RESUMEN
The Metropolitan Area of São Paulo (MASP) is among the largest urban areas in the Southern Hemisphere. Vehicular emissions are of great concern in metropolitan areas and MASP is unique due to the use of biofuels on a large scale (sugarcane ethanol and biodiesel). In this work, tunnel measurements were employed to assess vehicle emissions and to calculate emission factors (EFs) for heavy-duty and light-duty vehicles (HDVs and LDVs). The EFs were determined for particulate matter (PM) and its chemical compounds. The EFs obtained for 2018 were compared with previous tunnel experiments performed in the same area. An overall trend of reduction of fine and coarse PM, organic carbon (OC), and elemental carbon (EC) EFs for both LDVs and HDVs was observed if compared to those observed in past years, suggesting the effectiveness of vehicular emissions control policies implemented in Brazil. A predominance of Fe, Cu, Al, and Ba emissions was observed for the LDV fleet in the fine fraction. Cu presented higher emissions than two decades ago, which was associated with the increased use of ethanol fuel in the region. For HDVs, Zn and Pb were mostly emitted in the fine mode and were linked with lubricating oil emissions from diesel vehicles. A predominance in the emission of three- and four-ring polycyclic aromatic hydrocarbons (PAHs) for HDVs and five-ring PAHs for LDVs agreed with what was observed in previous studies. The use of biofuels may explain the lower PAH emissions for LDVs (including carcinogenic benzo[a]pyrene) compared to those observed in other countries. The tendency observed was that LDVs emitted higher amounts of carcinogenic species. The use of these real EFs in air quality modeling resulted in more accurate simulations of PM concentrations, showing the importance of updating data with real-world measurements.
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Contaminantes Atmosféricos , Hidrocarburos Policíclicos Aromáticos , Contaminantes Atmosféricos/análisis , Emisiones de Vehículos/análisis , Biocombustibles , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa , Monitoreo del Ambiente/métodos , Brasil , Material Particulado/análisis , Carbono/análisis , Hidrocarburos Policíclicos Aromáticos/análisis , EtanolRESUMEN
Recently, extreme wildfires have damaged important ecosystems worldwide and have affected urban areas miles away due to long-range transport of smoke plumes. We performed a comprehensive analysis to clarify how smoke plumes from Pantanal and Amazon forests wildfires and sugarcane harvest burning also from interior of the state of São Paulo (ISSP) were transported and injected into the atmosphere of the Metropolitan Area of São Paulo (MASP), where they worsened air quality and increased greenhouse gas (GHG) levels. To classify event days, multiple biomass burning fingerprints as carbon isotopes, Lidar ratio and specific compounds ratios were combined with back trajectories modeling. During smoke plume event days in the MASP fine particulate matter concentrations exceeded the WHO standard (>25 µg m-3), at 99 % of the air quality monitoring stations, and peak CO2 excess were 100 % to 1178 % higher than non-event days. We demonstrated how external pollution events such as wildfires pose an additional challenge for cities, regarding public health threats associated to air quality, and reinforces the importance of GHG monitoring networks to track local and remote GHG emissions and sources in urban areas.
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Contaminantes Atmosféricos , Contaminación del Aire , Incendios , Saccharum , Incendios Forestales , Contaminantes Atmosféricos/análisis , Brasil , Ecosistema , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/análisis , Contaminación del Aire/análisis , Material Particulado/análisis , Humo/análisis , Bosques , Monitoreo del AmbienteRESUMEN
Complement factor D (FD) is a rate-limiting enzyme of the alternative pathway (AP). Recent studies have suggested that it is synthesized as an inactive precursor and that its conversion to enzymatically active FD is catalyzed by mannan-binding lectin-associated serine protease 3 (MASP3). However, whether MASP3 is essential for AP complement activity remains uncertain. It has been shown that Masp1/3 gene knockout did not prevent AP complement overactivation in a factor H-knockout mouse, and a human patient lacking MASP3 still retained AP complement activity. In this study, we have assessed AP complement activity in a Masp3-knockout mouse generated by CRISPR/Cas9 editing of the Masp1/3 gene. We confirmed specific Masp3 gene inactivation by showing intact MASP1 protein expression and absence of mature FD in the mutant mice. Using several assays, including LPS- and zymosan-induced C3b deposition and rabbit RBC lysis tests, we detected plasma concentration-dependent AP complement activity in Masp3 gene-inactivated mice. Thus, although not measurable in 5% plasma, significant AP complement activity was detected in 20-50% plasma of Masp3 gene-inactivated mice. Furthermore, whereas FD gene deletion provided more than 90% protection of CD55/Crry-deficient RBCs from AP complement-mediated extravascular hemolysis, Masp3 gene deletion only provided 30% protection in the same study. We also found pro-FD to possess intrinsic catalytic activity, albeit at a much lower level than mature FD. Our data suggest that MASP3 deficiency reduces but does not abrogate AP complement activity and that this is explained by intrinsic pro-FD activity, which can be physiologically relevant in vivo.
