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1.
J Autoimmun ; 117: 102595, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33453462

RESUMO

BACKGROUND: Genetic variation at a multigene cluster at chromosome 3p21.31 and the ABO blood group have been associated with the risk of developing severe COVID-19, but the mechanism remains unclear. Complement activation has been associated with COVID-19 severity. OBJECTIVE: The aim of this study was to examine whether chromosome 3p21.31 and the ABO variants are linked to the activation of the complement cascade in COVID-19 patients. METHODS: We considered 72 unrelated European hospitalized patients with genetic data and evaluation of circulating C5a and soluble terminal complement complex C5b-9 (SC5b-9). Twenty-six (36.1%) patients carried the rs11385942 G>GA variant and 44 (66.1%) non-O blood group associated with increased risk of severe COVID-19. RESULTS: C5a and SC5-b9 plasma levels were higher in rs11385949 GA carriers than in non-carriers (P = 0.041 and P = 0.012, respectively), while C5a levels were higher in non-O group than in O group patients (P = 0.019). The association between rs11385949 and SC5b-9 remained significant after adjustment for ABO and disease severity (P = 0.004) and further correction for C5a (P = 0.018). There was a direct relationship between upper airways viral load and SC5b-9 in carriers of the rs11385949 risk allele (P = 0.032), which was not observed in non-carriers. CONCLUSIONS: The rs11385949 G>GA variant, tagging the chromosome 3 gene cluster variation and predisposing to severe COVID-19, is associated with enhanced complement activation, both with C5a and terminal complement complex, while non-O blood group with C5a levels. These findings provide a link between genetic susceptibility to more severe COVID-19 and complement activation.


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Cromossomos Humanos Par 3/genética , Ativação do Complemento/genética , Grupo com Ancestrais do Continente Europeu , Genótipo , Família Multigênica/genética , Idoso , Complemento C5a/genética , Progressão da Doença , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco , Carga Viral
2.
Kidney Int ; 98(5): 1084-1087, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33126970

RESUMO

Gain-of-function variants in CFB encoding factor B (FB), a component of the alternative pathway C3 convertase, have been reported in a minority of patients with aHUS and result in massive C3 activation. Zhang et al. describe the functional characterization of a novel FB variant (p.Ser367Arg) that they identified in 2 unrelated aHUS pedigrees who had undetectable C3 levels. The mutant FB caused strong C3 cleavage in fluid-phase but also C3 deposition on cell surface. This commentary addresses the implications of these findings for understanding the complexity of complement-related genetic renal diseases.


Assuntos
Síndrome Hemolítico-Urêmica Atípica , Fator B do Complemento , Síndrome Hemolítico-Urêmica Atípica/genética , Ativação do Complemento/genética , Fator B do Complemento/genética , Via Alternativa do Complemento/genética , Humanos , Mutação
3.
Nat Med ; 26(10): 1609-1615, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32747830

RESUMO

Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutic and public health strategies. Viral-host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronaviruses. To determine whether conditions associated with dysregulated complement or coagulation systems impact disease, we performed a retrospective observational study and found that history of macular degeneration (a proxy for complement-activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) are risk factors for SARS-CoV-2-associated morbidity and mortality-effects that are independent of age, sex or history of smoking. Transcriptional profiling of nasopharyngeal swabs demonstrated that in addition to type-I interferon and interleukin-6-dependent inflammatory responses, infection results in robust engagement of the complement and coagulation pathways. Finally, in a candidate-driven genetic association study of severe SARS-CoV-2 disease, we identified putative complement and coagulation-associated loci including missense, eQTL and sQTL variants of critical complement and coagulation regulators. In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility. The results highlight the value of using a multimodal analytical approach to reveal determinants and predictors of immunity, susceptibility and clinical outcome associated with infection.


