RESUMO
Ficolins recognize pathogen associated molecular patterns and activate the lectin pathway of complement system. However, our knowledge regarding pathogen recognition of human ficolins is still limited. We therefore set out to explore and investigate the possible interactions of the two main serum ficolins, ficolin-2 and ficolin-3 with different Gram-negative bacteria. We used recombinant ficolin molecules and normal human serum, which were detected with anti-ficolin monoclonal antibodies. In addition we investigated the capacity of these pathogens to activate the lectin pathway of complement system. We show for the first time that human ficolin-2 recognizes the nonpathogenic spirochete Leptospira biflexa serovar Patoc, but not the pathogenic Leptospira interrogans serovar Kennewicki strain Fromm. Additionally, human ficolin-2 and ficolin-3 recognize pathogenic Pasteurella pneumotropica, enteropathogenic Escherichia coli (EPEC) serotype O111ab:H2 and enteroaggregative E. coli (EAEC) serogroup O71 but not four enterohemorrhagic E. coli, three EPEC, three EAEC and two nonpathogenic E. coli strains (DH5α and HB101). The lectin pathway was activated by Pasteurella pneumotropica, EPEC O111ab:H2 and EAEC O71 after incubation with C1q depleted human serum. In conclusion, this study provide novel insight in the binding and complement activating capacity of the lectin pathway initiation molecules ficolin-2 and ficolin-3 towards relevant Gram-negative pathogens of pathophysiological relevance.
Assuntos
Lectina de Ligação a Manose da Via do Complemento/imunologia , Escherichia coli/imunologia , Glicoproteínas/imunologia , Lectinas/imunologia , Leptospira/imunologia , Pasteurella pneumotropica/imunologia , Humanos , Proteínas Recombinantes/imunologia , FicolinasRESUMO
Mannose-binding lectin (MBL) is one of the five recognition molecules in the lectin complement pathway. Common variant alleles in the promoter and structural regions of the human MBL gene (MBL2) influence the stability and serum concentration of the protein. Epidemiological studies have shown that MBL2 variant alleles are associated with susceptibility to and the course of different types of infectious and inflammatory conditions. However, it has been suggested that these alleles are maintained in different populations due to selected advantages for carriers. We investigated the MBL2 allelic variation in indigenous individuals from 12 different West Central South America localities spanning from the desert coast, high altitude Andean plates and the Amazon tropical forest within the territories of Peru (nâ=â249) (Departments of Loreto, Ucayali, Lambayeque, Junin, Ayacucho, Huancayo and Puno), and Ecuador (nâ=â182) (Region of Esmeraldas and Santo Domingo de los Colorados). The distribution of MBL2 genotypes among the populations showed that the defective variant LYPB haplotype was very common. It showed the highest frequencies in Puno (Taquile (0.80), Amantani (0.80) and Anapia (0.58) islander communities of the Lake Titicaca), but lower frequencies of 0.22 in Junin (Central Andean highland) and Ucayali (Central Amazonian forest), as well as 0.27 and 0.24 in the Congoma and Cayapa/Chachis populations in the Amazonian forest in Ecuador were also observed. Our results suggest that the high prevalence of the MBL2 LYPB variant causing low levels of functional MBL in serum may mainly reflect a random distribution due to a population bottleneck in the founder populations.
Assuntos
Indígena Americano ou Nativo do Alasca/genética , Lectina de Ligação a Manose/genética , Alelos , Suscetibilidade a Doenças , Equador , Frequência do Gene , Genótipo , Haplótipos , Humanos , Lectina de Ligação a Manose/sangue , Peru , Polimorfismo de Nucleotídeo Único , Multimerização ProteicaRESUMO
El gen MBL (Mannose Binding Lectin) codifica una proteína de la inmunidad innata que activa el sistema del complemento, así como recluta macrófagos y quimioquinas proinflamatorias. Estudios realizados en otras latitudes han asociado susceptibilidad o resistencia a enfermedades infecciosas, autoinmunes y cardiovasculares con alelos deficientes de MBL. Sin embargo, muchos estudios no son concluyentes debido a la rareza de estos alelos en las poblaciones estudiadas. Previamente hemos demostrado que en las islas del Lago Titicaca, el alelo deficiente B tiene la más alta prevalencia del mundo. Por ello, queremos corroborar su presencia en zonas más cálidas que son más propicias a enfermedades infecciosas. Para ello se analizó el genotipo de 94 individuos procedentes de la región amazónica de Andoas-Loreto. Aunque en menor proporción que en las islas del Lago Titicaca, la frecuencia de la variante deficiente B en Andoas es más alta que en otras poblaciones del mundo. Esta frecuencia y su gran exposición a enfermedades tropicales, hacen de Andoas una población interesante para estudiar el rol de las variantes de MBL en el desarrollo de las mismas.
The gene MBL codifies for a protein that has a role in innate immunity by activating the complement system as well as recruiting macrophages and proinflammatory chemokines. Studies performed around the world have associated susceptibility/resistance to infectious, autoimmune and cardiovascular diseases, with deficient alleles of MBL. However, many of these studies remain inconclusive because of the rarity of these alleles. We have previously shown that the frequency of defective allele B in the islands of Lake Titicaca is the highest in the world. Now, we want to evaluate the frequency of this allele in Amazonian areas that are more prone to infectious diseases. We have genotyped 94 individuals from Andoas-Loreto and found a higher frequency of the defective allele B compared to other populations (but lower than that from Lake Titicaca). This frequency and the high exposure to tropical diseases make the population of Andoas interesting to study the role of the MBL variants in the development these diseases.
Assuntos
Humanos , Masculino , Adolescente , Adulto , Feminino , Pré-Escolar , Criança , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Genótipo , Genética Populacional , Etnicidade , Haplótipos , Imunidade Inata/genética , Lectina de Ligação a Manose/genética , Variação Genética , Epidemiologia Descritiva , Estudos TransversaisRESUMO
Se determinaron las combinaciones de variantes genéticas en 4 sitios del gen de la proteína asociada al sistema inmune MBL (mannose binding lectin), en 19 pobladores de las islas de Anapia-Suana del Lago Titicaca. Se encuentran solamente 3 combinaciones (haplotipos): LYPB, HYPA y LYPA y se observa alta frecuencia (0.58) del haplotipo defectuoso LYPB en las mencionadas islas sobrepasando a otras frecuencias previamente reportadas en el mundo. Este haplotipo es poco frecuente en poblaciones europeas, asiáticas y africanas. La deficiencia sérica de LYPB predispone a infecciones como tuberculosis, VIH-1 y a enfermedades autoinmunes como artritis reumatoide y lupus eritematoso entre otras. Con estos antecedentes nuestros futuros esfuerzos se dirigirán a investigar la razón de la alta frecuencia de LYPB en estas islas y determinar la de las otras islas aledañas.
We have analized the combination of variants at 4 sites of the gene MBL (mannose binding lectin) which is part of the immune system, in 19 normal individuals from the islands of Anapia-Suana in the Lake Titicaca. OnIy 3 combinations (haplotypes) were registered: LYPB, HYPA and LYPA; the proportion of the pressumed defective haplotype LYPB is 0.58 being the highest ever recorded. This haplotype is rare among European, Asian and African populations. It predisposes to infectious diseases as tuberculosis and AIDS as well as autoimmune diseases like reumatoid arthritis and lupus erithematosumo This finding lead our future efforts to elucidate the reason of this high frequency of LYPB and to determine its proportion in other islands of the Titicaca Lake.