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1.
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
2.
Am J Hematol ; 95(5): 456-464, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31990387

RESUMO

The complement system is an innate immune defense cascade that can cause tissue damage when inappropriately activated. Evidence for complement over activation has been reported in small cohorts of patients with sickle cell disease (SCD). However, the mechanism governing complement activation in SCD has not been elucidated. Here, we observe that the plasma concentration of sC5b-9, a reliable marker for terminal complement activation, is increased at steady state in 61% of untreated SCD patients. We show that greater complement activation in vitro is promoted by SCD erythrocytes compared to normal ones, although no significant differences were observed in the regulatory proteins CD35, CD55, and CD59 in whole blood. Complement activation is positively correlated with the percentage of dense sickle cells (DRBCs). The expression levels of CD35, CD55, and CD59 are reduced in DRBCs, suggesting inefficient regulation when cell density increases. Moreover, the surface expression of the complement regulator CD46 on granulocytes was inversely correlated with the plasma sC5b-9. We also show increased complement deposition in cultured human endothelial cells incubated with SCD serum, which is diminished by the addition of the heme scavenger hemopexin. Treatment of SCD patients with hydroxyurea produces substantial reductions in complement activation, measured by sC5b-9 concentration and upregulation of CD46, as well as decreased complement activation on RBCs in vitro. In conclusion, complement over activation is a common pathogenic event in SCD that is associated with formation of DRBCs and hemolysis. And, it affects red cells, leukocytes and endothelial cells. This complement over activation is partly alleviated by hydroxyurea therapy.


Assuntos
Anemia Falciforme/terapia , Contagem de Células/métodos , Ativação do Complemento/genética , Hemólise/fisiologia , Hidroxiureia/uso terapêutico , Adolescente , Adulto , Feminino , Humanos , Hidroxiureia/farmacologia , Pessoa de Meia-Idade , Adulto Jovem
3.
Front Immunol ; 10: 1936, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440263

RESUMO

The complement system is crucial for defense against pathogens and the removal of dying cells or immune complexes. Thus, clinical indications for possible complete complement deficiencies include, among others, recurrent mild or serious bacterial infections as well as autoimmune diseases (AID). The diagnostic approach includes functional activity measurements of the classical (CH50) and alternative pathway (AP50) and the determination of the C3 and C4 levels, followed by the quantitative analysis of individual components or regulators. When biochemical analysis reveals the causal abnormality of the complement deficiency (CD), molecular mechanisms remains frequently undetermined. Here, using direct sequencing analysis of the coding region we report the pathogenic variants spectrum that underlie the total or subtotal complement deficiency in 212 patients. We identified 107 different hemizygous, homozygous, or compound heterozygous pathogenic variants in 14 complement genes [C1Qß (n = 1), C1r (n = 3), C1s (n = 2), C2 (n = 12), C3 (n = 5), C5 (n = 12), C6 (n = 9), C7 (n = 17), C8 ß (n = 7), C9 (n = 3), CFH (n = 7), CFI (n = 18), CFP (n = 10), CFD (n = 2)]. Molecular analysis identified 17 recurrent pathogenic variants in 6 genes (C2, CFH, C5, C6, C7, and C8). More than half of the pathogenic variants identified in unrelated patients were also found in healthy controls from the same geographic area. Our study confirms the strong association of meningococcal infections with terminal pathway deficiency and highlights the risk of pneumococcal and auto-immune diseases in the classical and alternative pathways. Results from this large genetic investigation provide evidence of a restricted number of molecular mechanisms leading to complement deficiency and describe the clinical potential adverse events of anti-complement therapy.


Assuntos
Proteínas do Sistema Complemento/deficiência , Proteínas do Sistema Complemento/genética , Doenças da Deficiência Hereditária de Complemento/genética , Doenças da Deficiência Hereditária de Complemento/imunologia , Adolescente , Adulto , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Ativação do Complemento/genética , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Feminino , Humanos , Masculino , Infecções Meningocócicas/genética , Infecções Meningocócicas/imunologia , Adulto Jovem
4.
Kidney Int ; 95(6): 1443-1452, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30982675

