Deficiency of the mannan-binding lectin pathway of complement and poor outcome in cystic fibrosis: bacterial colonization may be decisive for a relationship

Abstract

In cystic fibrosis (CF) prognosis concerning lung damage development is highly variable and difficult to predict. Mannan-binding lectin (MBL) deficiency has been reported to be associated with poor outcome in CF lung disease. MBL is a recognition molecule of the MBL pathway of the complement system and is encoded by a gene characterized by a high degree of polymorphism. Some genotypes result in low serum concentrations of MBL. MBL-associated serine protease 2 (MASP-2) is another protein belonging to the MBL pathway. A mutation resulting in low levels of MASP-2 in serum has been described recently. In the present study, 112 CF patients aged 4-54 years were investigated for MBL and MASP-2 genotypes, serum levels of MBL and MASP-2 and the MBL pathway function in serum. No correlation to reduced lung function or need for lung transplantation was seen, either for MBL deficiency, MASP-2 gene mutation or reduced MBL pathway function. However, in the 27 patients colonized with Staphylococcus aureus, MBL-deficient genotypes were associated with decreased lung function. As expected, MBL pathway function in serum was reduced both in MBL-deficient patients and in patients carrying a mutant MASP-2 allele. An unexpected finding was that CF patients had higher serum levels of MBL than healthy controls when corrected for MBL genotype. In conclusion, MBL pathway function was affected both by MBL and by MASP-2 genotypes. However, MBL or MASP-2 levels in serum did not affect the clinical outcome in the cohort of CF patients studied.

Fig. 1

MBL concentration in cystic fibrosis patients and controls according to MBL genotype. Serum MBL concentration was in most genotypes higher in CF patients than in controls. Horizontal bars indicate the mean levels. To compare the concentrations, the Mann–Whitney U-test was performed in genotypes with 10 or more individuals in each group. **P < 0·01 and n.s. indicates a non-significant difference.

Fig. 2

Lung function expressed as proportion of predicted forced expiratory volume in 1 second (FEV₁%pred) in relation to MBL genotype. No difference in lung function according to MBL genotype was found in CF patients. Patients that had undergone lung transplantation were not included in the comparison. Horizontal lines indicate median values.

Fig. 3

Lung function expressed as proportion of predicted forced expiratory volume in 1 second (FEV₁%pred) in CF patients heterozygous for MASP-2 gene mutation (AG) compared to wild-types (AA). No difference in lung function according to MASP-2 genotype was found in CF patients. Patients that had undergone lung transplantation were not included in the comparison. AG refers to patients heterozygous for A→G mutation in exon 3 of the MASP-2 gene. AA refers to wild types. Horizontal lines indicate median values.

Fig. 4

MBL pathway function (MBLpf) in serum in relation to MBL genotype in cystic fibrosis patients and healthy controls. MBL suff refers to individuals with MBL-sufficient genotypes, and MBL def refers to individuals with MBL-deficient genotypes (Table 1). **P < 0·01(Mann–Whitney U-test). Horizontal lines indicate median values.

Fig. 5

MBL pathway function (MBLpf) in serum in relation to MASP-2 genotypes in cystic fibrosis patients and healthy controls. AA refers to MASP-2 gene wild-type homozygotes. AG refers to individuals heterozygous for A→G mutation in exon 3 of the MASP-2 gene. AA, MBL suff refers to MASP-2 gene wild-type homozygotes that have an MBL-sufficient genotype. In the AG groups, all individuals had MBL-sufficient genotypes. *P < 0·05 (Mann–Whitney U-test) and n.s. indicates a non significant difference. Vertical lines show median values.