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Lectina de Unión a Manosa , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa , Animales , Humanos , Ratones , Conejos , Factor D del Complemento/metabolismo , Vía Alternativa del Complemento/fisiología , Lectina de Unión a Manosa de la Vía del Complemento , Proteínas del Sistema Complemento , Ratones Noqueados , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genéticaRESUMEN
Repetitive elements cause assembly fragmentation in complex eukaryotic genomes, limiting the study of their variability. The genome of Trypanosoma cruzi, the parasite that causes Chagas disease, has a high repetitive content, including multigene families. Although many T. cruzi multigene families encode surface proteins that play pivotal roles in host-parasite interactions, their variability is currently underestimated, as their high repetitive content results in collapsed gene variants. To estimate sequence variability and copy number variation of multigene families, we developed a read-based approach that is independent of gene-specific read mapping and de novo assembly. This methodology was used to estimate the copy number and variability of MASP, TcMUC, and Trans-Sialidase (TS), the three largest T. cruzi multigene families, in 36 strains, including members of all six parasite discrete typing units (DTUs). We found that these three families present a specific pattern of variability and copy number among the distinct parasite DTUs. Inter-DTU hybrid strains presented a higher variability of these families, suggesting that maintaining a larger content of their members could be advantageous. In addition, in a chronic murine model and chronic Chagasic human patients, the immune response was focused on TS antigens, suggesting that targeting TS conserved sequences could be a potential avenue to improve diagnosis and vaccine design against Chagas disease. Finally, the proposed approach can be applied to study multicopy genes in any organism, opening new avenues to access sequence variability in complex genomes. IMPORTANCE Sequences that have several copies in a genome, such as multicopy-gene families, mobile elements, and microsatellites, are among the most challenging genomic segments to study. They are frequently underestimated in genome assemblies, hampering the correct assessment of these important players in genome evolution and adaptation. Here, we developed a new methodology to estimate variability and copy numbers of repetitive genomic regions and employed it to characterize the T. cruzi multigene families MASP, TcMUC, and transsialidase (TS), which are important virulence factors in this parasite. We showed that multigene families vary in sequence and content among the parasite's lineages, whereas hybrid strains have a higher sequence variability that could be advantageous to the parasite's survivability. By identifying conserved sequences within multigene families, we showed that the mammalian host immune response toward these multigene families is usually focused on the TS multigene family. These TS conserved and immunogenic peptides can be explored in future works as diagnostic targets or vaccine candidates for Chagas disease. Finally, this methodology can be easily applied to any organism of interest, which will aid in our understanding of complex genomic regions.
