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1.
Molecules ; 25(12)2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32604797

RESUMO

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Mineração de Dados/métodos , Infecções por HIV/epidemiologia , Infecções por HIV/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Anti-Inflamatórios/uso terapêutico , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Bases de Dados Genéticas , Regulação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/patogenicidade , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Inflamação , Interferons/genética , Interferons/imunologia , Interleucinas/genética , Interleucinas/imunologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
3.
Science ; 367(6478): 688-694, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32029629

RESUMO

Synapses between engram cells are believed to be substrates for memory storage, and the weakening or loss of these synapses leads to the forgetting of related memories. We found engulfment of synaptic components by microglia in the hippocampi of healthy adult mice. Depletion of microglia or inhibition of microglial phagocytosis prevented forgetting and the dissociation of engram cells. By introducing CD55 to inhibit complement pathways, specifically in engram cells, we further demonstrated that microglia regulated forgetting in a complement- and activity-dependent manner. Additionally, microglia were involved in both neurogenesis-related and neurogenesis-unrelated memory degradation. Together, our findings revealed complement-dependent synapse elimination by microglia as a mechanism underlying the forgetting of remote memories.


Assuntos
Proteínas do Sistema Complemento/fisiologia , Hipocampo/fisiologia , Transtornos da Memória/fisiopatologia , Memória de Longo Prazo/fisiologia , Microglia/fisiologia , Retenção Psicológica/fisiologia , Sinapses/fisiologia , Animais , Antígenos CD55 , Proteínas do Sistema Complemento/genética , Transtornos da Memória/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Microglia/imunologia , Fagocitose
4.
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
5.
Fish Shellfish Immunol ; 96: 190-200, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31765792

RESUMO

Complement is a complex component of innate immune system, playing an important role in defense against pathogens and host homeostasis. The complement system has been comprehensively studied in mammals, however less is known about complement in teleost, especially in tetraploid common carp (Cyprinus carpio). In this study, a total of 110 complement genes were identified and characterized in common carp, which include almost all the homologs of mammalian complement genes. These genes were classified into three pathways (alternative pathways, lectin pathways and classical pathways), similar to those in mammals. Phylogenetic and selection pressure analysis showed that the complement genes were evolving-constrained and the function was conserved. Most of the complement genes were highly expressed in spleen, liver, brain and skin among the tested 12 health tissues of common carp. After Aeromonas hydrophila infection in the common carp, many members of complement genes were activated to bring about an immune response and expressed to against any pathogenic encroachment. Gene expression divergences which were found between two homoeologous genes suggested the functional divergences of the homoeologous genes after the 4R WGD event, revealing the evolutionary fate of the tetraploid common carp after the recent WGD.


Assuntos
Carpas/genética , Proteínas do Sistema Complemento/genética , Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Genoma/imunologia , Imunidade Inata/genética , Aeromonas hydrophila/fisiologia , Animais , Carpas/imunologia , Proteínas do Sistema Complemento/imunologia , Evolução Molecular , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Filogenia , RNA Mensageiro/genética
6.
BMB Rep ; 53(1): 10-19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31865964

RESUMO

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The AD pathophysiology entails chronic inflammation involving innate immune cells including microglia, astrocytes, and other peripheral blood cells. Inflammatory mediators such as cytokines and complements are also linked to AD pathogenesis. Despite increasing evidence supporting the association between abnormal inflammation and AD, no well-established inflammatory biomarkers are currently available for AD. Since many reports have shown that abnormal inflammation precedes the outbreak of the disease, non-invasive and readily available peripheral inflammatory biomarkers should be considered as possible biomarkers for early diagnosis of AD. In this minireview, we introduce the peripheral biomarker candidates related to abnormal inflammation in AD and discuss their possible molecular mechanisms. Furthermore, we also summarize the current state of inflammatory biomarker research in clinical practice and molecular diagnostics. We believe this review will provide new insights into biomarker candidates for the early diagnosis of AD with systemic relevance to inflammation during AD pathogenesis. [BMB Reports 2020; 53(1): 10-19].


