Relationship between gene polymorphisms of mannose‐binding lectin (MBL) and two molecular forms of MBL

Abstract

Mannose-binding lectin (MBL) activates complement through MBL-associated serine proteases (MASP). A deficiency in MBL due to mutations at exon 1 of the human MBL gene is reported to cause vulnerability to infection. We examined sera of known MBL genotype by gel filtration and assessed their elution patterns using an ELISA for MBL and identified two MBL forms, a high-molecular-mass form and a lower-molecular-mass form. By the identification of either or both forms in individual sera, three types of patterns emerged: type 1 consisted of a high-molecular form; type 2, of a low-molecular form; and type 3, of both forms. Types 1, 2 and 3 corresponded, respectively, to a wild type (A/A), a homozygous mutation at codon 54 (B/B) and their heterozygote (A/B). One exception was a heterozygous LXPA/LYPB phenotype that exhibited the type-2 pattern. Binding to mannan and MASP-1/3 occurred exclusively with the high-molecular form. An apparent MBL deficiency does not in fact represent a deficiency in MBL molecules but rather the presence of circulating oligomeric mutant MBL with impaired function.

Mannose-binding lectin and its genetic variants

“…Mannose-binding lectin and its genetic variants P Garred et al recently become clear that MBL obtained from different genotypes may be present in larger amounts than previously anticipated and that they represent different oligomerization patterns in serum 32,[50][51][52][53] ( Figure 3 and 6). Variant MBL binds bacteria and mannan with lower avidity than normal MBL without activating the complement system.…”

Association of a new mannose-binding lectin variant with severe malaria in Gabonese children

“…12,13 In African, European, Asian and native American populations, the promoter haplotypes HYP and LYQ cause the highest and LXP the lowest MBL concentration in plasma [13][14][15][16][17][18][19] (see Table 1 for the official nomenclature of these and other MBL2 variants). Lower polymerization level and reduced plasma concentration of MBL multimers are associated with the variants B, C and D, which occur in the first exon of the gene.…”

“…The B, C and D aminoacid changes in the collagenous tail disturb the assembly process of the protein, resulting in reduced ligand binding and a relative increase of low-molecular-mass MBL that has reduced capability of activating complement. 16,18,20 To date, the MBL2*XA, B, C and D variants have been associated with the predisposition and/or severity of various immunodeficiencies, autoimmune and infectious diseases in childhood and adult age (for a review, see Eisen and Minchinton; Kilpatrick 21,22 ). Alternatively, the MBL2*HA diplotype and/or high plasma concentrations of MBL multimers have been associated with protection to some of these diseases, 14,23,24 but to predispose to and/ or to increase the severity of leprosy, tuberculosis, 21,25 visceral leishmaniasis, 26 sporadic ulcerative colitis 27 and rheumatic heart disease.…”

Rapid Bead‐Based Immunoassay for Measurement of Mannose‐Binding Lectin

“…This principle is also employed when MBL bound mannan is used as an initiator to detect lectin pathway-dependent complement activation [15]. Nevertheless, to detect the total antigenic content of MBL including lower oligomerized MBL it is necessary to use other antibody combinations than the one used in this study [12,[16][17][18]. The coupling and validation of beads are easy and require no special equipment.…”