Mannose-binding lectin deficiency—revisited

doi:10.1016/S0161-5890(03)00104-4

Molecular Immunology

Volume 40, Issues 2–4, September 2003, Pages 73-84

https://doi.org/10.1016/S0161-5890(03)00104-4 Get rights and content

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.

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).

References (36)

K Ikeda et al.
Serum lectin with known structure activates complement through the classical pathway
J. Biol. Chem.
(1987)
R Malhotra et al.
Collectins and viral infections
Trends Microbiol.
(1995)
M.E Miller et al.
A familial, plasma associated defect of phagocytosis: new cause of recurrent bacterial infection
Lancet
(1968)
H Naito et al.
Metabolic properties of normal and mutant mannan-binding proteins in mouse plasma
Biochem. Biophys. Res. Commun.
(1999)
M Sumiya et al.
Molecular basis of opsonic defect in immunodeficient children
Lancet
(1991)
M Super et al.
Association of low levels of mannan-binding protein with a common defect in opsonisation
Lancet
(1989)
R Wallis
Structural and functional aspects of complement activation by mannose-binding protein
Immunobiology
(2002)
D.C.A Candy et al.
Yeast opsonisation in children with chronic diarrhoeal states
Arch. Dis. Child
(1980)
R.A.B Ezekowitz et al.
A human mannose-binding protein is an acute-phase reactant that shares sequence homology with other vertebrate lectins
J. Exp. Med.
(1988)
P Garred et al.
Diallelic polymorphism may explain variations of blood concentration of mannan-binding protein in Eskimos, but not in black Africans
Eur. J. Immunogenet.
(1992)

P Garred et al.

Dual role of mannan-binding protein in infections: another case of heterosis

Eur. J. Immunogenet.

(1994)

Garred, P., Madsen, H.O., Svejgaard, A., 1996. Genetics of human mannan-binding protein. In: Ezekowitz, R.A.B., Sastry,...

P Garred et al.

Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus

Arthritis Rheum.

(1999)

P Garred et al.

Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis

J. Clin. Invest.

(1999)

N.A Graudal et al.

The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis

Arthritis Rheum.

(2000)

N Guo et al.

The human ortholog of rhesus mannose-binding protein-A gene is an expressed pseudogene that localizes to chromosome 10

Mamm. Genome

(1998)

D.L Jack et al.

Mannose-binding lectin: targeting the microbial world for complement attack and opsonophagocytosis

Immunol. Rev.

(2001)

H Kurata et al.

Role of the collagen-like domain of the human serum mannan-binding protein in activation of complement and secretion of this lectin

Biochem. Biophys. Res. Commun.

(1993)

