Reagentes , Controle de Qualidade
9.
Clin Lab Med ; 39(4): 579-590, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31668271

RESUMO

The complement system is a critical component of both the innate and adaptive immune systems that augments the function of antibodies and phagocytes. Antigen-antibody immune complexes, lectin binding, and accelerated C3 tick-over can activate this well-coordinated and carefully regulated process. The importance of this system is highlighted by the disorders that arise when complement components or regulators are deficient or dysregulated. This article describes the pathways involved in complement activation and function, the regulation of these various pathways, and the interpretation of laboratory testing performed for the diagnosis of diseases of complement deficiency, exuberant complement activation, and complement dysregulation.


Assuntos
Proteínas do Sistema Complemento , Doenças da Deficiência Hereditária de Complemento , Testes Imunológicos , Convertases de Complemento C3-C5/análise , Convertases de Complemento C3-C5/metabolismo , Convertases de Complemento C3-C5/fisiologia , Proteínas do Sistema Complemento/análise , Proteínas do Sistema Complemento/metabolismo , Proteínas do Sistema Complemento/fisiologia , Doenças da Deficiência Hereditária de Complemento/sangue , Doenças da Deficiência Hereditária de Complemento/diagnóstico , Humanos , Modelos Biológicos
10.
Int J Mol Sci ; 20(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694344

RESUMO

Medullary sponge kidney (MSK) disease is a rare and neglected kidney condition often associated with nephrocalcinosis/nephrolithiasis and cystic anomalies in the precalyceal ducts. Little is known about the pathogenesis of this disease, so we addressed the knowledge gap using a proteomics approach. The protein content of microvesicles/exosomes isolated from urine of 15 MSK and 15 idiopathic calcium nephrolithiasis (ICN) patients was investigated by mass spectrometry, followed by weighted gene coexpression network analysis, support vector machine (SVM) learning, and partial least squares discriminant analysis (PLS-DA) to select the most discriminative proteins. Proteomic data were verified by ELISA. We identified 2998 proteins in total, 1764 (58.9%) of which were present in both vesicle types in both diseases. Among the MSK samples, only 65 (2.2%) and 137 (4.6%) proteins were exclusively found in the microvesicles and exosomes, respectively. Similarly, among the ICN samples, only 75 (2.5%) and 94 (3.1%) proteins were exclusively found in the microvesicles and exosomes, respectively. SVM learning and PLS-DA revealed a core panel of 20 proteins that distinguished extracellular vesicles representing each clinical condition with an accuracy of 100%. Among them, three exosome proteins involved in the lectin complement pathway maximized the discrimination between MSK and ICN: Ficolin 1, Mannan-binding lectin serine protease 2, and Complement component 4-binding protein ß. ELISA confirmed the proteomic results. Our data show that the complement pathway is involved in the MSK, revealing a new range of potential therapeutic targets and early diagnostic biomarkers.


Assuntos
Proteínas do Sistema Complemento/análise , Vesículas Extracelulares/patologia , Rim em Esponja Medular/urina , Proteínas/análise , Adulto , Exossomos/química , Exossomos/patologia , Vesículas Extracelulares/química , Feminino , Humanos , Masculino , Rim em Esponja Medular/patologia , Nefrolitíase/patologia , Nefrolitíase/urina , Proteômica
11.
J Am Soc Nephrol ; 30(12): 2449-2463, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31575699

RESUMO

BACKGROUND: Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade-based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country. METHODS: To evaluate this strategy's effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (n=397) between 2007 and 2016. RESULTS: The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients. CONCLUSIONS: Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Inativadores do Complemento/uso terapêutico , Transplante de Rim , Adulto , Síndrome Hemolítico-Urêmica Atípica/epidemiologia , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/cirurgia , Proteínas Inativadoras do Complemento C3b/genética , Proteínas do Sistema Complemento/análise , Feminino , França , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes Quiméricas/genética , Cuidados Pré-Operatórios , Modelos de Riscos Proporcionais , Recidiva , Sistema de Registros , Estudos Retrospectivos , Prevenção Secundária
12.
BMC Nephrol ; 20(1): 313, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399080

