Lectin Pathway Of Complement System Research Articles

Molecular evolution and functional characterization of the Lamprey Mannose-binding Lectin-associated Serine Protease 1-1ike (L-MASP1-like)

Mannose-binding Lectin-associated Serine Proteases (MASPs) play important roles in the lectin pathway of complement system. In this study, a MASP homologous was cloned and characterized from lamprey. Homology comparison of MASP1 and MASP2 sequences from other species and phylogenetic analysis showed that the lamprey MASP gene is probably the MASP1 homologue and was named L-MASP1-like. There is no motif17 in L-MASP1-like just as MASP1. The exon composition and the synteny analysis of MASP2 gene was different from that of MASP1. Comparison of the exon numbers and the overlapping location between the exons and the structural domain indicated that L-MASP1-like had its own uniqueness. The adjacent genes of L-MASP1-like display great changes in the arrangement pattern compared with jawed vertebrates. L-MASP1-like was mainly detected in liver, intestine, and kidney. Expression of L-MASP1-like was up-regulated in liver after lamprey was challenged by S. aureus. L-MASP1-like was also up-regulated in liver, intestine, and kidney after Aeromonas, Shewanella, and LPS stimulation. Furthermore, the lamprey serum depleted of L-MASP1-like protein inhibited the apoptosis of MCF-7 cells revealed by flow cytometry analysis. In summary, this study provides a novel understanding of L-MASP1-like in the prospects of the molecular evolution, its potential role in lamprey immune response, and the involvement in promoting cell apoptosis.

The lectin pathway of complement and the initial recognition of Leishmania infantum promastigotes

Visceral leishmaniasis (VL) is a neglected and highly lethal disease. VL is endemic in South American countries, with Brazil being responsible for 96% of the cases. In this continent, VL is caused by the protozoan Leishmania (Leishmania) infantum (L. infantum), transmitted by the bite of infected female phlebotomine sandflies. Immediately after the inoculation of L.infantum promastigotes into the vertebrate host, the complement, as part of the first line of innate response, becomes activated. L. infantum promastigotes glycocalyx is rich in carbohydrates that can activate the lectin pathway of complement system. In this study, we evaluated whether the lectin pathway collectins [manose binding lectin (MBL) and collectin-11 (CL-11)] and ficolins (-1, -2 and -3) interact with L.infantum promastigotes, using confocal microscopy and flow cytometry. The binding of MBL, CL-11 and ficolins -1 and -3, but not ficolin-2, was observed on the surface of live metacyclic promastigotes after incubation with normal human serum (NHS) or recombinant proteins. C3 and C4 deposition as well as complement mediated lyses was also demonstrated after interaction with NHS. These results highlight a role for collectins and ficolins in the initial immune response to L.infantum.

Mannose-binding lectin polymorphisms and rheumatoid arthritis: A short review and meta-analysis.

Mannose-binding lectin (MBL) is a pattern recognition receptor of the lectin pathway of complement system. MBL binds to carbohydrates on microorganism's surfaces leading to complement activation, opsonization and phagocytosis. Polymorphisms in the MBL gene (MBL2) are associated with variations on MBL serum levels and with the susceptibility to various infectious and autoimmune diseases. The involvement of the lectin pathway in rheumatoid arthritis (RA) has been demonstrated by several studies and although MBL has been considered to have a dual role in the pathogenesis of the disease, the association between MBL and RA remains inconclusive. In an attempt to clarify this relationship, we developed this short review summarizing accumulated evidences in regard to MBL and RA and a meta-analysis to evaluate the influence of MBL2 polymorphisms on the susceptibility to RA. Among a total of 217 articles that were identified following a predefined search strategy on PubMed, Scopus, Scielo, EMBASE and Cochrane databases, only 13 met all inclusion criteria and were included in the meta-analysis. Data assessment was conducted by three independent investigators and presented in odds ratio (OR) and 95% confidence intervals (CIs) using forest plot charts. Both heterogeneity and publication bias were analyzed. The results of the meta-analysis evidenced that MBL2 low producing OO and XX genotypes do not confer higher risk to RA, even when data were analyzed according to cohort's ethnicity. Further studies are needed in order to clarify the importance of other genes of the lectin pathway in the pathogenesis of RA.

Studies of the binding of ficolin-2 and ficolin-3 from the complement lectin pathway to Leptospira biflexa, Pasteurella pneumotropica and Diarrheagenic Escherichia coli

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.

Association of MASP2 polymorphisms and protein levels with rheumatic fever and rheumatic heart disease

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.