Assuntos
Doença de Alzheimer/imunologia , Proteínas do Sistema Complemento/metabolismo , Citocinas/metabolismo , Inflamação/imunologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Encéfalo/patologia , Proteínas do Sistema Complemento/genética , Microbioma Gastrointestinal/imunologia , Humanos , Inflamação/patologia , Camundongos , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia
7.
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
8.
Medicine (Baltimore) ; 98(44): e17031, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689742

RESUMO

The mechanisms underlying the potential risks of in vitro fertilization and embryo transfer (IVF-ET) have not been fully elucidated. The aim of this study was to explore changes in the complement and coagulation pathways in placentae subjected to IVF-ET in the first trimester compared to placentae from normal pregnancies. Four placenta samples in the first trimester were obtained from patients undergoing IVF-ET owing to oviductal factors only. An additional 4 control placentae were obtained from volunteers with normal pregnancies. A GeneChip Affymetrix HG-U133 Plus 2.0 Array was utilized to analyze the changes in gene expression between the normal and IVF-ET placentae. Differentially expressed genes (DEGs) were analyzed using the Database for Annotation and Visualization and Integrated Discovery bioinformatics resource, and gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted. Using real-time PCR, we confirmed the obtained microarray data in 10 dysregulated genes. Five of the gene products were further analyzed by immunohistochemistry (IHC) to determine their protein expression and localization. A total of fifty DEGs were identified in the complement and coagulation pathways in the IVF-ET treated placentae: 38 upregulated and 12 down-regulated. KEGG pathway analysis indicated that IVF-ET manipulation substantially over-activated the coagulation and complement pathways, while urokinase plasminogen activator- and urokinase plasminogen activator receptor-mediated trophoblastic invasion and tissue remodeling were inhibited. Furthermore, the 5 proteins analyzed by IHC were found to be localized specifically to the placenta. This is the first study to compare DEGs relating to the placental complement and coagulation pathways from patients undergoing IVF-ET treatment compared to those undergoing normal pregnancy. These findings identified valuable biomarkers and potential novel therapeutic targets to combat the unfavorable effects of IVF-ET.


Assuntos
Coagulação Sanguínea/genética , Proteínas do Sistema Complemento/genética , Transferência Embrionária , Fertilização In Vitro , Placenta/metabolismo , Primeiro Trimestre da Gravidez/metabolismo , Adulto , Regulação para Baixo , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Gravidez , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
9.
Fish Shellfish Immunol ; 95: 203-212, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31610293

RESUMO

The complement system constitutes a highly sophisticated and powerful body defense machinery acting in the innate immunity of both vertebrates and invertebrates. As central components of the complement system, significant effects of thioester-containing protein (TEP) family members on immunity have been reported in most vertebrates and in some invertebrates, but the spatiotemporal expression and regulatory patterns of TEP family genes under environmental stress have been less widely investigated in scallops. In this study, expression profiling of TEP family members in the Yesso scallop Patinopecten yessoensis (designated PyTEPs) was performed at all developmental stages, in different healthy adult tissues, and in mantles during exposure to different levels of acidification (pH = 6.5 and 7.5) for different time points (3, 6, 12 and 24 h); this profiling was accomplished through in silico analysis of transcriptome and genome databases. Spatiotemporal expression patterns revealed that PyTEPs had specific functional differentiation in all stages of growth and development of the scallop. Expression analysis confirmed the inducible expression patterns of PyTEPs during exposure to acidification. Gene duplication and alternative splicing events simultaneously occurred in PyTEP1. Seven different cDNA variants of PyTEP1 (designated PyTEP1-A-PyTEP1-G) were identified in the scallop mantle transcriptome during acidic stress. These variants were produced by the alternative splicing of seven differentially transcribed exons (exons 18-24), which encode the highly variable central region. The responses to immune stress may have arisen through the gene duplication and alternative splicing of PyTEP1. The sequence diversity of PyTEP1 isoforms and their different expression profiles in response to ocean acidification (OA) suggested a mechanism used by scallops to differentiate and regulate PyTEP1 gene expression. Collectively, these results demonstrate the gene duplication and alternative splicing of TEP family genes and provide valuable resources for elucidating their versatile roles in bivalve innate immune responses to OA challenge.


