Review
The mannan-binding lectin pathway of complement activation: biology and disease association

https://doi.org/10.1016/S0161-5890(01)00038-4Get rights and content

Abstract

Mannan-binding lectin (MBL) is a plasma protein found in association with several serine proteases (MASPs) forming the MBL complex. MBL recognises carbohydrate structures arranged in a particular geometry, such as those found on the surface of micro-organisms. When bound to e.g. bacteria the MBL complex will initiate the activation of the complement cascade. Mounting evidence supports the importance of the MBL pathway of complement activation in innate immunity. In this review, we focus on the structure and function of the proteins within the MBL pathway and address the properties of the pathway as an initiator of the host response against potential pathogenic micro-organisms.

Introduction

The innate immune system is considered as the first line of host defence against infectious agents, which have penetrated the mechanical barriers. It is comprised of soluble and membrane bound proteins with a predefined specificity, in many cases involving carbohydrate moieties. The adaptive immune system subsequently plays an important role in generating specific responses towards the infectious agents. Although considered as separate systems, components of the innate immune system interact with the adaptive system, thus conferring an instructive role of innate immunity on the adaptive immune defence (Fearon and Locksley, 1996).

Mounting evidence supports the importance of the mannan-binding lectin (MBL) pathway of complement activation in innate immunity. The initiator of the pathway consists of complexes of the plasma protein MBL and MBL-associated serine proteases (MASPs). MBL binds to carbohydrate structures presented by a wide range of pathogenic bacteria, viruses, fungi, and parasites. The involvement of the MBL pathway in first line host defence is indicated by the finding that the frequency of MBL deficiency in individuals with severe and repeated infections is significantly elevated as compared to a control population. The presence of promoter polymorphisms and mutations in exon one of the gene encoding MBL results in pronounced inter-individual variation in the level of circulating MBL, and studies have shown that low MBL level to be the most frequent immuno-deficiency. Although extensive studies have yielded detailed information on the structure of MBL and on the activity of the associated serine proteases our understanding of the structure and functions of the MBL complex is still incomplete. In this review, we will focus on the structure and function of the proteins within the MBL pathway and address the properties of the pathway as an initiator of the host response against potential pathogenic micro-organisms.

Section snippets

Structure and function

Collectins constitute a family of proteins containing a collagenous region and a carbohydrate-binding lectin domain (Holmskov et al., 1994). In humans four members of this group of proteins are known: the plasma protein MBL, the lung surfactant proteins SP-A and SP-D, and CL-L1, which is localised to the cytosol of hepatocytes (Hakansson and Reid, 2000). Two additional collectins, conglutinin and CL-43, are found in the bovidae. Proteins of the collectin family are composed of subunits made up

Mannan-binding lectin-associated proteins

Initial analysis of affinity purified MBL from both human and mouse serum revealed the presence of an MASP (referred to as P100 in the mouse) (Matsushita and Fujita, 1992, Takada et al., 1993). Later another MBL-associated serine protease termed MASP-2 (Thiel et al., 1997) as well as a smaller protein of 19 kDa, termed MBL-associated protein of 19 kDa (MAp19) (Stover et al., 1999a) or small MBL-associated protein (sMAP) (Takahashi et al., 1999) were identified as components of the MBL complex.

Mannan-binding lectin/MBL-associated serine protease complexes

Due to striking structural similarities it was initially believed that the quaternary structure of the complex initiating the MBL pathway of complement activation was highly homologous to that of the classical pathway. With the identification of three MASPs and a fourth MBL-associated protein with no protease domain, a picture of a more complex system than initially anticipated is emerging. Only little is known about the stoichiometric composition and the molecular interactions involved in the

Implications of quaternary structure

Super et al. (1989) showed that the capability of serum to deposit complement components C3b and C4b onto a mannan-coated surface was correlated to the levels of MBL in the circulation. This opsonic defect in MBL-deficient serum was subsequently linked to the codon 54 mutation (Sumiya et al., 1991). Using gel-permeation chromatography and sucrose density gradient centrifugation Lipscombe et al. (1995) showed that individuals homozygous for the structural mutations produced small amounts of MBL

Direct opsonisation by mannan-binding lectin

Besides opsonisation by the deposition of complement components on an activator via the MBL pathway, MBL has been reported to act directly as an opsonin (Kuhlman et al., 1989) Salmonella montevideo (displaying a mannose-rich O-polysaccharide) was thus found to be ingested by monocytes in an MBL-dependent manner using both human MBL (20 μg/ml) and recombinant MBL expressed in CHO cells (1 μg/ml). Another study showed that strains of influenza A virus displaying a high mannose oligosaccharide

