RESUMO
Introduction: MASP-2 is a mannose blinding lectin associate to serine protease in cerebrospinal fluid and its dynamics through the blood brain barrier is unknown. Objective: To describe MASP-2 diffusion pattern from blood to cerebrospinal fluid. Methods: A transversal observational prospective study was performed 56 control samples of cerebrospinal fluid and serum were employed. ELISA measured MASP-2. Two groups were made: control patients without organic brain disease with normal cerebrospinal fluid and normal barrier function and patients without inflammatory diseases with a blood cerebrospinal fluid barrier dysfunction. Results: MASP-2 concentration in cerebrospinal fluid increase with augment the Q Albumin. QMASP-2 vs. Q Albumin saturation curve indicates that MASP-2 is interacting with other molecules in the subarachnoid environment. The higher inter-individual variation of cerebrospinal fluid MASP-2 of the control compared to the serum MASP-2 indicates that MASP-2 is a protein derived from blood. Conclusions: MASP-2 in CSF is predominantly blood-derived. The saturation curve demonstrates that MASP-2 interacts with the starters of the lectin pathway like mannose binding lectin, ficolins and collectin LK(AU)
Introducción: MASP2 es una proteína de unión a manosa asociada a una proteasa de serina encontrada en la periferia, pero puede pasar a líquido cefalorraquídeo. Sin embargo, su dinámica a través de la barrera sangre-líquido cefalorraquídeo es aún desconocida. Objetivo: Describir la difusión del MASP-2 desde la sangre al líquido cefalorraquídeo. Métodos: Se realiza estudio observacional prospectivo de corte transversal donde se emplearon 56 muestras de suero y líquido cefalorraquídeo. Fue seleccionado un grupo control con pacientes sin enfermedad orgánica del cerebro, con líquido cefalorraquídeo y función de barrera normal y otro grupo de pacientes sin enfermedades inflamatorias del cerebro con disfunción de barrera sangre-líquido cefalorraquídeo. Resultados: La concentración de MASP-2 en líquido cefalorraquídeo aumentó con el incremento de la Q Albúmina. La curva de saturación de Q MASP-2 contra la Q Albúmina indicó que el MASP-2 se encuentra interactuando con otras moléculas en el espacio subaracnoideo. El aumento del coeficiente de variación individual de MASP-2 en líquido cefalorraquídeo de los controles comparado con el MASP-2 en suero indicó que el MASP-2 es una proteína derivada de la sangre. Conclusiones: La producción de MASP-2 en líquido cefalorraquídeo es predominantemente derivada de la sangre. La curva de saturación demostró que el MASP-2 interactúa con los iniciadores de la vía de las lectinas como lectina unida a manosa, las ficolinas y la colectina LK(AU)
Assuntos
Humanos , Ensaio de Imunoadsorção Enzimática , Barreira Hematoencefálica , Líquido Cefalorraquidiano/fisiologia , Serina Proteases Associadas a Proteína de Ligação a Manose , Manose , Estudos Transversais , Estudos ProspectivosRESUMO
Introduction: Defining mechanisms governing the diffusion from blood to cerebrospinal fluid is central to understanding immune function in the central nervous system. Objective: To describe the dynamics of diffusion of the lectin pathway components from blood to cerebrospinal fluid. Methods: It was organized the information available in PubMed database and of papers from journals, and abstract books from international congresses belongs mainly to Cuban authors all about the lectin pathway of complement including manan-binding lectin (MBL) and ficolins complexed with the MBL-associated serine proteases (MASP2), and of other components like MASP3, Map44 as regulatory components and the different starters like MBL, ficolins and CLLK. Results: All the lectin pathways component are blood derived proteins but at the same time it could be synthesized intrathecally. Most of the protein can be transferred from blood to cerebrospinal fluid in different aggregation forms and some of them can be described as a consuming curve. The control mechanism of regulation the lectin pathway can be followed by molecules as MASP3 and Map44. Conclusions: The under- constructed lectin pathway of the complement system required not only the available information in different journals. It had to be completed by reviewing the congress abstract book and congress website of the last years(AU)
Assuntos
Humanos , Líquido Cefalorraquidiano/fisiologiaRESUMO
Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) are components of the lectin pathway, which activate the complement system after binding to the HCV structural proteins E1 and E2. We haplotyped 11 MASP2 polymorphisms in 103 HCV patients and 205 controls and measured MASP-2 levels in 67 HCV patients and 77 controls to better understand the role of MASP-2 in hepatitis C susceptibility and disease severity according to viral genotype and fibrosis levels. The haplotype block MASP2*ARDP was associated with protection against HCV infection (OR = 0.49, p = .044) and lower MASP-2 levels in controls (p = .021), while haplotype block AGTDVRC was significantly increased in patients (OR = 7.58, p = .003). MASP-2 levels were lower in patients than in controls (p < .001) and in patients with viral genotype 1 or 4 (poor responders to treatment) than genotype 3 (p = .022) and correlated inversely with the levels of alkaline phosphatase, especially in individuals with fibrosis 3 or 4 (R = -.7, p = .005). MASP2 gene polymorphisms modulate basal gene expression, which may influence the quality of complement response against HCV. MASP-2 levels decrease during chronic disease, independently of MASP2 genotypes, most probably due to consumption and attenuation mechanisms of viral origin and by the reduced liver function, the site of MASP-2 production.