Assuntos
Processamento Alternativo , Proteínas do Sistema Complemento/genética , Pectinidae/genética , Pectinidae/imunologia , Água do Mar/química , Ácidos , Animais , Perfilação da Expressão Gênica , Concentração de Íons de Hidrogênio , Imunidade Inata , Oceanos e Mares , Filogenia , Estresse Fisiológico
10.
Oncol Rep ; 42(6): 2686-2693, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31578581

RESUMO

In recent years, efforts to treat cancer by improving the immune function of patients have received a great deal of attention. As part of the immune system, complement is also under such evaluation. Among the many components of the complement system, complement decay accelerating factor (CD55 or DAF) is known to inhibit complement­mediated cell lysis. However, little is known about the role of CD55 in terms of cancer therapy. The present study aimed to demonstrate that increased levels of CD55 are strongly correlated with the progression of colorectal cancer. A novel CD55 chimeric monoclonal antibody was developed that may boost the immune response, thereby suppressing cancer. The CD55 antibody treatment activated complement and therefore suppressed the proliferation, invasion and migration of colorectal cancer cells. This tumoricidal activity is partly explained by the inflammatory response via the activation of proinflammatory cytokines. In addition, the CD55 antibody treatment synergistically enhanced the tumoricidal activity of 5­FU in colorectal cancer cells, suggesting that combined treatment may be a better strategy in colorectal cancer therapy.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos CD55/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Antígenos CD55/imunologia , Antígenos CD55/farmacologia , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Proteínas do Sistema Complemento/genética , Citotoxicidade Imunológica/efeitos dos fármacos , Sinergismo Farmacológico , Fluoruracila/farmacologia , Células HT29 , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica
11.
Malar J ; 18(1): 312, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533836

RESUMO

BACKGROUND: Anaemia is a major consequence of malaria, caused by the removal of both infected and uninfected red blood cells (RBCs) from the circulation. Complement activation and reduced expression of complement regulatory proteins (CRPs) on RBCs are an important pathogenic mechanism in severe malarial anaemia in both Plasmodium falciparum and Plasmodium vivax infection. However, little is known about loss of CRPs on RBCs during mild malarial anaemia and in low-density infection. METHODS: The expression of CRP CR1, CD55, CD59, and the phagocytic regulator CD47, on uninfected normocytes and reticulocytes were assessed in individuals from two study populations: (1) P. falciparum and P. vivax-infected patients from a low transmission setting in Sabah, Malaysia; and, (2) malaria-naïve volunteers undergoing P. falciparum induced blood-stage malaria (IBSM). For clinical infections, individuals were categorized into anaemia severity categories based on haemoglobin levels. For IBSM, associations between CRPs and haemoglobin level were investigated. RESULTS: CRP expression on RBC was lower in Malaysian individuals with P. falciparum and P. vivax mild malarial anaemia compared to healthy controls. CRP expression was also reduced on RBCs from volunteers during IBSM. Reduction occurred on normocytes and reticulocytes. However, there was no significant association between reduced CRPs and haemoglobin during IBSM. CONCLUSIONS: Removal of CRPs occurs on both RBCs and reticulocytes during Plasmodium infection even in mild malarial anaemia and at low levels of parasitaemia.


Assuntos
Anemia/parasitologia , Proteínas do Sistema Complemento/genética , Eritrócitos/metabolismo , Malária Falciparum/complicações , Malária Vivax/complicações , Adulto , Proteínas do Sistema Complemento/metabolismo , Eritrócitos/parasitologia , Feminino , Humanos , Malária Falciparum/parasitologia , Malária Vivax/parasitologia , Malásia , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/fisiologia , Plasmodium vivax/fisiologia , Adulto Jovem
12.
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
13.
Commun Biol ; 2: 290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396570

RESUMO

Regulation of complement activation in the host cells is mediated primarily by the regulators of complement activation (RCA) family proteins that are formed by tandemly repeating complement control protein (CCP) domains. Functional annotation of these proteins, however, is challenging as contiguous CCP domains are found in proteins with varied functions. Here, by employing an in silico approach, we identify five motifs which are conserved spatially in a specific order in the regulatory CCP domains of known RCA proteins. We report that the presence of these motifs in a specific pattern is sufficient to annotate regulatory domains in RCA proteins. We show that incorporation of the lost motif in the fourth long-homologous repeat (LHR-D) in complement receptor 1 regains its regulatory activity. Additionally, the motif pattern also helped annotate human polydom as a complement regulator. Thus, we propose that the motifs identified here are the determinants of functionality in RCA proteins.


