Search

Objectives The human mannose-binding lectin ( MBL) and ficolins ( FCN) are involved in pathogen recognition in the first line of defence. They support activation of the complement lectin cascade in the presence of MBL-associated serine protease 2 ( MASP-2), a protein that cleaves the C4 and C2 complement components. Recent studies found that distinct MBL2 and FCN2 promoter variants and their corresponding serum levels are associated with relative protection from urogenital schistosomiasis. Methods We investigated the contribution of MASP-2 levels and MASP2 polymorphisms in a Nigerian study group, of 163 individuals infected with Schistosoma haematobium and 183 healthy subjects. Results MASP-2 serum levels varied between younger children (≤12 years) and older children (>12 years) and adults ( P = 0.0001). Younger children with a patent infection had significantly lower MASP-2 serum levels than uninfected children ( P = 0.0074). Older children and adults (>12 years) with a current infection had higher serum MASP-2 levels than controls ( P = 0.032). MBL serum levels correlated positively with MASP-2 serum levels ( P = 0.01). MASP2 secretor haplotypes were associated with MASP-2 serum levels in healthy subjects. The heterozygous MASP2 p.P126L variant was associated with reduced serum MASP-2 levels ( P = 0.01). Conclusions The findings indicate that higher MASP-2 serum levels are associated with relative protection from urogenital schistosomiasis in Nigerian children. [ABSTRACT FROM AUTHOR]

The lectin pathway (LP) of complement has a protective function against invading pathogens. Recent studies have also shown that the LP plays an important role in ischemia/reperfusion (I/R)-injury. MBL-associated serine protease (MASP)-2 appears to be crucial in this process. The serpin C1-inhibitor is the major inhibitor of MASP-2. In addition, aprotinin, a Kunitz-type inhibitor, was shown to inhibit MASP-2 activity in vitro. In this study we investigated whether the Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI) is also able to inhibit MASP-2. Ex vivo LP was induced and detected by C4-deposition on mannan-coated plates. The MASP-2 activity was measured in a fluid-phase chromogenic assay. rTFPI in the absence or presence of specific monoclonal antibodies was used to investigate which TFPI-domains contribute to MASP-2 inhibition. Here, we identify TFPI as a novel selective inhibitor of MASP-2, without affecting MASP-1 or the classical pathway proteases C1s and C1r. Kunitz-2 domain of TFPI is required for the inhibition of MASP-2. Considering the role of MASP-2 in complement-mediated I/R-injury, the inhibition of this protease by TFPI could be an interesting therapeutic approach to limit the tissue damage in conditions such as cerebral stroke, myocardial infarction or solid organ transplantation. [ABSTRACT FROM AUTHOR]

The mannose-binding lectin (MBL) pathway of complement system is activated when carbohydrate-bound MBL forms complexes with different serine proteases (MASP-1, MASP-2 and MASP-3), among which MASP-2 has a predominant functional role. Polymorphisms impairing the quantity and/or the functional activity of proteins encoded by the MBL2 and MASP2 genes have been reported in all human populations showing different allelic frequency and distribution. This likely reflects the existence of environmental influences on MBL2 and MASP2 genetic evolution. Herewith, we conducted a study in a children population from Mozambique to analyse the genetic diversity of sequences corresponding to the promoter and collagen-like region (exon 1) of MBL2 and to the CUB-1 and epidermal growth factor domain (exon 3) of MASP2, which are critical regions for the formation of functional MBL/MASP-2 complexes. Our results show a high prevalence of MBL-intermediate/low genotypes (43.5%); the description of new alleles and a high level of sequence polymorphism at both MBL2 and MASP2, with no statistical evidence for positive or balancing selection. Furthermore, Biacore analyses performed to explore the functional relevance of the MASP2 variants found [T73M (2.9%), R84Q (12.7%) and P111L (25.4%)] were compared with those of two previously reported variants (R103C and D105G). None of the analysed MASP2 variants, with the exception of D105G, interfered with interactions with either MBL or ficolins (H and L). [ABSTRACT FROM AUTHOR]