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Enfermedad de Chagas , Trypanosoma cruzi , Humanos , Animales , Ratones , Trypanosoma cruzi/genética , Variaciones en el Número de Copia de ADN , Genoma de Protozoos , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Familia de Multigenes , Enfermedad de Chagas/parasitología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mamíferos/genéticaRESUMEN
INTRODUCTION: Chagas disease (CD), caused by Trypanosoma cruzi, is a major public health issue worldwide affecting 6-7 million people, mainly in Latin America. The complement system plays a crucial role in host immune defense against T. cruzi infection and during the chronic phase of CD; however, the role of the MBL-associated serine protease 1 (MASP1) gene encoding MASP-1, MASP-3, and MAp44 complement proteins has not yet been reported in CD. This study investigated the possible association between MASP1 gene polymorphisms and MASP-3 protein serum levels in chronic CD and its clinical forms. METHODS: Five polymorphisms of MASP1 gene regulatory regions were genotyped in 214 patients with CD and 197 healthy controls (rs7609662 G>A, rs13064994 C>T, rs72549262 C>G, rs1109452 C>T and rs850314 G>A). MASP-3 serum levels were assessed in 70 patients and 66 healthy controls. Clinical data, serum levels of complement proteins (ficolin-2, ficolin-3 and MBL) and inflammatory markers (pentraxin-3 and hsCRP) were also included in the analyses. RESULTS: A significant association of the MASP1 GC_CCA haplotype with CD (padj= 0.002; OR 3.17 [1.19-8.39]) and chronic chagasic cardiomyopathy (CCC) (padj= 0.013; OR 4.57 [1.37-15.16] was observed. MASP-3 and pentraxin-3 levels were positively correlated in the patients (rho = 0.62; p = 0.0001). MASP-3 levels were not associated with MASP1 polymorphisms or CD and its clinical forms. Furthermore, no correlation was observed between MASP-3 levels and that of ficolin-2, ficolin-3, MBL and hsCRP. CONCLUSION: Our findings suggest a possible role for the MASP1 GC_CCA haplotype in susceptibility to chronic CD and CCC clinical forms.
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Enfermedad de Chagas , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa , Proteína C-Reactiva , Enfermedad de Chagas/genética , Proteínas del Sistema Complemento , Humanos , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/metabolismo , Polimorfismo GenéticoRESUMEN
Trypanosoma cruzi, the etiological agent of Chagas disease (CD), is a heterogeneous species with high genetic and phenotypic diversity. MASP is the second largest multigene family of T. cruzi. The high degree of polymorphism of the family associated with its location at the surface of infective forms of T. cruzi suggests that MASP participates in mechanisms of host-parasite interaction. In this work, MASP members were divided into 7 subgroups based on protein sequence similarity, and one representative member from each subgroup was chosen to be expressed recombinantly. Immunogenicity of recombinant MASP proteins (rMASP) was investigated using different sera panels from T. cruzi infected mice. To mimic a natural condition in which different MASP members are expressed at the same time in the parasite population, a multiplex bead-based flow cytometry assay was also standardized. Results showed that rMASPs are poorly recognized by sera from mice infected with Colombiana strain, whereas sera from mice infected with CL Brener and Y display high reactivity against the majority of rMASPs tested. Flow cytometry showed that MASP recognition profile changes 10 days after infection. Also, multiplex assay suggests that MASP M1 and M2 are more immunogenic than the other MASP members evaluated that may play an immunodominant role during infection.
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Enfermedad de Chagas , Trypanosoma cruzi , Animales , Variación Antigénica , Enfermedad de Chagas/parasitología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/metabolismo , Ratones , Proteínas Protozoarias/metabolismo , Trypanosoma cruzi/genética , Trypanosoma cruzi/metabolismoRESUMEN
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)
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Humanos , Ensayo de Inmunoadsorción Enzimática , Barrera Hematoencefálica , Líquido Cefalorraquídeo/fisiología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa , Manosa , Estudios Transversales , Estudios ProspectivosRESUMEN
The aim of this systematic review and meta-analysis was to pool the data on Single Nucleotide Polymorphisms (SNPs) in immune response genes associated with dental caries. Nineteen studies were included in the review and 18 in the meta-analysis. Twenty-two SNPs were evaluated, which are linked to six different genes (MBL2, LFT, MASP2, DEFB1, FCN2 and MUC5B). Most SNPs (81.8%) are related to the possible functional impact on protein coding. The MBL2 gene was associated with caries experience in the analysis of the homozygote (OR = 2.12 CI95%[1.12-3.99]) and heterozygote (OR = 2.22 CI95%[1.44-3.44]) genotypes. The MUC5B gene was associated according to an analysis of the heterozygous genotype (OR = 1.83 CI95%[1.08-3.09]). Thus, SNPs related to immune response genes are linked to the phenotype of caries experience. Although the meta-analysis showed that the genes MBL2 and MUC5B were associated with caries, these results should be interpreted with caution due to the quality of the evidence.
