Mannose-binding lectin deficiency—revisited
Section snippets
Background
During the recent decade there has been an emerging interest for mannose-binding lectin (MBL) due to its role in innate immunity and especially the possible association between MBL polymorphisms and disease (Jack et al., 2001). In this survey we present a mixture of old and new data (Garred et al., 1996). Our results highlight the complex way in which the MBL genetic system affect the level, in relation to the assembly as well as the function of the molecule.
The seminal discovery of MBL
The molecular structure of human MBL
In 1988, a human cDNA clone from human liver that encoded MBL was isolated (Ezekowitz et al., 1988). The following year the human MBL gene (mbl2) was cloned and sequenced independently by Taylor et al. and Sastry et al. (Sastry et al., 1989, Taylor et al., 1989). The mlb2 gene has been located to chromosome 10q11.1–q21. However, in the same chromosomal region an expressed MBL pseudogene (mbl1) has been found, which seems to be a human homologue to the functional mouse and rhesus mbl-A, while
Polymorphisms of the human mbl2 gene
Michiko Sumiya working in John A. Summerfield’s laboratory in London sequenced the mlb2 gene from three unrelated children suffering from recurrent infections who had low MBL serum concentrations and opsonic deficiency (Sumiya et al., 1991). In each child, she found a point mutation at codon 54 of exon 1 of the mlb2 gene causing a substitution of glycine with aspartic acid (GGC to GAC) (allele B, the normal allele is named A). Further studies of these three families suggested an autosomal
Structural consequences of MBL polymorphisms
By changing clone 131-01 as capture antibody in the MBL ELISA detection system (Garred et al., 1992) with another monoclonal antibody clone (131-11) produced at the Statens Serum Institute still using clone 131-01 as detector antibody we experienced to our surprise that we could detect MBL antigen from structural homozygous individuals in amounts similar to the amounts observed from A/O heterozygotes, but still lower than in A/A normals. Fig. 5 shows the results from 92 sera obtained with the
Concluding remarks
In clinical studies both measurements of antigenic concentration, functional activity and (structural) characterization of MBL variant alleles have been used (Turner and Hamvas, 2000). Some researchers may even argue for the superiority of one particular method over the other. However, most MBL disease associations are found with homozygosity or compound heterozygosity for variant alleles. Thus, it is critical to able to discriminate between XA/O and O/O, which are not distinguishable by the
Acknowledgements
The authors want to thank Miss Vibeke Weirup, Bente Frederiksen and Bettina Holm for excellent technical assistance. This work was supported by the Novo Nordisk Research Foundation, The Danish Council for Development Research, the Danish Medical Research Council and EU Grant (QLGI-CT-2001-01039).
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