Assuntos
Ativação do Complemento/imunologia , Infecções por Coronavirus/mortalidade , Hemorragia/epidemiologia , Degeneração Macular/epidemiologia , Pneumonia Viral/mortalidade , Trombocitopenia/epidemiologia , Trombose/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Coagulação Sanguínea/genética , Transtornos da Coagulação Sanguínea/epidemiologia , Ativação do Complemento/genética , Infecções por Coronavirus/sangue , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Expressão Gênica , Hemorragia/sangue , Hemorragia/imunologia , Doenças da Deficiência Hereditária de Complemento/epidemiologia , Doenças da Deficiência Hereditária de Complemento/imunologia , Humanos , Hipertensão/epidemiologia , Intubação Intratraqueal , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Obesidade/epidemiologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Modelos de Riscos Proporcionais , Respiração Artificial , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Trombocitopenia/sangue , Trombose/sangue
4.
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
5.
FASEB J ; 34(7): 8787-8795, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32525600

RESUMO

The dynamics, such as transmission, spatial epidemiology, and clinical course of Coronavirus Disease-2019 (COVID-19) have emerged as the most intriguing features and remain incompletely understood. The genetic landscape of an individual in particular, and a population in general seems to play a pivotal role in shaping the above COVID-19 dynamics. Considering the implications of host genes in the entry and replication of SARS-CoV-2 and in mounting the host immune response, it appears that multiple genes might be crucially involved in the above processes. Herein, we propose three potentially important genetic gateways to COVID-19 infection; these could explain at least in part the discrepancies of its spread, severity, and mortality. The variations within Angiotensin-converting enzyme 2 (ACE2) gene might constitute the first genetic gateway, influencing the spatial transmission dynamics of COVID-19. The Human Leukocyte Antigen locus, a master regulator of immunity against infection seems to be crucial in influencing susceptibility and severity of COVID-19 and can be the second genetic gateway. The genes regulating Toll-like receptor and complement pathways and subsequently cytokine storm induced exaggerated inflammatory pathways seem to underlie the severity of COVID-19, and such genes might represent the third genetic gateway. Host-pathogen interaction is a complex event and some additional genes might also contribute to the dynamics of COVID-19. Overall, these three genetic gateways proposed here might be the critical host determinants governing the risk, severity, and outcome of COVID-19. Genetic variations within these gateways could be key in influencing geographical discrepancies of COVID-19.


Assuntos
Betacoronavirus/fisiologia , Ativação do Complemento/genética , Infecções por Coronavirus/genética , Antígenos HLA/genética , Interações Hospedeiro-Patógeno/genética , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Receptores Virais/genética , Receptores Toll-Like/genética , Grupos de Populações Continentais/genética , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/genética , Resistência à Doença/imunologia , Predisposição Genética para Doença , Variação Genética , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação , Metagenômica , Mutação de Sentido Incorreto , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , Prognóstico , Locos de Características Quantitativas , Receptores Virais/fisiologia , Risco , Receptores Toll-Like/imunologia , Resultado do Tratamento
6.
Invest Ophthalmol Vis Sci ; 61(3): 18, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32176267

RESUMO

Purpose: To study the levels of complement activation in different disease stages of AMD and the influence of genetic polymorphisms in complement genes. Methods: We included 797 patients with AMD and 945 controls from the European Genetic Database. Patients were grouped into five AMD stages: early AMD, intermediate AMD, central geographic atrophy, active choroidal neovascularization or inactive choroidal neovascularization. Differences in complement activation, as defined by the systemic C3d/C3 ratio, between AMD stages were evaluated using general linear modeling. In addition, we evaluated the influence of 18 genetic AMD polymorphisms in complement genes and their effect on complement activation. Differences in complement activation between stages were evaluated stratifying by complement associated haplotypes. Results: Complement activation levels differed significantly between AMD disease stages. As compared with controls, the C3d/C3 ratio was higher in patients with intermediate AMD (P < 0.001) and central geographic atrophy (P = 0.001). Two polymorphisms in CFH (rs10922109 and rs570618) and one in CFB (rs116503776) were significantly associated with complement activation. The association between AMD disease stage and complement activation was more pronounced in patients with haplotypes associated with the highest complement activation. Conclusions: In general, consecutive AMD disease stages showed increasing levels of complement activation, especially in individuals with a genetic burden in complement genes. These findings contribute to the discussion on the pathogenesis of AMD in relation to complement activation and might suggest refinement in patient selection and the optimum window of treatment with complement inhibitors. Prospective studies are needed to confirm these results.