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Caries Dental , Caries Dental/genética , Susceptibilidad a Caries Dentarias , Genotipo , Humanos , Inmunidad , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa , Polimorfismo de Nucleótido Simple , beta-DefensinasRESUMEN
BACKGROUND: Deposition of complement factors on Mycobacterium leprae may enhance phagocytosis. Such deposition may occur through the lectin pathway of complement. Three proteins of the lectin pathway are produced from the gene MASP1: Mannan-binding lectin-associated serine protease 1 (MASP-1) and MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44). Despite their obvious importance, the roles played by these proteins have never been investigated in leprosy disease. METHODOLOGY: We haplotyped five MASP1 polymorphisms by multiplex sequence-specific PCR (intronic rs7609662*G>A and rs13064994*C>T, exon 12 3'-untranslated rs72549262*C>G, rs1109452*C>T and rs850314*G>A) and measured MASP-1, MASP-3 and MAp44 serum levels in 196 leprosy patients (60%, lepromatous) and 193 controls. PRINCIPAL FINDINGS: Lower MASP-3 and MAp44 levels were observed in patients, compared with controls (P = 0.0002 and P<0.0001, respectively) and in lepromatous, compared with non-lepromatous patients (P = 0.008 and P = 0.002, respectively). Higher MASP-3 levels were present in controls carrying variants/haplotypes associated with leprosy resistance (rs13064994*T, rs1109452_rs850314*CG within GT_CCG and rs850314*A: OR = 0.5-0.6, Pcorr = 0.01-0.04). Controls with rs1109452*T, included in susceptibility haplotypes (GT_GTG/GT_CTG: OR = 2.0, Pcorr = 0.03), had higher MASP-1 and lower MASP-3 levels (P≤0.009). Those with GC_CCG, presented increasing susceptibility (OR = 1.7, Pcorr = 0.006) and higher MAp44 levels (P = 0.015). MASP-3 expression decreased in patients, compared with controls carrying rs1109452_rs850314*CA or CG (P≤0.02), which may rely on exon 12 CpG methylation and/or miR-2861/miR-3181 mRNA binding. CONCLUSION: Polymorphisms regulating MASP-3/MAp44 availability in serum modulate leprosy susceptibility, underlining the importance of lectin pathway regulation against pathogens that exploit phagocytosis to parasitize host macrophages.
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Predisposición Genética a la Enfermedad , Lepra/genética , Lepra/patología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/análisis , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Mycobacterium leprae/inmunología , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios Transversales , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Chagas Disease (CD) is an anthropozoonosis caused by Trypanosoma cruzi. With complex pathophysiology and variable clinical presentation, CD outcome can be influenced by parasite persistence and the host immune response. Complement activation is one of the primary defense mechanisms against pathogens, which can be initiated via pathogen recognition by pattern recognition molecules (PRMs). Collectin-11 is a multifunctional soluble PRM lectin, widely distributed throughout the body, with important participation in host defense, homeostasis, and embryogenesis. In complex with mannose-binding lectin-associated serine proteases (MASPs), collectin-11 may initiate the activation of complement, playing a role against pathogens, including T. cruzi. In this study, collectin-11 plasma levels and COLEC11 variants in exon 7 were assessed in a Brazilian cohort of 251 patients with chronic CD and 108 healthy controls. Gene-gene interactions between COLEC11 and MASP2 variants were analyzed. Collectin-11 levels were significantly decreased in CD patients compared to controls (p<0.0001). The allele rs7567833G, the genotypes rs7567833AG and rs7567833GG, and the COLEC11*GGC haplotype were related to T. cruzi infection and clinical progression towards symptomatic CD. COLEC11 and MASP2*CD risk genotypes were associated with cardiomyopathy (p = 0.014; OR 9.3, 95% CI 1.2-74) and with the cardiodigestive form of CD (p = 0.005; OR 15.2, 95% CI 1.7-137), suggesting that both loci act synergistically in immune modulation of the disease. The decreased levels of collectin-11 in CD patients may be associated with the disease process. The COLEC11 variant rs7567833G and also the COLEC11 and MASP2*CD risk genotype interaction were associated with the pathophysiology of CD.