RESUMO

BACKGROUND: Complement activation plays a substantial role in the pathogenesis of primary membranous nephropathy (pMN). C5b-9, C3c, MBL, and factor B have been documented in the subepithelial immune deposits. However, the changing of complement activation products in circulation and urine is not clear. METHODS: We measured the circulating and urinary levels of C1q, MBL, C4d, Bb, properdin, C3a, C5a, and sC5b-9, in 134 patients with biopsy-proven pMN, by enzyme-linked immunosorbent assay. All the plasma values were corrected by eGFR and all the urinary values were corrected by urinary creatinine and urinary protein excretion. Anti-PLA2R antibodies were measured in all patients. RESULTS: The plasma complement activation products were elevated both in the patients with and without anti-PLA2R antibodies. C3a levels were remarkably increased in the circulation and urine, much higher than the elevated levels of C5a. C5b-9 was in normal range in plasma, but significantly higher in urine. The urinary C5a had a positive correlation with anti-PLA2R antibody levels and urinary protein. The plasma level of C4d was elevated, but C1q and MBL were comparable to healthy controls. Positive correlations were observed between plasma C4d/MBL and urinary protein, only in the patients with positive anti-PLA2R antibodies but not in those without. The plasma level of Bb was elevated and had positive correlation with urinary protein only in the patients without anti-PLA2R antibodies. CONCLUSION: Complement activation products were remarkable increased in pMN and may serve as sensitive biomarkers of disease activity. The complement may be activated through lectin pathway with the existence of anti-PLA2R antibodies, while through alternative pathway in the absence of antibody.


Assuntos
Ativação do Complemento , Proteínas do Sistema Complemento/análise , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/urina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Complemento C1q/análise , Complemento C1q/urina , Complemento C3a/análise , Complemento C3a/urina , Complemento C4/análise , Complemento C4/urina , Complemento C5a/análise , Complemento C5a/urina , Fator B do Complemento/análise , Fator B do Complemento/urina , Complexo de Ataque à Membrana do Sistema Complemento/análise , Complexo de Ataque à Membrana do Sistema Complemento/urina , Proteínas do Sistema Complemento/urina , Creatinina/sangue , Creatinina/urina , Feminino , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/terapia , Humanos , Masculino , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/urina , Pessoa de Meia-Idade , Properdina/análise , Properdina/urina , Receptores da Fosfolipase A2/análise , Receptores da Fosfolipase A2/sangue , Receptores da Fosfolipase A2/imunologia , Análise de Regressão , Estatísticas não Paramétricas , Adulto Jovem
13.
Arthritis Rheumatol ; 71(9): 1400-1412, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31385462

RESUMO

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.


Assuntos
Lúpus Eritematoso Sistêmico/classificação , Reumatologia/normas , Adulto , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Anticorpos Antifosfolipídeos/sangue , Anticorpos Antifosfolipídeos/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Coortes , Proteínas do Sistema Complemento/análise , Técnicas de Apoio para a Decisão , Técnica Delfos , Europa (Continente) , Feminino , Humanos , Cooperação Internacional , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Sociedades Médicas , Estados Unidos
14.
Ann Biol Clin (Paris) ; 77(4): 447-452, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31339492

RESUMO

The complement system is composed of a set of plasma or membrane proteins. Complement protein deficiencies can be inherited or acquired, through the presence of autoantibodies or through consumption. We evaluated the analytical performance of the Optilite® analyser for the determination of the C3 and C4 levels and for the evaluation of the total complement activity. The intra- and inter-series CVs were evaluated and have showed satisfactory results, the concordances with analysers currently used in the laboratory (BNII® and BCT®, Siemens) are very good, as is the agreement between the serum and plasma samples. We also determined the reference values for the different parameters tested in view of a routine use of Optilite® analyser in the laboratory.


Assuntos
Complemento C3/análise , Complemento C4/análise , Proteínas do Sistema Complemento/análise , Testes Hematológicos/instrumentação , Adulto , Artefatos , Automação Laboratorial/instrumentação , Automação Laboratorial/normas , Análise Química do Sangue/instrumentação , Análise Química do Sangue/métodos , Análise Química do Sangue/normas , Coagulação Sanguínea/fisiologia , Complemento C3/metabolismo , Complemento C4/metabolismo , Proteínas do Sistema Complemento/metabolismo , Contaminação de Equipamentos , Testes Hematológicos/métodos , Testes Hematológicos/normas , Humanos , Padrões de Referência , Reprodutibilidade dos Testes
15.
J Interferon Cytokine Res ; 39(7): 410-415, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31173544