Assuntos
Ativação do Complemento/genética , Degeneração Macular/genética , Degeneração Macular/imunologia , Polimorfismo de Nucleotídeo Único , Idoso , Proteína C-Reativa/análise , Estudos de Casos e Controles , Complemento C3/análise , Complemento C3d/análise , Bases de Dados Genéticas , Haplótipos , Humanos , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Triglicerídeos/sangue
7.
BMC Cancer ; 20(1): 121, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054454

RESUMO

BACKGROUND: The epidermal growth factor receptor (EGFR) is pivotal for growth of epithelial cells and is overexpressed in several epithelial cancers like head and neck squamous cell carcinoma (HNSCC). EGFR signalling is also involved in diverse innate immune functions in epithelia. We previously found a role for EGFR in modulating the complement system in skin, this prompted an investigation into EGFR role in complement modulation in HNSCC. METHODS: We used patient derived HNSCC cell lines with varying sensitivities to EGFR inhibitors, and generated EGFR inhibition resistant cell lines to study the role of EGFR in modulating complement in HNSCC. RESULTS: We found that HNSCC cell lines activate the complement system when incubated with human serum. This complement activation was increased in cell lines sensitive to EGFR inhibition following the use of the tyrosine kinase inhibitor Iressa. Sensitive cell line made resistant to EGFR-inhibitors displayed complement activation and a decrease in complement regulatory proteins even in the absence of EGFR-inhibitors. Complement activation did not cause lysis of HNSCC cells, and rather led to increased extracellular signal-regulated kinase (ERK) phosphorylation in one cell line. CONCLUSION: These data indicate that EGFR has a complement modulatory role in HNSCC, and that a prolonged EGFR-inhibition treatment in sensitive cancer cells increases complement activation. This has implications in understanding the response to EGFR inhibitors, in which resistance and inflammatory skin lesions are two major causes for treatment cessation.


Assuntos
Ativação do Complemento/genética , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Cetuximab/farmacologia , Ativação do Complemento/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
8.
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
9.
Nephrology (Carlton) ; 25(1): 40-47, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30838755

RESUMO

BACKGROUND: Immunoglobulin A (IgA) vasculitis with nephritis (IgAVN) and IgA nephropathy (IgAN) are widely considered as related diseases. Considerable evidences support the notion of involvement of complement activation in both IgAVN and IgAN. Our previous studies identified a genetic variant in complement factor H (CFH), rs6677604, as an IgAN-susceptible variant by genome-wide association study, and further confirmed its linkage to CFHR3-1Δ and proved its influence on complement activation and thereby on IgAN susceptibility. AIM: To explore the role of rs6677604 in complement activation of IgAVN. METHODS: In this study, we enrolled 632 patients with IgAVN, 1178 patients with IgAN and 902 healthy controls. The genotype of rs6677604 was measured by TaqMan allele discrimination assays or was extracted from genome-wide association study data. RESULTS: The frequency of the rs6677604-A allele was significantly higher in IgAVN than in IgAN. However, no significant differences were observed between IgAVN and the controls. Higher complement factor H (FH) levels were observed in IgAVN than IgAN, and positive correlation between circulating FH and C3 levels was present in IgAVN. In both IgAVN and IgAN, rs6677604-A was associated with less intensity of glomerular C3 deposits. In agreement with the higher frequency of rs6677604-A in IgAVN, the glomerular C3 deposits of patients with IgAVN were less intense than those in IgAN. CONCLUSION: Our findings suggest that genetic variation in CFH (rs6677604) is involved in the phenotype of complement activation in both IgAVN and IgAN. Moreover, rs6677604 might contribute to the difference of complement activation intensity between IgAVN and IgAN.


