Article

Mannose-binding lectin deficiency - revisited

Department of Clinical Immunology, Tissue Typing Laboratory-7631, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Molecular Immunology (Impact Factor: 3). 10/2003; 40(2-4):73-84. DOI: 10.1016/S0161-5890(03)00104-4
Source: PubMed

ABSTRACT 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.

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    • "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 [6] [7] [8]. "
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    • "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. "
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    • "Human mannose binding lectin (MBL) is a C-type (Ca 2 + dependent ) mammalian lectin of the innate immune system, coded by the MBL2 gene and specifically synthesized in the liver in two forms, serum MBL (S-MBL) and intracellular MBL (I-MBL), encoded by a single mRNA (Garred, 2003; Kilpatrick, 2002; Ma, 1997; Turner, 2003). Both forms exist as homo-oligomers of 32 kDa units and three subunits form a " structural unit " (Kurata, 1994). "
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