Assuntos
Moléculas de Adesão Celular/metabolismo , Ativação do Complemento , Proteínas do Sistema Complemento/metabolismo , Receptores de Complemento 3b/metabolismo , Motivos de Aminoácidos , Animais , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/genética , Cnidários/química , Cnidários/metabolismo , Proteínas do Sistema Complemento/química , Proteínas do Sistema Complemento/genética , Sequência Conservada , Humanos , Filogenia , Conformação Proteica , Domínios Proteicos , Receptores de Complemento 3b/química , Receptores de Complemento 3b/genética , Relação Estrutura-Atividade , Proteínas Virais/química , Proteínas Virais/metabolismo
14.
Kidney Int ; 96(4): 995-1004, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31420192

RESUMO

Malignant hypertension is listed among the causes of secondary thrombotic microangiopathy, but pathogenic mutations in complement genes have been reported in patients with hypertension-induced thrombotic microangiopathy. Here we investigated the frequency and severity of hypertension in 55 patients with primary atypical hemolytic uremic syndrome (aHUS). A genetic analysis was performed in all patients, and funduscopic examination was performed in all the patients with Grades 2 and 3 hypertension. A cohort of 110 patients with malignant hypertension caused by diseases other than aHUS served as control. Thirty-six patients with aHUS presented Grade 2 or Grade 3 hypertension and funduscopic examination showed malignant hypertension in 19. Genetic abnormalities in complement were found in 19 patients (37% among patients with malignant hypertension). Plasmapheresis was performed in 46 patients and 26 received eculizumab. Renal and hematological responses were significantly lower after plasmapheresis (24%) than after eculizumab (81%). Renal survival was significantly higher in patients treated with eculizumab (85% at one, three and five years) compared to patients who did not receive this treatment (54%, 46% and 41%), respectively. Response to eculizumab was independent of hypertension severity and the presence of complement genetic abnormalities. Among patients with malignant hypertension caused by other diseases the prevalence of thrombotic microangiopathy was very low (5%). Thus, severe and malignant hypertension are common among patients with aHUS and eculizumab treatment leads to a higher renal survival when compared to plasmapheresis. However, thrombotic microangiopathy is uncommon among patients presenting with malignant hypertension caused by diseases other than aHUS.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/complicações , Proteínas do Sistema Complemento/genética , Hipertensão Maligna/epidemiologia , Índice de Gravidade de Doença , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/terapia , Inativadores do Complemento/uso terapêutico , Feminino , Humanos , Hipertensão Maligna/diagnóstico , Hipertensão Maligna/genética , Hipertensão Maligna/terapia , Incidência , Masculino , Pessoa de Meia-Idade , Plasmaferese , Estudos Retrospectivos , Adulto Jovem
15.
Arch. Health Sci. (Online) ; 26(1): 62-66, 28/08/2019.
Artigo em Português | LILACS | ID: biblio-1046127

RESUMO

Introdução: O sistema complemento é composto por diversas proteínas plasmáticas e é um importante mecanismo de defesa da imunidade inata e adquirida, que exerce funções homeostáticas e fisiológicas, como a remoção de células apoptóticas e complexos imunes. A deficiência neste mecanismo pode ser hereditária ou adquirida, e leva ao aumento da susceptibilidade a doenças infecciosas e não infecciosas, raras e fatais. Objetivo: Descrever as principais causas e consequências da deficiência do sistema complemento e relacioná-las com múltiplas patologias. Material e Métodos: Trata-se de uma revisão bibliográfica narrativa, tendo como base de dados, artigos publicados no Scientific Electronic Library Online (SciELO), National Library of Medicine (PubMed), Medical Literature Analysis and retrieval System Online (MEDLINE), nos últimos 5 anos. Resultados: A associação do complemento e doenças foram observadas em situações de deficiência do sistema complemento, anormalidades na regulação e nas inflamações. Mutações genéticas ou aumento do consumo do complemento levam à ativação imprópria ou excessiva do complemento, podendo conduzir a consequências lesivas e ao desenvolvimento de diversas doenças, como, lúpus eritematoso sistêmico, síndrome urêmica hemolítica atípica, glomerulopatia C3, hemoglobinúria paroxística noturna, glomerulonefrite pós-infecciosas, artrite reumatoide, dentre outras. Conclusão: É evidente a participação do sistema complemento na patogênese e patogenia de diversas doenças. O investimento em pesquisas, que visem ampliar o entendimento do papel do mecanismo do sistema complemento, pode contribuir para o desenvolvimento de intervenções terapêuticas paliativas e ou de cura de diversas doenças, com a consequente melhoria da qualidade de vida dos indivíduos acometidos.