Assuntos
Ativação do Complemento/genética , Glomerulonefrite por IGA/genética , Rim/imunologia , Polimorfismo de Nucleotídeo Único , Vasculite/genética , Adulto , Estudos de Casos e Controles , Complemento C3/metabolismo , Fator H do Complemento/genética , Fator H do Complemento/metabolismo , Feminino , Frequência do Gene , Predisposição Genética para Doença , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/imunologia , Humanos , Rim/patologia , Masculino , Fenótipo , Vasculite/sangue , Vasculite/diagnóstico , Vasculite/imunologia , Adulto Jovem
10.
Semin Immunol ; 45: 101331, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31711769

RESUMO

Glomerulonephritis (GN) refers to a group of renal diseases affecting the glomeruli due to the damage mediated by immunological mechanisms. A large proportion of the disease manifestations are caused by disturbances in the complement system. They can be due to genetic errors, autoimmunity, microbes or abnormal immunoglobulins, like modified IgA or paraproteins. The common denominator in most of the problems is an overactive or misdirected alternative pathway complement activation. An assessment of kidney function, amount of proteinuria and hematuria are crucial elements to evaluate, when glomerulonephritis is suspected. However, the cornerstones of the diagnoses are renal biopsy and careful examination of the complement abnormality. Differential diagnostics between the various forms of GN is not possible based on clinical features, as they may vary greatly. This review describes the known mechanisms of complement dysfunction leading to different forms of primary GN (like IgA glomerulonephritis, dense deposit disease, C3 glomerulonephritis, post-infectious GN, membranous GN) and differences to atypical hemolytic uremic syndrome. It also covers the basic elements of etiology-directed therapy and prognosis of the most common forms of GN. Common principles in the management of GN include treatment of hypertension and reduction of proteinuria, some require immunomodulating treatment. Complement inhibition is an emerging treatment option. A thorough understanding of the basic disease mechanism and a careful follow-up are needed for optimal therapy.


Assuntos
Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Suscetibilidade a Doenças/imunologia , Glomerulonefrite/etiologia , Glomerulonefrite/metabolismo , Animais , Infecções Bacterianas/complicações , Biomarcadores , Ativação do Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Glomerulonefrite/diagnóstico , Glomerulonefrite por IGA/etiologia , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Glomerulonefrite Membranoproliferativa/etiologia , Glomerulonefrite Membranoproliferativa/metabolismo , Glomerulonefrite Membranoproliferativa/patologia , Síndrome Hemolítico-Urêmica/etiologia , Síndrome Hemolítico-Urêmica/metabolismo , Síndrome Hemolítico-Urêmica/patologia , Humanos
11.
Semin Immunol ; 45: 101339, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31718864

RESUMO

Complement is a key component of the innate immune defence and in addition forms a bridge to the adaptive immune responses. As such complement is of vital importance for efficient protection against infections. However, the activity of the complement system can also aberrantly be directed against the tissues of the body itself and contribute to organ damage in a variety of diseases. In several rheumatic diseases complement activation is suggested to play a pronounced role. This review will highlight the role of both complement activation and complement regulation in rheumatic disease. A contribution of complement to the disease process is often suggested based on the presence of complement activation fragments in the target tissues or the presence of complement activation fragments in the circulation. The role that complement plays in different rheumatic diseases is often unknown but is thought to contribute to tissue damage as a consequence of autoantibody mediated immune complex formation and deposition. In addition reduced complement inhibition mediated by endogenous complement regulators can also enhance complement activity and tissue damage. In observational studies, it is difficult to distinguish whether complement activation is a result of enhanced activation or decreased regulation. Until recently, strong conclusions on the relative importance of complement activation to the pathology were largely restricted to animal experiments. Usage of complement targeting therapeutics in humans will hopefully give us the opportunity to study the actual contribution of complement activation towards disease progression and tissue damage in rheumatic disease into more detail.