RESUMO

Secondary hemolytic uremic syndrome (HUS) is a heterogeneous group of thrombotic microangiopathies associated with various underlying conditions. Whether it belongs to the spectrum of complement-mediated HUS remains controversial. We analysed the presentation, outcome, and frequency of complement gene rare variants in a cohort of 110 patients with secondary HUS attributed to drugs (29%), autoimmune diseases (24%), infections (17%), malignancies (10%), glomerulopathies (9%), extra-renal organ transplantation (8%), and pancreatitis (3%). The frequency of complement gene rare variants was similar in patients with secondary HUS (5%) and in healthy individuals (6% and 8% in French and European controls, respectively). At diagnosis, 40% of patients required dialysis and 18% had neurological manifestations. Fifty percent of patients received plasmatherapy and 35% were treated with eculizumab. Haematological and complete renal remission was achieved in 80% and 24% of patients, respectively. Thirty-nine percent of patients progressed to chronic kidney disease (stages 3-4) and an additional 37% reached end-stage renal disease. Eleven percent of patients died, most often from complications of the underlying cause of HUS. Only one patient experienced an HUS relapse. Patients treated with eculizumab presented with more severe HUS and were more likely to require dialysis at the time of diagnosis as compared to patients not treated with eculizumab. Rates of hematological remission, chronic kidney disease (stages 3-4), and end-stage renal disease were similar in the two groups. Secondary HUS is an acute nonrelapsing form of HUS, not related to complement dysregulation. The efficacy of eculizumab in this setting is not yet established.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Proteínas do Sistema Complemento/genética , Síndrome Hemolítico-Urêmica/etiologia , Falência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/mortalidade , Síndrome Hemolítico-Urêmica Atípica/patologia , Síndrome Hemolítico-Urêmica Atípica/terapia , Criança , Pré-Escolar , Ativação do Complemento/genética , Inativadores do Complemento/uso terapêutico , Proteínas do Sistema Complemento/imunologia , Progressão da Doença , Feminino , França/epidemiologia , Síndrome Hemolítico-Urêmica/mortalidade , Síndrome Hemolítico-Urêmica/patologia , Síndrome Hemolítico-Urêmica/terapia , Humanos , Rim/imunologia , Rim/patologia , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Plasmaferese/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Diálise Renal/estatística & dados numéricos , Insuficiência Renal Crônica/patologia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
5.
Haematologica ; 104(12): 2501-2511, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30890598

RESUMO

A typical hemolytic uremic syndrome (aHUS) is a prototypic thrombotic microangiopathy attributable to complement dysregulation. Hypertensive emergency, characterized by elevation of systolic (>180 mmHg) or diastolic (>120 mmHg) blood pressure together with end-organ damage, can cause thrombotic microangiopathy which may mimic aHUS. We retrospectively evaluated the clinical, biological and complement genetic characteristics of 76 and 61 aHUS patients with and without hypertensive emergency, respectively. Patients with hypertensive emergency-aHUS were more frequently males, with neurological involvement, and a slightly higher hemoglobin level. At least one rare complement variant was identified in 51.3% (39/76) and 67% (41/61) patients with or without hypertensive emergency, respectively (P=0.06). In both groups, renal prognosis was severe with 23% and 40% of patients reaching end-stage renal disease after a 5-year follow-up (P=0.1). The 5-year renal survival was 77% in patients without hypertensive emergency or a complement variant, and below 25% in the three groups of patients with hypertensive emergency and/or a complement variant (P=0.02). Among patients without hypertensive emergency, the 5-year renal survival was 100% vs 40% in those treated or not with eculizumab, respectively (P<0.001). Conversely, the 5-year renal survival of patients with hypertensive emergency was 46% vs 23% in those treated or not with eculizumab, respectively (P=0.18). In conclusion, information on the presence or absence of hypertensive emergency and rare complement variants is essential to stratify the long-term renal prognosis of patients with aHUS.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/mortalidade , Complemento C3/genética , Variação Genética , Hipertensão/complicações , Adulto , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/etiologia , Complemento C3/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Emergências , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
6.
Clin J Am Soc Nephrol ; 14(3): 364-377, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30674459