RESUMO

Cytokines activation and low complement levels are common in systemic lupus erythematosus (SLE) patients. This study is aimed to explore the relationship and clinical significance of cytokines and complements with SLE activity. Serum samples of 140 SLE patients and 36 age- and gender-matched healthy controls (HC) were collected. Serum interleukin (IL)-6, IL-17, high-sensitivity C-reactive proteins (hsCRP), and complements (C3, C4) were measured in all samples. These patients were divided into 3 subgroups based on clinical disease activity with SLE Disease Activity Index 2000 (SLEDAI-2K): stationary status subgroup, mild activity subgroup, and moderate/severe activity subgroup. The serum IL-6, IL-17, and hsCRP levels in SLE patients (4.72 ± 0.28 pg/mL, 23.34 ± 1.32 pg/mL, and 4.78 ± 0.34 mg/mL) were significantly higher than those in the HC group (1.51 ± 0.05 pg/mL, 18.28 ± 1.93 pg/mL, and 1.32 ± 0.29 mg/mL), whereas C3 and C4 levels in SLE patients (0.80 ± 0.28 and 0.21 ± 0.08 g/L) were significantly lower than those in the HC group (1.49 ± 0.08 and 0.36 ± 0.02 g/L). A positive correlation was noted between the SLEDAI-2K scores and serum IL-6, IL-17, and hsCRP levels. These results support the proinflammatory cytokines and complements in the pathogenesis of SLE. The serum IL-6, IL-17, and hsCRP levels were correlated with the disease activity.


Assuntos
Proteínas do Sistema Complemento/análise , Interleucina-17/sangue , Interleucina-6/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/fisiopatologia , Adulto , Proteína C-Reativa/análise , Feminino , Humanos , Masculino
16.
Medicine (Baltimore) ; 98(18): e15329, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045771

RESUMO

RATIONALE: Gain of function (GOF) mutations in PIK3CD gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 lymphopenia, reduced class-switched memory B cells, lymphadenopathy, cytomegalovirus and/or epstein-Barr virus (EBV) viremia, and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. PATIENT CONCERNS: We report a patient who was diagnosed with systemic lupus erythematosus (SLE) at a young age and was recently found to carry heterozygous mutations in PIK3CD. The patient not only presented with recurrent sinopulmonary infections, CD4 lymphopenia, lymphadenopathy, EBV viremia, and elevated serum IgM, but also met classification criteria of SLE based on persistent proteinuria and hematuria, leukopenia and anemia, low level of serum complement, and positive autoantibody for antinuclear antibodies. DIAGNOSES: Activated PI3Kδ syndrome. INTERVENTIONS: Oral prednisolone and hydroxychloroquine combined with mycophenolate mofetil was given to the patient. He was currently receiving intravenous immunoglobulin per month in association with hydroxychloroquine, low-dose prednisolone, and mycophenolate mofetil. OUTCOMES: At present, the level of complement restored to normal, hematuria and proteinuria disappeared, and liver function returned to normal. LESSONS: SLE may be a novel phenotype of GOF mutation in PI3CKD gene (GOF PIK3CD).


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação com Ganho de Função/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Lúpus Eritematoso Sistêmico/genética , Adolescente , Anticorpos Antinucleares/sangue , Grupo com Ancestrais do Continente Asiático/genética , Classe I de Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Proteínas do Sistema Complemento/análise , Proteínas do Sistema Complemento/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/etiologia , Infecções por Vírus Epstein-Barr/imunologia , Glucocorticoides/uso terapêutico , Herpesvirus Humano 4/imunologia , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Fenótipo , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Doenças da Imunodeficiência Primária
17.
Clin Transl Oncol ; 21(12): 1680-1686, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30955196

RESUMO

PURPOSE: Inflammatory bowel disease (IBD) is an important risk factor for colon cancer. Novel serum immunoinflammation-related protein complexes (IIRPCs) have shown associations with early cancer detection. Herein, we investigated the potential of serum IIRPCs for discriminating between IBD and colorectal cancer (CRC) patients. METHODS: Serum protein complexes of 65 healthy controls, 57 CRC, 69 (ulcerative colitis) UC, and 67 (Crohn's disease) CD patients were isolated by native-PAGE. The gray values of serum IIRPCs bands in the gel were quantified using Quantity One software. The receiver-operating characteristic (ROC) curves were constructed to assess the discriminating ability by calculating the area under the ROC curve. RESULTS: The serum IIRPCs levels in IBD and CRC patients were significantly elevated compared to healthy controls. ROC analysis indicated certain diagnostic ability of serum IIRPCs in differentiating IBD from CRC. Specifically, "a3" complex discriminated UC from CRC, with an AUC value of 0.722, sensitivity of 69.4% and specificity of 63.8%. Similarly, "b4" complex discriminated UC from CRC, with an AUC value of 0.709, sensitivity of 70.4%, and specificity of 60.0%. In addition, the "a3" complex also discriminated CD from CRC, with an AUC value of 0.785, sensitivity of 73.1%, and specificity of 74.1%, while the "b4" complex showed a tendency to discriminate CD from CRC, with an AUC value of 0.663, sensitivity of 67.9% and specificity of 50.0%. Thus, an equation based on multiple IIRPCs was built to further improve the discriminating power. CONCLUSIONS: Serum IIRPCs can be used to discriminate IBD from CRC and may also be associated with early screening of colitis-associated cancer.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/diagnóstico , Mediadores da Inflamação/sangue , Doenças Inflamatórias Intestinais/diagnóstico , Adulto , Sedimentação Sanguínea , Proteína C-Reativa/análise , Colite Ulcerativa/sangue , Colite Ulcerativa/diagnóstico , Neoplasias Colorretais/sangue , Fator H do Complemento/análise , Proteínas do Sistema Complemento/análise , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Diagnóstico Diferencial , Detecção Precoce de Câncer , Feminino , Haptoglobinas/análise , Humanos , Doenças Inflamatórias Intestinais/sangue , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade
19.
Hum Vaccin Immunother ; 15(10): 2491-2500, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30883271