Assuntos
Haplótipos , Hepacivirus , Hepatite C/genética , Hepatite C/metabolismo , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Estudos de Casos e Controles , Éxons , Feminino , Predisposição Genética para Doença , Genótipo , Hepacivirus/genética , Hepatite C/diagnóstico , Hepatite C/virologia , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Mannan-binding lectin (MBL) - associated serine protease 2 (MASP-2) co-activates the lectin pathway of complement in response to several viral infections. The quality of this response partly depends on MASP2 gene polymorphisms, which modulate MASP-2 function and serum levels. In this study we investigated a possible role of MASP2 polymorphisms, MASP-2 serum levels and MBL-mediated complement activation in the susceptibility to HIV/AIDS and HBV/HCV coinfection. METHODS: A total of 178 HIV patients, 89 (50%) coinfected with HBV/HCV, 51.7% female, average age 40 (12-73) years, and 385 controls were evaluated. MASP-2 levels and MBL-driven complement activation were evaluated by enzyme-linked immunosorbent assay and 11 MASP2 polymorphisms from the promoter to the last exon were haplotyped using multiplex sequence-specific PCR. RESULTS: Genotype distribution was in Hardy-Weinberg equilibrium and differed between HIV+ patients and controls (P=0.030), irrespective of HBV or HCV coinfection. The p.126L variant, which was associated with MASP-2 levels <200ng/mL (OR=5.0 [95%CI=1.3-19.2] P=0.019), increased the susceptibility to HIV infection (OR=5.67 [95%CI=1.75-18.33], P=0.004) and to HIV+HBV+ status (OR=6.44 [95%CI=1.69-24.53, P=0.006). A similar association occurred with the ancient haplotype harboring this variant, AGCDV (OR=2.35 [95%CI=1.31-4.23], P=0.004). On the other hand, p.126L in addition to other variants associated with low MASP-2 levels-p.120G, p.377A and p.439H, presented a protective effect against AIDS (OR=0.25 [95%CI=0.08-0.80], P=0.020), independently of age, sex, hepatic function and viral load. MASP-2 serum levels were lower in HIV+ and HIV+HBV+ patients than in controls (P=0.0004). Among patients, MASP-2 levels were higher in patients with opportunistic diseases (P=0.001) and AIDS (P=0.004). MASP-2 levels correlated positively with MBL/MASP2-mediated C4 deposition (r=0.29, P=0.0002) and negatively with CD4+ cell counts (r=-0.21, P=0.018), being related to decreased CD4+ cell counts (OR=5.8 [95%CI=1.23-27.5, P=0.026). CONCLUSIONS: Genetically determined MASP-2 levels seem to have a two-edge effect in HIV and probably HCV/HBV coinfection, whereas low levels increase the susceptibility to infection, but on the other side protects against AIDS.
Assuntos
Infecções por HIV/genética , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Síndrome da Imunodeficiência Adquirida/enzimologia , Síndrome da Imunodeficiência Adquirida/genética , Síndrome da Imunodeficiência Adquirida/imunologia , Adolescente , Adulto , Idoso , Criança , Coinfecção/enzimologia , Coinfecção/genética , Coinfecção/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Predisposição Genética para Doença/genética , Genótipo , Infecções por HIV/enzimologia , Infecções por HIV/imunologia , Hepatite B/enzimologia , Hepatite B/genética , Hepatite B/imunologia , Hepatite C/enzimologia , Hepatite C/genética , Hepatite C/imunologia , Humanos , Masculino , Serina Proteases Associadas a Proteína de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
The lectin pathway of the complement system has a pivotal role in the defense against infectious organisms. After binding of mannan-binding lectin (MBL), ficolins or collectin 11 to carbohydrates or acetylated residues on pathogen surfaces, dimers of MBL-associated serine proteases 1 and 2 (MASP-1 and MASP-2) activate a proteolytic cascade, which culminates in the formation of the membrane attack complex and pathogen lysis. Alternative splicing of the pre-mRNA encoding MASP-1 results in two other products, MASP-3 and MAp44, which regulate activation of the cascade. A similar mechanism allows the gene encoding MASP-2 to produce the truncated MAp19 protein. Polymorphisms in MASP1 and MASP2 genes are associated with protein serum levels and functional activity. Since the first report of a MASP deficiency in 2003, deficiencies in lectin pathway proteins have been associated with recurrent infections and several polymorphisms were associated with the susceptibility or protection to infectious diseases. In this review, we summarize the findings on the role of MASP polymorphisms and serum levels in bacterial, viral and protozoan infectious diseases.