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Enfermedad de Chagas/genética , Enfermedad de Chagas/fisiopatología , Colectinas/genética , Epistasis Genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Adulto , Anciano , Anciano de 80 o más Años , Brasil , Estudios de Casos y Controles , Colectinas/sangre , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Background: MBL-associated serine proteases (MASP-1, MASP-2, MASP-3, MAp-44, and MAp-19) are key factors in the activation of the lectin pathway of complement. Serum levels of these components have been associated with recurrence and poor survival of some types of cancer, such as colorectal and ovarian cancer. In this investigation, we determined the serum levels of MASP-1, MASP-2, MASP-3, MAp-44, and MAp-19 in patients with cervical cancer and cervical intraepithelial neoplasia (CIN). Methods:A total of 351 women who underwent screening for cervical cancer or treatment at the Erasto Gaertner Cancer Hospital in Curitiba-Brazil, were enrolled in the study. Based on their latest cervical colposcopy-guided biopsy results, they were divided into four groups: CIN-I: n = 52; CIN-II: n = 73; CIN-III: n = 141; and invasive cancer: n = 78. All the serum protein levels were determined by time-resolved immunofluorometric assay (TRIFMA). Results:Patients with invasive cancer presented significantly higher MASP-2, MASP-1, and MAp-19 serum levels than other groups (p < 0.0001; p = 0.012; p = 0.025 respectively). No statistically significant differences in MASP-3 and MAp-44 serum levels were found between the four studied groups. In addition, high MASP-2, MASP-1, and MAp-19 serum levels were significantly associated with poor survival in patients with invasive cancer and relapse (p = 0.002, p = 0.0035 and p = 0.025, respectively). Conclusion:High MASP-2, MASP-1, and MAp-19 serum levels were associated with cervical cancer progression and worse disease prognosis. These novel findings demonstrate the involvement of the serine proteases of the lectin pathway in the pathogenesis of cervical cancer and future investigations should clarify their role in the disease process.
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Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/metabolismo , Proteínas de Neoplasias/sangre , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/mortalidad , Estudios Transversales , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Tasa de Supervivencia , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapiaRESUMEN
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.
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Haplotipos , Hepacivirus , Hepatitis C/genética , Hepatitis C/metabolismo , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Estudios de Casos y Controles , Exones , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Hepacivirus/genética , Hepatitis C/diagnóstico , Hepatitis C/virología , Humanos , Intrones , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
ntroducción: El sistema del complemento puede ser activado por tres vías: clásica, alternativa y de las lectinas, esta última en fase de estudio para su completamiento. Objetivo: Describir hasta donde se ha avanzado en la construcción de la vía de las lectinas, sus iniciadores, activadores, reguladores, cascada enzimática y sus funciones biológicas. Metodología: Se realizó una revisión sobre el tema en estudio empleando artículos de libre acceso en la base de datos Pubmed y los trabajos publicados por el grupo de trabajo de la Universidad de Goettigen, la Universidad de Aarhus en Dinamarca y el Laboratorio Central de Líquido Cefalorraquídeo (LABCEL) de la Universidad de Ciencias Médicas de La Habana en los últimos cinco años comprendidos en el período de enero de 2012 a marzo del 2017. Desarrollo: Los iniciadores de la vía de las lectinas son las moléculas de reconocimiento colectinas y ficolinas circulantes en sangre, que participan en muchos procesos del organismo. Los activadores de esta vía son las MASP 1, 2 presentes como proenzimas; y la MASP 3, MAp 19 y 44 actúan como reguladoras. La cascada enzimática luego del reconocimiento es similar a la ruta clásica. Conclusiones: Las colectinas y ficolinas inician la vía de las lectinas. Sus activadores son las MASP 1, 2. Los reguladores son la MASP-3, y las MAp 19 y 44. Similar a la clásica en su cascada enzimática. Es la más antigua en la filogenia por eso participa en muchos procesos en el organismo(AU)
Introduction. The complement system can be activated in three ways: classical, alternative and lectins, the latter in the study phase for its completion. Objective. To describe the progress made in the construction of the lectin pathway, its initiators, activators, regulators, enzymatic cascade and its biological functions. Methods. A review was made on the subject under study using articles of free access in the Pubmed database and the works published by the working group of the University of Goettigen, the University of Aarhus in Denmark and the Central Laboratory of Cefalorraquìdeo liquid (LABCEL) of the University of Medical Sciences of Havana in the last five years included in the period from January 2012 to March 2017. Development. The initiators of the lectin pathway are the collectin recognition molecules and circulating ficolins in blood, which participate in many processes of the organism. The activators of this pathway are MASP 1, 2 present as proenzymes; and MASP 3, MAp 19 and 44 act as regulators. The enzymatic cascade after recognition is similar to the classical route. Conclusions. Collectins and ficolines initiate the lectin pathway. Its activators are MASP 1, 2. The regulators are MASP-3, and MAp 19 and 44. Similar to the classic in its enzymatic cascade. It is the oldest in phylogeny so it participates in many processes in the body.(AU)
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Humanos , Colectinas , Lectinas , Activadores de Enzimas , Serina Proteasas Asociadas a la Proteína de Unión a la ManosaRESUMEN
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.