Assuntos
Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Suscetibilidade a Doenças , Doenças Reumáticas/etiologia , Doenças Reumáticas/metabolismo , Animais , Autoimunidade , Ativação do Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Regulação da Expressão Gênica , Humanos , Transdução de Sinais
12.
Semin Immunol ; 45: 101337, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31757607

RESUMO

Preeclampsia is a serious vascular complication of the human pregnancy, whose etiology is still poorly understood. In preeclampsia, exacerbated apoptosis and fragmentation of the placental tissue occurs due to developmental qualities of the placental trophoblast cells and/or mechanical and oxidative distress to the syncytiotrophoblast, which lines the placental villi. Dysregulation of the complement system is recognized as one of the mechanisms of the disease pathology. Complement has the ability to promote inflammation and facilitate phagocytosis of placenta-derived particles and apoptotic cells by macrophages. In preeclampsia, an overload of placental cell damage or dysregulated complement system may lead to insufficient clearance of apoptotic particles and placenta-derived debris. Excess placental damage may lead to sequestration of microparticles, such as placental vesicles, to capillaries in the glomeruli of the kidney and other vulnerable tissues. This phenomenon could contribute to the manifestations of typical diagnostic symptoms of preeclampsia: proteinuria and new-onset hypertension. In this review we propose that the complement system may serve as a regulator of the complex tolerance and clearance processes that are fundamental in healthy pregnancy. It is therefore recommended that further research be conducted to elucidate the interactions between components of the complement system and immune responses in the context of complicated and healthy pregnancy.


Assuntos
Proteínas do Sistema Complemento/imunologia , Tolerância Imunológica , Imunomodulação , Animais , Apoptose , Autoimunidade , Ativação do Complemento/genética , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Suscetibilidade a Doenças , Feminino , Humanos , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/metabolismo , Gravidez , Receptores de Complemento/metabolismo
13.
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
14.
EBioMedicine ; 45: 303-313, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262714

RESUMO

BACKGROUND: The complement system is a central component of the innate immune system. Constitutive biosynthesis of complement proteins is essential for homeostasis. Dysregulation as a consequence of genetic or environmental cues can lead to inflammatory syndromes or increased susceptibility to infection. However, very little is known about steady state levels in children or its kinetics during infection. METHODS: With a newly developed multiplex mass spectrometry-based method we analyzed the levels of 32 complement proteins in healthy individuals and in a group of pediatric patients infected with bacterial or viral pathogens. FINDINGS: In plasma from young infants we found reduced levels of C4BP, ficolin-3, factor B, classical pathway components C1QA, C1QB, C1QC, C1R, and terminal pathway components C5, C8, C9, as compared to healthy adults; whereas the majority of complement regulating (inhibitory) proteins reach adult levels at very young age. Both viral and bacterial infections in children generally lead to a slight overall increase in complement levels, with some exceptions. The kinetics of complement levels during invasive bacterial infections only showed minor changes, except for a significant increase and decrease of CRP and clusterin, respectively. INTERPRETATION: The combination of lower levels of activating and higher levels of regulating complement proteins, would potentially raise the threshold of activation, which might lead to suppressed complement activation in the first phase of life. There is hardly any measurable complement consumption during bacterial or viral infection. Altogether, expression of the complement proteins appears surprisingly stable, which suggests that the system is continuously replenished. FUND: European Union's Horizon 2020, project PERFORM, grant agreement No. 668303.


Assuntos
Doenças Transmissíveis/imunologia , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/química , Inflamação/imunologia , Adolescente , Adulto , Proteína C-Reativa/genética , Proteína C-Reativa/imunologia , Criança , Pré-Escolar , Clusterina/genética , Clusterina/imunologia , Doenças Transmissíveis/genética , Ativação do Complemento/genética , Proteínas do Sistema Complemento/classificação , Proteínas do Sistema Complemento/isolamento & purificação , Feminino , Homeostase , Humanos , Lactente , Recém-Nascido , Inflamação/genética , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Adulto Jovem
15.
Int J Mol Sci ; 20(14)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31331124

RESUMO

Epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer with high mortality rates in the advanced stage. Chronic inflammation is a recognized risk factor for cSCC progression and the complement system, as a part of innate immunity, belongs to the microenvironment of tumors. The complement system is a double-edged sword in cancer, since complement activation is involved in anti-tumor cytotoxicity and immune responses, but it also promotes cancer progression directly and indirectly. Recently, the role of several complement components and inhibitors in the regulation of progression of cSCC has been shown. In this review, we will discuss the role of complement system components and inhibitors as biomarkers and potential new targets for therapeutic intervention in cSCC.