Assuntos
Infecções Bacterianas/imunologia , Serina Proteases Associadas a Proteína de Ligação a Manose/imunologia , Infecções por Protozoários/imunologia , Viroses/imunologia , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Lectina de Ligação a Manose da Via do Complemento/genética , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Polimorfismo Genético , Infecções por Protozoários/genética , Infecções por Protozoários/parasitologia , Infecções por Protozoários/patologia , Transdução de Sinais , Viroses/genética , Viroses/patologia , Viroses/virologiaRESUMO
MASP-2 is a key protein of the lectin pathway of complement system. Several MASP2 polymorphisms were associated with MASP-2 serum levels or functional activity. Here we investigated a possible association between MASP2 polymorphisms and MASP-2 serum levels with the susceptibility to rheumatic fever (RF) and rheumatic heart disease (RHD). We haplotyped 11 MASP2 polymorphisms with multiplex sequence-specific PCR in 145 patients with history of RF from south Brazil (103 with RHD and 42 without cardiac lesion [RFo]) and 342 healthy controls. MASP-2 levels were determined by ELISA. The low MASP-2 producing p.377A and p.439H variants were negatively associated with RF (P=0.02, OR=0.36) and RHD (P=0.01, OR=0.25). In contrast, haplotypes that share the intron 9 - exon 12 g.1961795C, p.371D, p.377V and p.439R polymorphisms increased the susceptibility to RHD (P=0.02, OR=4.9). MASP-2 levels were associated with MASP2 haplotypes and were lower in patients (P<0.0001), which may reflect protein consumption due to complement activation. MASP2 gene polymorphisms and protein levels seem to play an important role in the development of RF and establishment of RHD.
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Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Febre Reumática/genética , Cardiopatia Reumática/genética , Adolescente , Adulto , Sequência de Bases , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos/genética , Humanos , Masculino , Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Febre Reumática/sangue , Cardiopatia Reumática/sangue , Análise de Sequência de DNA , Adulto JovemRESUMO
Variations in genes involved in the immune response pathways may influence the interaction between viruses (such as Human T-lymphotropic virus, HTLV-1) and the host. The mannose binding lectin (MBL) and its associated serine protease type 2 (MASP-2) promote the activation of the lectin pathway of the complement system. As the interaction of complement system with HTLV-1 is not well understood, the MBL2 promoter/exon 1 polymorphisms and a MASP2 missense polymorphism were examined in a Northeast Brazilian population, looking for a possible relationship between these variations and the susceptibility to HTLV-1 infection. The present study describes an association between a polymorphism in the MASP2 gene and susceptibility to HTLV-1 infection, and provides further evidence of an association between the MBL2 gene and HTLV-1 infection. These findings suggest an important role of the complement system activation, via the lectin pathway, in the susceptibility to HTLV-1 infection.
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Predisposição Genética para Doença , Infecções por HTLV-I/genética , Infecções por HTLV-I/imunologia , Lectina de Ligação a Manose/genética , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Polimorfismo Genético , Adulto , Brasil , Proteínas do Sistema Complemento/imunologia , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Regiões Promotoras Genéticas , Adulto JovemRESUMO
Purpose To screen proteins/peptides in urine of Renal Cell Carcinoma (RCC) patients by SELDI-TOF (Surface Enhanced Laser Desorption Ionization - Time of Flight) in search of possible biomarkers. Material and Methods Sixty-one urines samples from Clear Cell RCC and Papillary RCC were compared to 29 samples of control urine on CM10 chip. Mass analysis was performed in a ProteinChip Reader PCS 4,000 (Ciphergen Biosystems, Fremont, CA) with the software Ciphergen Express 3.0. All chips were read at low and at high laser energy. For statistical analysis the urine samples were clustered according to the histological classification (Clear Cell and Papillary Carcinoma). For identification urine was loaded on a SDS PAGE gel and bands of most interest were excised, trypsinized and identified by MS/MS. Databank searches were performed in Swiss-Prot database using the MASCOT search algorithm and in Profound. Results Proteins that were identified from urine of controls included immunoglobulin light chains, albumin, secreted and transmembrane 1 precursor (protein K12), mannan-binding lectin-associated serine protease-2 (MASP-2) and vitelline membrane outer layer 1 isoform 1. Identification of immunoglobulins and isoforms of albumin are quite common by proteomics and therefore cannot be considered as possible molecular markers. K12 and MASP-2 play important physiological roles, while vitellite membrane outer layer 1 role is unknown since it was never purified in humans. Conclusions The down expression of Protein K-12 and MASP-2 make them good candidates for RCC urine marker and should be validated in a bigger cohort including the other less common histological RCC subtypes. .