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Infecciones por VIH/genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Síndrome de Inmunodeficiencia Adquirida/enzimología , Síndrome de Inmunodeficiencia Adquirida/genética , Síndrome de Inmunodeficiencia Adquirida/inmunología , Adolescente , Adulto , Anciano , Niño , Coinfección/enzimología , Coinfección/genética , Coinfección/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Infecciones por VIH/enzimología , Infecciones por VIH/inmunología , Hepatitis B/enzimología , Hepatitis B/genética , Hepatitis B/inmunología , Hepatitis C/enzimología , Hepatitis C/genética , Hepatitis C/inmunología , Humanos , Masculino , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/inmunología , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
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.
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Infecciones Bacterianas/inmunología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/inmunología , Infecciones por Protozoos/inmunología , Virosis/inmunología , Infecciones Bacterianas/genética , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/patología , Lectina de Unión a Manosa de la Vía del Complemento/genética , Proteínas del Sistema Complemento/genética , Proteínas del Sistema Complemento/inmunología , Regulación de la Expresión Génica/inmunología , Humanos , Lectina de Unión a Manosa/genética , Lectina de Unión a Manosa/inmunología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Polimorfismo Genético , Infecciones por Protozoos/genética , Infecciones por Protozoos/parasitología , Infecciones por Protozoos/patología , Transducción de Señal , Virosis/genética , Virosis/patología , Virosis/virologíaRESUMEN
DNA sequencing, nested polymerase chain reaction (PCR), and PCR-restriction fragment length polymorphism were used to investigate mutations in the coding regions of the bovine myeloid antimicrobial peptide-28 (BMAP-28) and mannan-binding lectin-associated serine protease-2 (MASP-2) genes in 249 Chinese Holstein dairy cows. The associations between the polymorphisms and somatic cell score (SCS) were analyzed to determine the potential of these genes as genetic markers for breeding mastitis-resistant dairy cattle. The results revealed a C-86G synonymous mutation in the BMAP-28 gene that caused no alteration in the amino acid sequence. G553A mutation was found in the MASP-2 gene that led to the substitution of glycine with serine. The chi-square test showed that the G553A mutation was in Hardy-Weinberg equilibrium in the Chinese Holstein dairy cows, whereas the C-86G mutation was not. The variance analysis of the influence of group loci and different genotypes on the SCS showed that the SCS of genotype CC was significantly lower than those of genotypes CG and GG (P < 0.05) of the C-86G mutation, and that the SCS of genotype GG was significantly lower than those of genotypes GA and AA (P < 0.05) of the G553A mutation. Genotype combination analysis showed that the combination of the BMAP-28 genotype CC and the MASP-2 genotype GG was the best one, in which the SCS was significantly lower than those in the other combinations. Thus, this combination might be useful as a molecular and genetic marker of mastitis in Chinese Holstein dairy cows.