Introduction: The complement system is composed of several plasma proteins and is an important defense mechanism of innate and acquired immunity, which exerts homeostatic and physiological functions, such as the removal of apoptotic cells and immune complexes. Deficiency in this mechanism may be hereditary or acquired, and leads to increased susceptibility to infectious and non-infectious, rare and fatal diseases. Objective: To describe the main causes and consequences of the deficiency of the complement system and to relate them to multiple pathologies. Material and Methods: This is a bibliographical narrative review, based on data published in SciELO (Scientific Electronic Library Online), PubMed (National Library of Medicine), MEDLINE (Medical Literature Analysis and retrieval System Online), last five years. Results:The associations of complement and diseases were observed in situations of deficiency of the complement system, abnormalities in regulation and inflammation. Genetic mutations lead to inappropriate or excessive activation of the complement, as well as increased the consumption of the complement. This can lead to harmful consequences and the development of several diseases, such as systemic lupus erythematosus, atypical hemolytic uremic syndrome, C3 glomerulopathy, nocturnal paroxysmal hemoglobinuria, postpartum glomerulonephritis, infectious diseases, rheumatoid arthritis, among others. Conclusion: The participation of the complement system in the pathogenesis and pathogenesis of several diseases is evident. Investing in research, aimed at broadening the understanding of the role of the complement system mechanism, may contribute to the development of palliative therapeutic interventions and or cure of various diseases, with the consequent improvement in the quality of life of affected individuals.


Assuntos
Proteínas do Sistema Complemento/deficiência , Doença/etiologia , Proteínas do Sistema Complemento/genética , Ativação do Complemento
16.
Brain ; 142(9): 2722-2736, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31289819

RESUMO

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.


Assuntos
Proteínas do Sistema Complemento/genética , Redes Reguladoras de Genes/genética , Esclerose Múltipla/genética , Degeneração Neural/genética , Vias Visuais/fisiopatologia , Adulto , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Feminino , Seguimentos , Heterogeneidade Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Retina/patologia , Tomografia de Coerência Óptica
17.
Saudi J Kidney Dis Transpl ; 30(3): 701-705, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249236

RESUMO

In evaluating a patient with thrombotic microangiopathy (TMA), it is necessary to rule out thrombotic thrombocytopenic purpura before a diagnosis of atypical hemolytic uremic syndrome (aHUS) is made. There have been reports that mutations of complement factors can coexist with partial A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13 deficiency. Here, we report the case of a 6-year-old girl who was initially diagnosed as nephrotic syndrome and developed TMA after five years of onset of illness. She had poor response to treatment and had multiple relapses due to associated complement factor mutation. Hence, genetic evaluation has to be considered in all children presenting with aHUS.


Assuntos
Proteína ADAMTS13/genética , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Proteínas do Sistema Complemento/genética , Mutação , Púrpura Trombocitopênica Trombótica/diagnóstico , Proteína ADAMTS13/deficiência , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/imunologia , Síndrome Hemolítico-Urêmica Atípica/terapia , Criança , Proteínas do Sistema Complemento/imunologia , Diagnóstico Diferencial , Evolução Fatal , Feminino , Predisposição Genética para Doença , Humanos , Fenótipo , Valor Preditivo dos Testes , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/terapia , Resultado do Tratamento
18.
World Neurosurg ; 131: e23-e31, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31238169

RESUMO

BACKGROUND: Intracranial aneurysm (IA) represents a cerebrovascular disorder that featured by dilation or bulging of the weakened blood vessel wall. When it ruptures, an IA leads to subarachnoid hemorrhage with high disability and mortality rates. Despite the numerous studies focusing on IA ruptures, little research on IA pathogenesis has been reported. In this study, we aimed to reveal key genes related to IA formation. METHODS: Four datasets from Gene Expression Omnibus data were downloaded, normalized, and separated into the IA group and the normal vessel control group for analyses. We screened for differentially expressed genes (DEGs) between groups and conducted functional enrichment, pathway enrichment, and gene set enrichment analysis analyses among significant DEGs. RESULTS: according to our analyses, significant DEGs majorly associate with smooth muscle system and the complement system. Among all DEGs, 5 down-regulated genes (MYH11, CNN1, MYOCD, ACTA1, and LMOD1) and 3 up-regulated genes (C1QB, C3AR1, and VSIG4) are most relevant in IA formation. CONCLUSIONS: Key DEGs identified in this study are related to IA pathogenesis. Among identified DEGs, LMOD1 is the most significant and merits more attention.