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Mannose-binding lectin (MBL) binds to SARS-CoV-2, inhibits infection of susceptible cells, and activates the complement system via the lectin pathway. In this study, we investigated the association of MBL2 polymorphisms with the risk of hospitalization and clinical worsening in patients with COVID-19. A total of 550 patients with COVID-19 were included (94 non-hospitalized and 456 hospitalized). Polymorphisms in MBL2 exon 1 (codons 52, 54 and 57) and promoter region (−550, −221, and +4) were determined by real-time PCR. MBL and complement proteins were measured by Luminex. A higher frequency of the H/H genotype and the HYPA haplotype was observed in non-hospitalized patients when compared to hospitalized. In addition, critically ill patients carrying haplotypes associated with high MBL levels (HYPA/HYPA + HYPA/LYPA + HYPA/LYQA + LYPA/LYQA + LYPA/LYPA + LYQA/LYQA + LXPA/HYPA + LXPA/LYQA + LXPA/LYPA) were protected against lower oxygen saturation levels (P = 0.02), use of invasive ventilation use (P = 0.02, OR 0.38), and shock (P = 0.01, OR 0.40), independent of other potential confounders adjusted by multivariate analysis. Our results suggest that variants in MBL2 associated with high MBL levels may play a protective role in the clinical course of COVID-19.
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Complement deficiencies have been considered to be rare for many decades, but this assumption is changing year by year. Recognition of these conditions significantly increases thanks to the availability of different testing approaches and due to clinical awareness. Furthermore, sequencing technologies (including Sanger sequencing, targeted gene panels, and whole exome/genome sequencing) may facilitate the identification of the underlying disease-causing genetic background. On the other hand, functional characterization of the identified possibly pathogenic variations and performing family studies, as illustrated by some of our cases, remain similarly important to establish a precise clinical diagnosis facilitating the most appropriate management. Here, we present 4 illustrative cases with complement deficiencies of diverse etiologies and also provide an educative, step-by-step description on how to identify the underlying cause of complement deficiency based on the results of complement laboratory testing.
Mannose-binding lectin levels and MBL2 gene polymorphisms are associated with dengue infection in Brazilian children at the early ages
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Citation Excerpt :
Moreover, having the Q allele in homozygosis or heterozygosis was associated with a protective effect against dengue infection in children. Previous studies have shown an association between higher levels of MBL and the presence of the variant Q allele when compared with the wild-type P allele (Garred et al., 2003; Madsen et al., 1998). In contrast, results from a large prospective study of 1,800 Polish neonates found an association between higher levels of serum MBL with the P allele (St. Swierzko et al., 2009).
The mannose-binding lectin (MBL) plays an important role in innate immunity. Genetically determined variations in serum levels of MBL may influence the susceptibility and clinical outcome of dengue infection in early life.
We investigated the MBL2 gene polymorphisms and serum levels of MBL (total and functional) in children with asymptomatic (n=17) and symptomatic (n=29) primary dengue infections and age-matched uninfected children (n=84) enrolled in a birth cohort with dengue in Brazil. Polymorphisms of the MBL2 gene were assessed by reverse transcription-polymerase chain reaction (RT-PCR), whereas the enzyme-linked immunosorbent assay (ELISA) was used to quantify serum levels of MBL.
We found that the X allele and YX genotype in the MBL2 were more frequent in the dengue cases than in the control group. Likewise, the LXPA haplotype was exclusively found in dengue cases, thus probably related to dengue infection in our setting. Moreover, we found a higher frequency of the O allele and AO genotype in the control group. Serum levels of total and functional MBL were higher in dengue naïve infants than in dengue cases.
MBL2 variants related to lower production of serum MBL were associated with dengue infection in infants, whereas intermediate to high levels of total and functional serum MBL were associated with protection against dengue infection. These findings highlight the role of MBL2 variants and serum levels of MBL in the susceptibility of children to dengue disease at early ages.
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Leprosy is an infectious disease that may present different clinical forms depending on host immune response to Mycobacterium leprae. Mannose-binding lectin (MBL) is an acute phase protein associated with the pathophysiology of leprosy. Some studies have shown that there is a correlation between serum levels of MBL and polymorphisms in its gene associated with susceptibility per se and to different clinical forms. The aim of this study was to conduct a systematic review of publications in the literature that studied the association of MBL with leprosy. Databases were searched until December 2020 (PROSPERO: CRD42020158458), and additional searches were conducted scanning the reference lists of the articles. Two independent reviewers assessed the study quality using the Newcastle-Ottawa Quality Assessment Scale. Finally, 10 eligible articles were included in the study. The overall results indicated that both low MBL serum levels and polymorphisms in the structural or promoter region of its gene seem to be associated as protective factors against the development of severe forms. The results suggest that MBL may play a role in the clinical progression of leprosy.
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Restenosis after carotid endarterectomy (CEA) limits its long-term efficacy for stroke prevention. Thus, it is of utmost importance to identify the factors that predispose a patient to restenosis after CEA. This systemic review aims to survey the current literature regarding restenosis after CEA and discuss the predictive value of carotid plaque features.
A systemic review of studies on the predictive value of carotid plaque features for restenosis after CEA was conducted according to the PRISMA guidelines. PubMed/MEDLINE and Embase databases were searched up to March 20, 2020. Two authors independently extracted the data and assessed the risk of bias with the Quality in Prognosis Studies tool. Given the heterogeneity in the measurement of prognostic factors, types of CEA, and clinical outcomes, a qualitative synthesis was performed.
Twenty-one articles with a sample size that ranged from 11 to 1203 were included in this systematic review. Based on the presence of calcification in original carotid plaques, two progression patterns of restenosis were hypothesized: patients with calcified plaques may experience a temporary increase in the intima-media thickness (IMT) followed by a decrease in IMT after CEA, whereas patients with noncalcified plaques may experience a gradual increase in IMT after CEA. Accordingly, patients with a high calcium score may have a high restenosis rate within 6 months after CEA and a low restenosis rate thereafter. Thus, the late restenosis rate in patients with uniformly echogenic plaques was lower than that in patients with uniformly echolucent plaques. Pathologically, a lipid-rich, inflammatory carotid plaque is associated with a decreased risk of restenosis within 1 year after CEA, mainly owing to the relatively mild reactive intimal hyperplasia at the surgical site and active inflammation in the remaining media and adventitia. Molecular predictors for restenosis included a Mannose-binding lectin 2 genotype, preoperative C-reactive protein, serum homocysteine, apolipoprotein J, vitamin C, and telomere length of carotid plaques.
This review demonstrated that carotid plaque features, including imaging features, cellular composition, and molecular features, are correlated with the risk of restenosis after CEA. A comprehensive evaluation of plaque characteristics may help to stratify the risk of restenosis after CEA.
The role of the lectin pathway of the complement system in SARS-CoV-2 lung injury
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Although some evidence showed the activation of complement systems in COVID-19 patients, proinflammatory status and lectin pathway remain unclear. Thus, the present study aimed to demonstrate the role of MBL and ficolin-3 in the complement system activation and compared to pandemic Influenza A virus H1N1 subtype infection (H1N1pdm09) and control patients. A total of 27 lungs formalin-fixed paraffin-embedded samples (10 from H1N1 group, 6 from the COVID-19 group, and 11 from the control group) were analyzed by immunohistochemistry using anti-IL-6, TNF-alfa, CD163, MBL e FCN3 antibodies. Genotyping of target polymorphisms in the MBL2 gene was performed by real-time PCR. Proinflammatory cytokines such as IL-6 and TNF-alpha presented higher tissue expression in the COVID-19 group compared to H1N1 and control groups. The same results were observed for ICAM-1 tissue expression. Increased expression of the FCN3 was observed in the COVID-19 group and H1N1 group compared to the control group. The MBL tissue expression was higher in the COVID-19 group compared to H1N1 and control groups. The genotypes AA for rs180040 (G/A), GG for rs1800451 (G/A) and CC for rs5030737 (T/C) showed a higher prevalence in the COVID-19 group. The intense activation of the lectin pathway, with particular emphasis on the MBL pathway, together with endothelial dysfunction and a massive proinflammatory cytokines production, possibly lead to a worse outcome in patients infected with SARS-Cov-2. Moreover, 3 SNPs of our study presented genotypes that might be correlated with high MBL tissue expression in the COVID-19 pulmonary samples.

