Antibody‐mediated activation of the classical pathway of complement may compensate for mannose‐binding lectin deficiency

Abstract

Deficiency of mannose-binding lectin (MBL), a recognition molecule of the lectin pathway of complement, is associated with increased susceptibility to infections. The high frequency of MBL deficiency suggests that defective MBL-mediated innate immunity can be compensated by alternative defense strategies. To examine this hypothesis, complement activation by MBL-binding ligands was studied. The results show that the prototypic MBL ligand mannan can induce complement activation via both the lectin pathway and the classical pathway. Furthermore, antibody binding to mannan restored complement activation in MBLdeficient serum in a C1q-dependent manner. Cooperation between the classical pathway and the lectin pathway was also observed for complement activation by protein 60 from Listeria monocytogenes. MBL pathway analysis at the levels of C4 and C5b-9 in the presence of classical pathway inhibition revealed a large variation of MBL pathway activity, depending on mbl2 gene polymorphisms. MBL pathway dysfunction in variant allele carriers is associated with reduced MBL ligand binding and a relative increase of low-molecular-mass MBL. These findings indicate that antibody-mediated classical pathway activation can compensate for impaired target opsonization via the MBL pathway in MBL-deficient individuals, and imply that MBL deficiency may become clinically relevant in absence of a concomitant adaptive immune response.

Mannose-binding lectin levels and infections in children after allogeneic hematopoietic SCT

“…16 The ELISA we used strongly correlates with both the functional activity of the lectin pathway and the presence of low-producing MBL2 genotypes. 17 Furthermore, ELISA measurements of MBL allow an estimation of in vivo MBL status that may be caused by gene polymorphisms including, but not restricted to, the six well-known polymorphisms in the promoter and the first exon. This is in agreement with our previous observation that measurement of MBL in serum is a more sensitive parameter to measure association with disease than MBL genotyping.…”

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.…”