RESUMO

BACKGROUND AND OBJECTIVES: Inherited complement hyperactivation is critical for the pathogenesis of atypical hemolytic uremic syndrome (HUS) but undetermined in postdiarrheal HUS. Our aim was to investigate complement activation and variants of complement genes, and their association with disease severity in children with Shiga toxin-associated HUS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Determination of complement biomarkers levels and next-generation sequencing for the six susceptibility genes for atypical HUS were performed in 108 children with a clinical diagnosis of post-diarrheal HUS (75 Shiga toxin-positive, and 33 Shiga toxin-negative) and 80 French controls. As an independent control cohort, we analyzed the genotypes in 503 European individuals from the 1000 Genomes Project. RESULTS: During the acute phase of HUS, plasma levels of C3 and sC5b-9 were increased, and half of patients had decreased membrane cofactor protein expression, which normalized after 2 weeks. Variants with minor allele frequency <1% were identified in 12 Shiga toxin-positive patients with HUS (12 out of 75, 16%), including pathogenic variants in four (four out of 75, 5%), with no significant differences compared with Shiga toxin-negative patients with HUS and controls. Pathogenic variants with minor allele frequency <0.1% were found in three Shiga toxin-positive patients with HUS (three out of 75, 4%) versus only four European controls (four out of 503, 0.8%) (odds ratio, 5.2; 95% confidence interval, 1.1 to 24; P=0.03). The genetic background did not significantly affect dialysis requirement, neurologic manifestations, and sC5b-9 level during the acute phase, and incident CKD during follow-up. However, the only patient who progressed to ESKD within 3 years carried a factor H pathogenic variant. CONCLUSIONS: Rare variants and complement activation biomarkers were not associated with severity of Shiga toxin-associated HUS. Only pathogenic variants with minor allele frequency <0.1% are more frequent in Shiga toxin-positive patients with HUS than in controls.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Ativação do Complemento/genética , Proteínas do Sistema Complemento/genética , Infecções por Escherichia coli/genética , Variação Genética , Escherichia coli Shiga Toxigênica/patogenicidade , Fatores Etários , Síndrome Hemolítico-Urêmica Atípica/imunologia , Síndrome Hemolítico-Urêmica Atípica/microbiologia , Pré-Escolar , Progressão da Doença , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Feminino , França , Frequência do Gene , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno , Humanos , Lactente , Falência Renal Crônica/genética , Falência Renal Crônica/imunologia , Falência Renal Crônica/microbiologia , Masculino , Fenótipo , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Escherichia coli Shiga Toxigênica/imunologia , Fatores de Tempo
7.
J Immunol ; 200(7): 2464-2478, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29500241

RESUMO

Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and overactivation of the complement alternative pathway. Typically, gene analysis for aHUS and C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-center analysis of 610 rare genetic variants in 13 mostly complement genes (CFH, CFI, CD46, C3, CFB, CFHR1, CFHR3, CFHR4, CFHR5, CFP, PLG, DGKE, and THBD) from >3500 patients with aHUS and C3G. We report 371 novel rare variants (RVs) for aHUS and 82 for C3G. Our new interactive Database of Complement Gene Variants was used to extract allele frequency data for these 13 genes using the Exome Aggregation Consortium server as the reference genome. For aHUS, significantly more protein-altering rare variation was found in five genes CFH, CFI, CD46, C3, and DGKE than in the Exome Aggregation Consortium (allele frequency < 0.01%), thus correlating these with aHUS. For C3G, an association was only found for RVs in C3 and the N-terminal C3b-binding or C-terminal nonsurface-associated regions of CFH In conclusion, the RV analyses showed nonrandom distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Complemento C3/genética , Fator H do Complemento/genética , Via Alternativa do Complemento/genética , Glomerulonefrite Membranoproliferativa/genética , Síndrome Hemolítico-Urêmica Atípica/patologia , Complemento C3/metabolismo , Via Alternativa do Complemento/fisiologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Glomerulonefrite Membranoproliferativa/patologia , Humanos , Masculino , Mutação de Sentido Incorreto/genética
8.
Transfus Apher Sci ; 54(2): 212-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27177491

RESUMO

The spectrum of the thrombotic microangiopathies (TMA) encompasses a heterogeneous group of disorders with hereditary and acquired forms. Endothelial cell injury in the microvasculature is common to all TMAs, whatever the pathophysiological process. In this review we describe genetic mutations characteristic of certain TMAs and review their contributions to disease. Recent identification of novel pathologic mutations has been enabled by exome studies. The monogenic forms of TMA are more frequently caused by recessive alterations in von Willebrand factor cleaving protease ADAMST13, leading to congenital thrombotic thrombocytopenic purpura, or cobalamine C and DGKE genes, leading to an atypical hemolytic-uremic syndrome (aHUS)-like TMA. aHUS, whether idiopathic or linked to a known complement amplifying condition, is a TMA that primarily affects kidney function. It often results from a combination of an underlying genetic susceptibility with environmental factors activating the alternative complement pathway. Pathogenic variants in at least five complement genes coding for complement factor H (CFH) complement factor I (CFI), MCP (CD46), C3 and complement factor B (CFB) have been demonstrated to increase the risk of developing aHUS, but several more genes have been implicated. A new challenge is to separate disease-associated genetic variants from the broader background of variants or polymorphisms present in all human genomes that are rare, potentially functional, but may or may not be pathogenic.