Assuntos
Carcinoma de Células Escamosas/etiologia , Proteínas do Sistema Complemento/imunologia , Neoplasias Cutâneas/etiologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/genética , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
16.
Res Vet Sci ; 124: 346-351, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31060014

RESUMO

OBJECTIVE: Mannose-binding lectin (MBL)-associated serine protease1 (MASP1) is the central enzyme in the innate immune system, which has biological functions of antibacterial and anti-inflammatory activities. Moreover, MASP1 represents a candidate gene reflecting the complement activity. This study is to investigate the entire exons of MASP1 in Chinese Holstein cattle with DNA sequencing to identify novel single nucleotide polymorphisms (SNPs). METHODS: Novel SNPs were identified through gene sequencing and genotyped by the PCR Restriction Fragment Length Polymorphism (PCR-RFLP) and Created Restriction Site PCR (CRS-PCR). The relationship between the milk performance traits and complement activity in Chinese Holstein cattle was analyzed using the General Linear Model (GLM) procedure with the SAS software (version 8.0). RESULTS: Two novel SNPs (i.e., g.5766A > G and g.51228A > C) were detected. The SNP g.5766A > G was located in the first intron and the SNP g.51228A > C was located in the 3'-untranslated regions of MASP1. The polymorphism at g.5766A > G was correlated with protein percentage (P < 0.05). Moreover, the polymorphism at g.51228A > C had only two genotypes, and this SNP had no significant correlation with CH50, ACH50, fat percentage, protein percentage, 305-day milk yields, or SCS scores. CONCLUSION: MASP1, reflecting the complement activity, may not be significantly related to mastitis. However, MASP1 could be implemented in the breeding program to improve the production performance of Chinese Holstein cattle.


Assuntos
Bovinos/fisiologia , Ativação do Complemento/genética , Hemólise/fisiologia , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Polimorfismo de Nucleotídeo Único , Animais , Bovinos/genética , Bovinos/imunologia , China , Feminino , Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo , Mastite Bovina , Leite/metabolismo
17.
Immunobiology ; 224(4): 511-517, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31109748

RESUMO

Factor I was first discovered in 1966. Its importance became apparent with the description of the original Factor I deficient patient in Boston in 1967. This patient presented with a hyperactive alternative complement pathway resulting in secondary complement deficiency due to continuous complement consumption. On the basis of these findings, the mechanism of the alternative pathway was worked out. In 1975, the surprise finding was made that elevating levels of Factor I in plasma down-regulated the alternative pathway. Attempts to exploit this finding for clinical use had a long and frustrating history and it was not until 2019 that the first patient was treated with the gene therapy vector for age related macular degeneration by Professor Sir Robert MacLaren in Oxford. This review follows the long and contorted course from initial observations to clinical use of complement Factor I.


Assuntos
Fator I do Complemento/fisiologia , Animais , Ativação do Complemento/genética , Ativação do Complemento/imunologia , Fator I do Complemento/química , Fator I do Complemento/uso terapêutico , Via Alternativa do Complemento/genética , Via Alternativa do Complemento/imunologia , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Suscetibilidade a Doenças , Humanos , Imunoconglutininas/imunologia , Transdução de Sinais , Relação Estrutura-Atividade
18.
Front Immunol ; 10: 885, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31134052