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Bovinos/genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas/genética , Alelos , Animales , Secuencia de Bases , China , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Sitios Genéticos , Heterocigoto , Análisis de los Mínimos Cuadrados , Leche , Datos de Secuencia Molecular , Mutación/genética , Carácter Cuantitativo Heredable , Análisis de Secuencia de ADNRESUMEN
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 Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Fiebre Reumática/genética , Cardiopatía Reumática/genética , Adolescente , Adulto , Secuencia de Bases , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos/genética , Humanos , Masculino , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/metabolismo , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Fiebre Reumática/sangre , Cardiopatía Reumática/sangre , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
BACKGROUND: Mannan-binding lectin-associated serine protease 2 (MASP-2) is a key protein of the lectin pathway of complement. MASP-2 levels have been associated with different polymorphisms within MASP2 gene as well as with the risk for inflammatory disorders and infections. Despite its clinical importance, MASP-2 remains poorly investigated in rheumatoid arthritis (RA). METHODS: In this case-control study, we measured MASP-2 serum levels in 156 RA patients, 44 patient relatives, and 100 controls from Southern Brazil, associating the results with nine MASP2 polymorphisms in all patients, 111 relatives, and 230 controls genotyped with multiplex SSP-PCR. RESULTS: MASP-2 levels were lower in patients than in controls and relatives (medians 181 vs. 340 or 285 ng/ml, respectively, P<0.0001). Conversely, high MASP-2 levels were associated with lower susceptibility to RA and to articular symptoms independently of age, gender, ethnicity, smoking habit, anti-CCP and rheumatoid factor positivity (OR = 0.05 [95%CI = 0.019-0.13], P<0.0001 between patients and controls; OR = 0.12, [95%CI = 0.03-0.45], P = 0.002 between patients and relatives; OR = 0.06, [95%CI = 0.004-0.73], P = 0.03 between relatives with and without articular symptoms). MASP2 haplotypes *2A1 and *2B1-i were associated with increased susceptibility to RA (OR = 3.32 [95%CI = 1.48-7.45], P = 0.004). Deficiency-causing p.120G and p.439H substitutions were associated with five times increased susceptibility to articular symptoms in relatives (OR = 5.13 [95%CIâ= 1.36-20.84], P = 0.02). There was no association of MASP-2 levels or MASP2 polymorphisms with autoantibodies, Sjögren's syndrome, nodules and functional class. CONCLUSIONS: In this study, we found the first evidence that MASP-2 deficiency might play an important role in the development of RA and articular symptoms among relatives of RA patients.
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Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/metabolismo , Polimorfismo Genético/genética , Adulto , Anciano , Artritis Reumatoide/patología , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: The gene MASP2 (mannan-binding lectin (MBL)-associated serine protease 2) encodes two proteins, MASP-2 and MAp19 (MBL-associated protein of 19 kDa), bound in plasma to MBL and ficolins. The binding of MBL/MASP-2 and ficolin/MASP-2 complexes to microorganisms activates the lectin pathway of complement and may increase the ingestion of intracellular pathogens such as Mycobacterium leprae. METHODS: We haplotyped 11 MASP2 polymorphisms with multiplex sequence-specific PCR in 219 Brazilian leprosy patients (131 lepromatous, 29 borderline, 21 tuberculoid, 14 undetermined, 24 unspecified), 405 healthy Brazilians and 291 Danish blood donors with previously determined MASP-2 and MAp19 levels. We also evaluated MASP-2 levels in further 46 leprosy patients and 69 Brazilian controls. RESULTS: Two polymorphisms flanking exon 5 of MASP2 were associated with a dominant effect on high MASP-2 levels and an additive effect on low MAp19 levels. Patients presented lower MASP-2 levels (Pâ=â0.0012) than controls. The frequency of the p.126L variant, associated with low MASP-2 levels (below 200 ng/mL), was higher in the patients (Pâ=â0.0002, ORâ=â4.92), as was the frequency of genotypes with p.126L (Pâ=â0.00006, ORâ=â5.96). The *1C2-l [AG] haplotype, which harbors p.126L and the deficiency-causing p.439H variant, has a dominant effect on the susceptibility to the disease (Pâ=â0.007, ORâ=â4.15). Genotypes composed of the *2B1-i and/or *2B2A-i haplotypes, both associated with intermediate MASP-2 levels (200-600 ng/mL), were found to be protective against the disease (Pâ=â0.0014, ORâ=â0.6). Low MASP-2 levels (Pâ=â0.022), as well as corresponding genotypes with *1C2-l and/or *2A2-l but without *1B1-h or *1B2-h, were more frequent in the lepromatous than in other patients (Pâ=â0.008, ORâ=â8.8). CONCLUSIONS: In contrast with MBL, low MASP-2 levels increase the susceptibility to leprosy in general and to lepromatous leprosy in particular. MASP2 genotypes and MASP-2 levels might thus be of prognostic value for leprosy progression.
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Exones , Predisposición Genética a la Enfermedad , Haplotipos , Lepra/genética , Lepra/metabolismo , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/metabolismo , Polimorfismo Genético , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Brasil , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes , Orden Génico , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
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.