Assuntos
Aneurisma Intracraniano/genética , Actinas/genética , Autoantígenos/genética , Proteínas de Ligação ao Cálcio/genética , Estudos de Casos e Controles , Complemento C1q/genética , Proteínas do Sistema Complemento/genética , Proteínas do Citoesqueleto/genética , Regulação para Baixo , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Proteínas dos Microfilamentos/genética , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Cadeias Pesadas de Miosina/genética , Proteínas Nucleares/genética , Receptores de Complemento/genética , Transativadores/genética , Regulação para Cima , Remodelação Vascular/genética
19.
Front Immunol ; 10: 853, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118930

RESUMO

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal failure. It is caused by genetic or acquired defects of the complement alternative pathway. Factor H autoantibodies (anti-FHs) have been reported in 10% of aHUS patients and are associated with the deficiency of factor H-related 1 (FHR1). However, FHR1 deficiency is not enough to cause aHUS, since it is also present in about 5% of Caucasian healthy subjects. In this study we evaluated the prevalence of genetic variants in CFH, CD46, CFI, CFB, C3, and THBD in aHUS patients with anti-FHs, using healthy subjects with FHR1 deficiency, here defined "supercontrols," as a reference group. "Supercontrols" are more informative than general population because they share at least one risk factor (FHR1 deficiency) with aHUS patients. We analyzed anti-FHs in 305 patients and 30 were positive. The large majority were children (median age: 7.7 [IQR, 6.6-9.9] years) and 83% lacked FHR1 (n = 25, cases) due to the homozygous CFHR3-CFHR1 deletion (n = 20), or the compound heterozygous CFHR3-CFHR1 and CFHR1-CFHR4 deletions (n = 4), or the heterozygous CFHR3-CFHR1 deletion combined with a frameshift mutation in CFHR1 that generates a premature stop codon (n = 1). Of the 960 healthy adult subjects 48 had the FHR1 deficiency ("supercontrols"). Rare likely pathogenetic variants in CFH, THBD, and C3 were found in 24% of cases (n = 6) compared to 2.1% of the "supercontrols" (P-value = 0.005). We also found that the CFH H3 and the CD46 GGAAC haplotypes are not associated with anti-FHs aHUS, whereas these haplotypes are enriched in aHUS patients without anti-FHs, which highlights the differences in the genetic basis of the two forms of the disease. Finally, we confirm that common infections are environmental factors that contribute to the development of anti-FHs aHUS in genetically predisposed individuals, which fits with the sharp peak of incidence during scholar-age. Further studies are needed to fully elucidate the complex genetic and environmental factors underlying anti-FHs aHUS and to establish whether the combination of anti-FHs with likely pathogenetic variants or other risk factors influences disease outcome and response to therapies.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Autoanticorpos/imunologia , Proteínas Sanguíneas/deficiência , Proteínas do Sistema Complemento/genética , Síndrome Hemolítico-Urêmica Atípica/imunologia , Autoantígenos/imunologia , Proteínas Sanguíneas/genética , Criança , Pré-Escolar , Fator H do Complemento/genética , Fator H do Complemento/imunologia , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino
20.
Proc Natl Acad Sci U S A ; 116(20): 9953-9958, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31036650

RESUMO

The complement system is highly efficient in targeting pathogens, but lack of its apposite regulation results in host-cell damage, which is linked to diseases. Thus, complement activation is tightly regulated by a series of proteins, which primarily belong to the regulators of complement activation (RCA) family. Structurally, these proteins are composed of repeating complement control protein (CCP) domains where two to four successive domains contribute to the regulatory functions termed decay-accelerating activity (DAA) and cofactor activity (CFA). However, the precise constitution of the functional units and whether these units can be joined to form a larger composition with dual function have not been demonstrated. Herein, we have parsed the functional units for DAA and CFA by constructing chimeras of the decay-accelerating factor (DAF) that exhibits DAA and membrane cofactor protein (MCP) that exhibits CFA. We show that in a four-CCP framework, a functional unit for each of the regulatory activities is formed by only two successive CCPs wherein each participates in the function, albeit CCP2 has a bipartite function. Additionally, optimal activity requires C-terminal domains that enhance the avidity of the molecule for C3b/C4b. Furthermore, by composing a four-CCP DAF-MCP chimera with robust CFA (for C3b and C4b) and DAA (for classical and alternative pathway C3 convertases), named decay cofactor protein, we show that CCP functional units can be linked to design a dual-activity regulator. These data indicate that the regulatory determinants for these two biological processes are distinct and modular in nature.


Assuntos
Proteínas do Sistema Complemento/metabolismo , Proteínas do Sistema Complemento/genética , Escherichia coli , Humanos , Proteína Cofatora de Membrana , Pichia , Domínios Proteicos , Engenharia de Proteínas , Estrutura Quaternária de Proteína
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