There is an emerging interest for mannose-binding lectin (MBL) due to its role in innate immunity. In this survey we present a mixture of old and new data describing the effect MBL polymorphisms may have on the level and function of the molecule. Three single nucleotide substitutions in exon 1 of the mbl2 gene cause a dominant decrease of functional MBL in the circulation. Additionally, promoter variants influence expression of MBL. It has been assumed that the structural variant alleles may disrupt the assembly of MBL trimers or accelerate the degradation of the protein, thereby causing the decrease in MBL serum concentrations. We have analysed 1183 different sera in a double sandwich antibody ELISA using the same antibody to capture and detect MBL and find the same results as have been presented previously showing that different MBL promoter alleles have profound effect of on the MBL serum concentration. The use of a new anti-MBL monoclonal antibody, however, has shown that the amount of MBL in the circulation is less dependent on the presence of structural variant alleles than previously anticipated. Molecular characterisation of MBL revealed that sera from donors homozygous for the normal MBL genotype predominantly contained high molecular weight MBL, while sera from individuals heterozygous for the variant alleles contained both high and low molecular weight MBL. The ratio between high and low molecular weight MBL was dependent on the MBL promoter type on the normal haplotype. Sera deriving from individuals homozygous for MBL variant alleles contained mainly low molecular weight MBL. Of the different oligomers of MBL only the high molecular weight forms bound mannan efficiently and activated complement. In contrast to a previous notion, we demonstrate that variant alleles give rise to relatively high levels of MBL in the circulation. However, the variant MBL has lower molecular weight and is dysfunctional compared to normal MBL. The physiological relevance of variant MBL remains to be established.
"Variants are denoted as D (codon 52), B (codon 54), and C (codon 57), whereas A is the common wild type allele (Garred et al., 2006). In addition, two other functional polymorphisms at promoter region of the MBL2 gene have been reported (−550: rs11003125,G > C, H/L and−221: rs7096206, C > G, X/Y) which have been shown to affect plasma MBL levels (Garred et al., 2003a). Furthermore, some reports have shown an association of combined exon1 and promoter MBL2 polymorphisms with plasma levels of MBL (Tsutsumi et al., 2001; Panda et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: Mannose binding lectin, a plasma protein protects host from virus, bacteria, and parasites. Deficiency in MBL levels has been associated with susceptibility to various infectious diseases including P. falciparum malaria. Common MBL polymorphisms in promoter and coding regions are associated with decrease in plasma MBL levels or production of deformed MBL, respectively. In the present study, we hypothesized that MBL2 variants and plasma MBL levels could be associated with different clinical phenotypes of severe P. falciparum malaria.
A hospital based study was conducted in eastern Odisha, India which is endemic to P. falciparum malaria. Common MBL-2 polymorphisms (codon 54, H-550L, and Y-221X) were typed in 336 cases of severe malaria (SM) [94 cerebral malaria (CM), 120 multi-organ dysfunction (MOD), 122 non-cerebral severe malaria (NCSM)] and 131 un-complicated malaria patients (UM). Plasma MBL levels were quantified by ELISA.
Severe malaria patients displayed lower plasma levels of MBL compared to uncomplicated falciparum malaria. Furthermore, on categorization of severe malaria patients into various subtypes, plasma MBL levels were very low in MOD patients compared to other categories. Higher frequency of AB genotype and allele B was observed in MOD compared to UM (AB genotype: P = 0.006; B allele: P = 0.008). In addition, prevalence of YX genotype of MBL Y-221X polymorphism was also statistically more frequent in MOD case than UM (P = 0.009).
The observations of the present study reveal that MBL-2 polymorphisms (codon 54 and Y-221X) and lower plasma MBL levels are associated with increased susceptibility to multi organ dysfunctions in P. falciparum malaria.
Frontiers in Microbiology 08/2015; 6. DOI:10.3389/fmicb.2015.00778 · 3.99 Impact Factor
"The presence of the X allele at position − 221 of the MBL2 promoter produces a lower amount of circulating MBL than that found in the presence of the Y allele. In addition, missense mutations in exon 1 abolish the assembly of the protein into its biologically active form   . "
[Show abstract][Hide abstract] ABSTRACT: Background
There is a considerable variation in the phenotype and course of the disease in cystic fibrosis (CF) even in patients with the same CFTR genotype, suggesting that other factors are important for prognosis. Mannose-binding lectin (MBL) has been proposed as one of these factors. We therefore investigated the influence of MBL2 gene variants on disease severity, age at acquisition of Pseudomonas aeruginosa, and survival in CF patients.
MBL2 variants were studied in 106 Argentinean pediatric CF patients carrying two severe CFTR mutations. Clinical phenotype was defined according to the Shwachman score and lung function tests. Age at infection with P. aeruginosa and age at death were also recorded.
MBL insufficiency was associated with a 3.5-fold risk of having a severe phenotype (CI 95%: 1.2–10.3, p = 0.03). It was also associated with an earlier onset of infection with P. aeruginosa (p = 0.035). No statistically significant differences were found in FEV1 and survival.
MBL insufficiency was associated with detrimental progression of the disease. These results together with previous findings suggest that the effect of MBL2 expression may be a major determinant of the severity of the clinical phenotype in patients with CF.
"It has been shown that heterozygous genotypes have less stable MBL oligomers (Larsen et al., 2004), which could result in an increased degradation of the protein (Matsushita et al., 1995; Naito et al., 1999). It has also been shown that less oligomerized MBL binds poorly to mannan and would therefore be less likely to be detected in the functional assays, which are mostly used to measure MBL levels (Garred et al., 2003b) and is less able to activate the LP (Larsen et al., 2004). In this review MBL-deficiency is defined by the measurement of functional binding of MBL to the ligand, unless otherwise stated. "
[Show abstract][Hide abstract] ABSTRACT: MBL-deficiency is a commonly occurring deficiency of the innate immune system, affecting a substantial part of the population and has been extensively studied. MBL appears to function as a disease modifier. The role of MBL in different conditions is context-dependent. Many clinical studies show conflicting results, which can be partially explained by different definitions of MBL-deficiency, including phenotype- and genotype-based approaches. In this review we give an overview of literature of MBL, its role in different pathologies, diseases and patient populations. We review MBL replacement studies, and discuss the potential of MBL substitution therapy. We finally suggest that new MBL substitution trials should be conducted within a predefined patient population. MBL-deficiency should be based on serum levels and confirmed by genotyping.
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