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Mannose-binding lectin deficiency—revisited

Abstract

Section snippets

Background

The molecular structure of human MBL

Polymorphisms of the human mbl2 gene

Structural consequences of MBL polymorphisms

Concluding remarks

Acknowledgements

J. Biol. Chem.

Trends Microbiol.

Lancet

Biochem. Biophys. Res. Commun.

Lancet

Lancet

Immunobiology

Yeast opsonisation in children with chronic diarrhoeal states

Arch. Dis. Child

A human mannose-binding protein is an acute-phase reactant that shares sequence homology with other vertebrate lectins

J. Exp. Med.

Diallelic polymorphism may explain variations of blood concentration of mannan-binding protein in Eskimos, but not in black Africans

Eur. J. Immunogenet.

Dual role of mannan-binding protein in infections: another case of heterosis

Eur. J. Immunogenet.

Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus

Arthritis Rheum.

Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis

J. Clin. Invest.

The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis

Arthritis Rheum.

The human ortholog of rhesus mannose-binding protein-A gene is an expressed pseudogene that localizes to chromosome 10

Mamm. Genome

Mannose-binding lectin: targeting the microbial world for complement attack and opsonophagocytosis

Immunol. Rev.

Role of the collagen-like domain of the human serum mannan-binding protein in activation of complement and secretion of this lectin

Biochem. Biophys. Res. Commun.