Assuntos
Proteína ADAMTS13/genética , Síndrome Hemolítico-Urêmica Atípica/genética , Proteínas do Sistema Complemento/genética , Genoma Humano , Proteína Cofatora de Membrana/genética , Polimorfismo Genético , Microangiopatias Trombóticas/genética , Animais , Humanos
9.
Blood ; 125(15): 2359-69, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25608561

RESUMO

The pathogenesis of atypical hemolytic uremic syndrome (aHUS) is strongly linked to dysregulation of the alternative pathway of the complement system. Mutations in complement genes have been identified in about two-thirds of cases, with 5% to 15% being in C3. In this study, 23 aHUS-associated genetic changes in C3 were characterized relative to their interaction with the control proteins factor H (FH), membrane cofactor protein (MCP; CD46), and complement receptor 1 (CR1; CD35). In surface plasmon resonance experiments, 17 mutant recombinant proteins demonstrated a defect in binding to FH and/or MCP, whereas 2 demonstrated reduced binding to CR1. In the majority of cases, decreased binding affinity translated to a decrease in proteolytic inactivation (known as cofactor activity) of C3b via FH and MCP. These results were used to map the putative binding regions of C3b involved in the interaction with MCP and CR1 and interrogated relative to known FH binding sites. Seventy-six percent of patients with C3 mutations had low C3 levels that correlated with disease severity. This study expands our knowledge of the functional consequences of aHUS-associated C3 mutations relative to the interaction of C3 with complement regulatory proteins mediating cofactor activity.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/metabolismo , Complemento C3/genética , Complemento C3/metabolismo , Mapas de Interação de Proteínas , Síndrome Hemolítico-Urêmica Atípica/patologia , Sítios de Ligação , Estudos de Coortes , Complemento C3/análise , Feminino , Humanos , Masculino , Modelos Moleculares , Mutação
10.
Blood ; 125(5): 775-83, 2015 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-25477495

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis, which is effectively controlled with eculizumab, a humanized monoclonal antibody that binds complement protein 5 (C5). The residual functional activity of C5 can be screened using a 50% hemolytic complement (CH50) assay, which is sensitive to the reduction, absence, and/or inactivity of any components of the classical and terminal complement pathway. Little data exist on complement blockade during treatment. From 2010 to 2012, clinical data, hemolysis biomarkers, complement assessment, and free eculizumab circulating levels were systematically measured immediately before every injection given to 22 patients with hemolytic PNH while receiving eculizumab therapy. During the study, 6 patients received ≥1 red blood cell transfusion. Lack of detectable CH50 activity (defined by CH50 ≤ 10% of normal values) was found in 184 samples (51%) and was significantly associated with lower lactate dehydrogenase levels (P = .002). Low levels of circulating free eculizumab (<50 µg/mL) correlated with detectable CH50 activity (CH50 > 10%; P = .004), elevated bilirubin levels (P < .0001), and the need for transfusions (P = .034). This study suggests that both CH50 activity and circulating free eculizumab levels may help physicians to manage PNH patients receiving eculizumab.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Complemento C5/antagonistas & inibidores , Monitoramento de Medicamentos/métodos , Hemoglobinúria Paroxística/tratamento farmacológico , Fatores Imunológicos/farmacocinética , Adulto , Idoso , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Bilirrubina/sangue , Biomarcadores/sangue , Ativação do Complemento/efeitos dos fármacos , Complemento C5/metabolismo , Transfusão de Eritrócitos , Feminino , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/imunologia , Hemoglobinúria Paroxística/patologia , Hemólise/efeitos dos fármacos , Hemólise/imunologia , Humanos , Imunoensaio , Fatores Imunológicos/sangue , Fatores Imunológicos/uso terapêutico , Infusões Intravenosas , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade
11.
Ann Biol Clin (Paris) ; 72(3): 271-80, 2014.
Artigo em Francês | MEDLINE | ID: mdl-24876138

RESUMO

The complement system is a complex system involving serum and membrane proteins interacting in a regulated manner. The complement system plays a major role in antibacterial immunity, in inflammation, and in immune complex processing. Therefore, deficiencies in complement proteins are associated with increased susceptibility to bacterial infections and autoimmune diseases. These deficiencies can be inherited or acquired. Most of them can be screened by simple laboratory tests but require a diagnosis in a specialized laboratory. All sequences of complement genes are known, and the discovery of a deficiency must lead to genetic testing. The discovery of a congenital deficiency requires a familial study and a prophylaxis. In this article, we review the complement cascade, the laboratory tests to explore it, and the main diseases associated with complement deficiencies.


Assuntos
Proteínas do Sistema Complemento/deficiência , Doenças Autoimunes/imunologia , Infecções Bacterianas/imunologia , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Suscetibilidade a Doenças/imunologia , Humanos , Síndromes de Imunodeficiência/imunologia
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