RESUMO

Invasive meningococcal disease is rare and potentially devastating but often vaccine-preventable. Evaluation of meningococcal vaccine effectiveness is impractical owing to relatively low disease incidence; protection is therefore estimated using serum bactericidal antibody (SBA) assays. Original experiments on natural immunity established a titer of ≥4 as the correlate of protection for SBA assays using human complement (hSBA), but human complement is relatively difficult to obtain and standardize. Use of baby rabbit complement (rSBA assays), per standard guidelines for serogroups A and C, generally results in comparatively higher titers. Postlicensure effectiveness data for serogroup C conjugate vaccines support acceptance of rSBA titers ≥8 as the correlate of protection for this serogroup, but no thresholds have been formally established for serogroups A, W, and Y. Studies evaluating MenACWY-TT (Nimenrix®; Pfizer Inc, Sandwich, UK) immunogenicity have used both hSBA and rSBA assays, and ultimately suggest that rSBA may be more appropriate for these measurements.


Assuntos
Proteínas do Sistema Complemento/análise , Proteínas do Sistema Complemento/imunologia , Vacinas Meningocócicas/imunologia , Ensaios de Anticorpos Bactericidas Séricos/normas , Animais , Anticorpos Antibacterianos/sangue , Humanos , Infecções Meningocócicas/diagnóstico , Infecções Meningocócicas/prevenção & controle , Coelhos/imunologia , Sorogrupo , Ensaios de Anticorpos Bactericidas Séricos/métodos , Fatores de Tempo , Vacinas Conjugadas/imunologia
20.
J Dairy Sci ; 102(5): 4606-4618, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30879823

RESUMO

Blood has been widely collected and analyzed for diagnosing and monitoring diseases in humans and animals; a range of plasma proteins and peptide can be used as biomarkers to describe pathological or physiological status. Changes in the environment such as high-altitude hypoxia (HAH) can lead to adaptive changes in the blood system of mammals. However, the adaptation mechanism induced by HAH remains unclear. In this study, we used 12 multiparous Jersey cattle (400 ± 35 kg, average 3 yr old, dry period). We applied an iTRAQ (isobaric tags for relative and absolute quantitation) proteomics approach and microRNA (miRNA) microarray to explore differences in the plasma proteomic and miRNA profiles of Jersey cattle exposed to HAH conditions in Nyingchi, Tibet (altitude 3,000 m) and HAH-free conditions in Shenyang, China (altitude 50 m). Such quantitative proteomic strategies are suitable for accurate and comprehensive prediction of miRNA targets. In total, 264 differentially expressed proteins (127 upregulated, fold-change >1.2; 137 downregulated, fold-change <0.8) and 47 differential miRNAs (25 upregulated, fold-change >2; 22 downregulated, fold-change <0.5) were observed in the HAH-stressed group compared with the HAH-free group. Integrative analysis of proteomic and miRNA profiles demonstrated that the biological processes associated with differentially expressed proteins were immune response, complement system, and conjugation system. Integrative analysis of canonical pathways showed that most were associated with acute phase response signaling (z-score = -0.125), liver X receptor/retinoid X receptor (LXR/RXR) activation pathway (z-score = 1.134), coagulation system (z-score = -0.943), and complement system (z-score = -0.632). The current results indicated that Jersey cattle exposed to HAH could adapt to that condition through regulation of inflammatory homeostasis by inhibiting the acute phase response, coagulation system, and complement system and promoting LXR/RXR activation.


Assuntos
Doença da Altitude/veterinária , Bovinos/fisiologia , Regulação da Expressão Gênica , MicroRNAs/genética , Proteômica , Transdução de Sinais , Altitude , Doença da Altitude/sangue , Animais , Biomarcadores/sangue , Bovinos/genética , China , Proteínas do Sistema Complemento/análise , Receptores X do Fígado/sangue , Distribuição Aleatória , Receptores X Retinoide/sangue , Tibet
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