RESUMO

APS is the association of antiphospholipid antibodies (aPL) with thromboses and/or recurrent pregnancy loss (RPL). Among patients with SLE, one-third have aPL and 10-15% have a manifestation of secondary APS. Animal studies suggested that complement activation plays an important role in the pathogenesis of thrombosis and pregnancy loss in APS. We performed a cross-sectional study on complement proteins and genes in 525 patients with aPL. Among them, 237 experienced thromboses and 293 had SLE; 111 had both SLE and thromboses, and 106 had neither SLE nor thrombosis. Complement protein levels were determined by radial immunodiffusion for C4, C3 and factor H; and by functional ELISA for mannan binding lectin (MBL). Total C4, C4A and C4B gene copy numbers (GCN) were measured by TaqMan-based realtime PCR. Two to six copies of C4 genes are frequently present in a diploid genome, and each copy may code for an acidic C4A or a basic C4B protein. We observed significantly (a) higher protein levels of total C4, C4A, C4B, C3, and anticardiolipin (ACLA) IgG, (b) increased frequencies of lupus anticoagulant and males, and (c) decreased levels of complement factor H, MBL and ACLA-IgM among patients with thrombosis than those without thrombosis (N = 288). We also observed significantly lower GCNs of total C4 and C4A among aPL-positive patients with both SLE and thrombosis than others. By contrast, aPL-positive subjects with SLE had significantly reduced protein levels of C3, total C4, C4A, C4B and ACLA-IgG, and higher frequency of females than those without SLE. Patients with thrombosis but without SLE (N = 126), and patients with SLE but without thrombosis (N = 182) had the greatest differences in mean protein levels of C3 (p = 2.6 × 10-6), C4 (p = 2.2 × 10-9) and ACLA-IgG (p = 1.2 × 10-5). RPL occurred in 23.7% of female patients and thrombotic SLE patients had the highest frequency of RPL (41.0%; p = 3.8 × 10-10). Compared with non-RPL females, RPL had significantly higher frequency of thrombosis and elevated C4 protein levels. Female patients with homozygous C4A deficiency all experienced RPL (p = 0.0001) but the opposite was true for patients with homozygous C4B deficiency (p = 0.017). These results provide new insights and biomarkers for diagnosis and management of APS and SLE.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Proteínas do Sistema Complemento/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Aborto Habitual/genética , Aborto Habitual/imunologia , Adulto , Animais , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/genética , Ativação do Complemento/genética , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/genética , Estudos Transversais , Feminino , Dosagem de Genes , Humanos , Inibidor de Coagulação do Lúpus/imunologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Gravidez , Fatores de Risco , Trombose/genética , Trombose/imunologia
19.
Transplantation ; 103(9): 1821-1833, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30964836

RESUMO

BACKGROUND: Brain death (BD)-associated inflammation has been implicated in decreased kidney allograft function and survival, but the underlying mechanisms have not been well distinguished from the conditions of critical care itself. We have developed a clinically translatable model to separate and investigate strategies to improve donor management and critical care. METHODS: Brain-dead (n = 12) and sham (n = 5) rhesus macaques were maintained for 20 hours under intensive care unit-level conditions. Samples were collected for immunophenotyping, analysis of plasma proteins, coagulation studies, and gene analysis for changes in immune and metabolic profile with comparison to naive samples (n = 10). RESULTS: We observed an increase in circulating leukocytes and cytokines, activation of complement and coagulation pathways, and upregulation of genes associated with inflammation in both brain-dead and sham subjects relative to naïve controls. Sham demonstrated an intermediate phenotype of inflammation compared to BD. Analysis of gene expression in kidneys from BD kidneys revealed a similar upregulation of inflammatory profile in both BD and sham subjects, but BD presented a distinct reduction in metabolic and respiratory processes compared to sham and naïve kidneys. CONCLUSION: BD is associated with activation of specific pathways of the innate immune system and changes to metabolic gene expression in renal tissue itself; however, sham donors presented an intermediate inflammatory response attributable to the critical care environment. The early onset and penetrating impact of this inflammatory response underscores the need for early intervention to prevent perioperative tissue injury to transplantable organs.


Assuntos
Morte Encefálica/imunologia , Morte Encefálica/metabolismo , Metabolismo Energético/genética , Imunidade Inata/genética , Inflamação/imunologia , Inflamação/metabolismo , Rim/metabolismo , Animais , Biomarcadores/sangue , Coagulação Sanguínea/genética , Fatores de Coagulação Sanguínea/genética , Fatores de Coagulação Sanguínea/metabolismo , Ativação do Complemento/genética , Cuidados Críticos , Citocinas/sangue , Citocinas/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Inflamação/sangue , Inflamação/genética , Macaca mulatta , Fatores de Tempo
20.
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
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