Review
Mannan-binding lectin deficiency — Good news, bad news, doesn't matter?

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Abstract

Mannan-binding lectin (MBL) deficiency has been classified as a commonly occurring immune disorder, affecting approximately 30% of the human population. MBL, being part of the innate immune system, supports the recognition of infectious pathogens by binding to carbohydrate moieties expressed on microorganisms and activates the lectin pathway of the complement system. MBL2 gene polymorphisms are associated with quantitative and qualitative MBL abnormalities in the serum. The clinical impact of MBL deficiency and its association to a wide variety of diseases has been extensively studied. The picture is puzzling as the studies suggest a detrimental or beneficial or no impact of low or high MBL serum levels on disease susceptibility. In this review we attempt to extract what is relevant from the literature and address controversial issues. We finally suggest that a comprehensive understanding of the role of MBL in human diseases requires considering its context-dependency.

Introduction

In the mammalian immune system, innate immunity is constantly active to maintain the host organism's integrity. Numerous components join together to serve the purpose of first line defense against invading pathogens, support of wound healing [1], remodeling of tissues and angiogenesis [2], [3] and clearance of apoptotic or necrotic cells [4]. The immune system's key components comprise the phagocytic and natural killer cell compartment, natural antibody production, cytokines and other soluble factors, and the complement system. Complement activation can occur through the classical, the alternative or the lectin pathway and mainly functions for pathogen opsonization, chemotaxis as well as activation of phagocytes, and direct pathogen lysis through the formation of the membrane attack complex [5].

Mannan binding lectin (MBL) is critical for complement activation via the lectin pathway, a branch that appeared by evolution more than 565 million years ago. A homolog of Mannan binding lectin (MBL) and other components of the lectin pathway, such as ficolins and MBL-associated serine proteases (MASPs) have been detected in ascidians, the closest invertebrate relative of mankind. Thus, the MBL pathway has been preserved throughout animal and hominoid evolution [6]. Because of the commonly believed crucial importance of the lectin pathway in immunity, MBL and its quantitatively widely varying serum levels and genetic polymorphisms have been subject to extensive studies for a potential role in mediating or promoting clinical diseases. Yet, the simple notion that individuals with apparently absent MBL may be healthy and the uncertainties in defining what is “normal” in MBL, both technically and conceptually, currently preclude a clear perception of the role of MBL in human immunity and health.

In this review, we will give a comprehensive survey of the state-of-the-art knowledge of MBL and discuss possible explanations for the thus far unclear and equivocal findings on MBL's role in immunity.

Section snippets

General features of MBL

MBL is synthesized in the liver and circulates in the serum. So far, only few reports have described the intracellular occurrence of MBL [7]. In inflammatory conditions, MBL can leave the blood stream due to vascular leakage and be detected in the mucus of the middle ear, nasopharyngeal secretion or inflamed synovial fluid, but also in normal amnion fluid [8], [9]. MBL is considered an acute phase reactant, i.e., in case of inflammation serum levels increase [10].

Structurally, MBL is a member

The MBL2 genetic polymorphisms

The search for genetic variations as a cause for MBL abnormalities began when low MBL serum levels were found to be associated with insufficient opsonisation capacity in an in-vitro assay [31]. The first MBL2 gene mutation was found in 1991 by Sumiya et al., [32] who described an exon 1 point mutation at codon 54 in which a glycine is replaced by aspartic acid (GGC to GAC). This mutation was supposed to underlie low MBL serum concentrations in three children with an opsonizing defect and

MBL serum levels

MBL serum levels determined in normal healthy populations have been reported to cover a range of 2–3 log orders of magnitude [21]. For example, MBL serum levels in randomly selected 286 voluntary blood donors ranged from 0 ng/ml to > 8000 ng/ml [47]. The observation of such a wide range detected in an apparently healthy population is intriguing and warrants some further deliberation. For MBL, both, technical and conceptual, aspects are worth being considered.

Technically, MBL serum levels are

MBL associated serine proteases (MASPs)

As outlined before, MASPs forming a complex with MBL play an important role in facilitating the binding of MBL to pathogens via the CRD and in mediating activation of the lectin pathway of the complement system. Interestingly, as only recently recognized, MASPs themselves are subject to frequent genetic polymorphisms. A MASP-2 polymorphism involving an amino acid exchange of aspartic acid by glycine at position 120 in exon 3 of the MASP-2 gene, termed D120, was recently described [141]. The

Conclusion

In light of the ongoing debate on the significance of MBL in maintaining the integrity of an individual's immunity and considering the vast number of controversial studies, it is difficult to find a definitive concept of the role of MBL. In this review we attempted to give a comprehensive survey of the current knowledge on MBL and to extract from the data a pragmatic view on how to deal with this controversial issue in the clinic.

Still, the term ‘MBL deficiency’ is listed under the term

Concluding remarks

The up-to-date research in the area of MBL and its function in opsonisation of pathogens, complement activation and regulation have provided exciting insights into the structure and network design of innate immunity. Given the so far ambiguous results of studies and the only preliminary results on the value of MBL replacement therapies, additional intensive research in both areas, basic and clinical, needs to be done to ultimately comprehend and properly appreciate the role of MBL.

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgments

This work was supported in part by a grant from the Austrian National Bank (#13075). We thank Lukas Kadan for providing us with graphic design. We are grateful to O.A. Haas for critically reviewing this manuscript and helpful discussion. We thank Marion Zavadil for editorial assistance.

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