The mannan-binding lectin pathway and disease

Since the first report by Super et al. (1989) of linkage between recurrent infections and low levels of MBL, a large number of papers have been published on association between MBL deficiency and increased susceptibility to various infectious as well as to autoimmune diseases. This has been reviewed in detail by Turner (1998) and Turner and Hamvas (2000) and only selected topics shall be discussed below. It should be noted that 90% of MBL deficient individuals do not acquire repeated

Concluding remarks

The understanding of the physiological properties and interactions of the proteins involved in the MBL pathway is rapidly increasing. The value of recombinant components has been great but natural, plasma-derived components are needed to support the conclusions. The generation of knock-out mice will be of great importance in addressing the physiological functions of the components. The recent discovery of a third MBL associated serine protease and the identification of distinct MBL complexes

References (121)

  • S.T. Iobst et al.

    Binding of sugar ligands to Ca(2+)-dependent animal lectins. I. Analysis of mannose binding by site-directed mutagenesis and NMR

    J. Biol. Chem.

    (1994)
  • W.K. Ip et al.

    Association of systemic lupus erythematosus with promoter polymorphisms of the mannose-binding lectin gene

    Arthritis Rheum.

    (1998)
  • J. Klabunde et al.

    Schistosoma mansoni: adhesion of mannan-binding lectin to surface glycoproteins of cercariae and adult worms

    Exp. Parasitol.

    (2000)
  • M. Kuhlman et al.

    The human mannose-binding protein functions as an opsonin

    J. Exp. Med.

    (1989)
  • Y.L. Lau et al.

    Mannose-binding protein in Chinese patients with systemic lupus erythematosus

    Arthritis Rheum.

    (1996)
  • R. Lekowski et al.

    Ulex europaeus agglutinin II (UEA-II) is a novel, potent inhibitor of complement activation

    Protein Sci.

    (2001)
  • M. Matsushita et al.

    The Gly-54→Asp allelic form of human mannose-binding protein (MBP) fails to bind MBP-associated serine protease

    Biochem. J.

    (1995)
  • H. Naito et al.

    Characterization of human serum mannan-binding protein promoter

    J. Biochem. (Tokyo)

    (1999)
  • R.T. Ogata et al.

    Substrate specificities of the protease of mouse serum Ra-reactive factor

    J. Immunol.

    (1995)
  • S. Oka et al.

    Isolation and characterization of two distinct mannan-binding proteins from rat serum

    Arch. Biochem. Biophys.

    (1988)
  • S.V. Petersen et al.

    Control of the classical and the MBL pathway of complement activation

    Mol. Immunol.

    (2000)
  • Peterslund, N.A., Koch, C., Jensenius, J.C., Thiel, S., Deficiency of mannan-binding lectin (MBL), association with...
  • K. Sastry et al.

    The human mannose-binding protein gene. Exon structure reveals its evolutionary relationship to a human pulmonary surfactant gene and localization to chromosome 10

    J. Exp. Med.

    (1989)
  • S. Sheriff et al.

    Human mannose-binding protein carbohydrate recognition domain trimerizes through a triple alpha-helical coiled-coil

    Nat. Struct. Biol.

    (1994)
  • C.M. Stover et al.

    Two constituents of the initiation complex of the mannan-binding lectin activation pathway of complement are encoded by a single structural gene

    J. Immunol.

    (1999)
  • J.A. Summerfield et al.

    Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series

    BMJ

    (1997)
  • M. Super et al.

    Distinct and overlapping functions of allelic forms of human mannose binding protein

    Nat. Genet.

    (1992)
  • J. Aittoniemi et al.

    Mannan binding lectin deficiency and concomitant immunodefects

    Arch. Dis. Child

    (1998)
  • A. Amoroso et al.

    Polymorphism at codon 54 of mannose-binding protein gene influences AIDS progression but not HIV infection in exposed children

    AIDS

    (1999)
  • Z. Bajtay et al.

    Mannan-binding lectin and C1q bind to distinct structures and exert differential effects on macrophages

    Eur. J. Immunol.

    (2000)
  • R. Bellamy et al.

    Mannose binding protein deficiency is not associated with malaria, hepatitis B carriage nor tuberculosis in Africans

    QJM

    (1998)
  • C. Caliezi et al.

    C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema

    Pharmacol. Rev.

    (2000)
  • C.D. Collard et al.

    Reoxygenation of hypoxic human umbilical vein endothelial cells activates the classic complement pathway

    Circulation

    (1997)
  • M.R. Dahl et al.

    A new mannan-binding lectin associated serine protease, MASP-3, and its association with distinct complexes of the MBL complement activation pathway

    Immunity

    (2001)
  • E.J. Davies et al.

    Mannose-binding protein gene polymorphism in systemic lupus erythematosus

    Arthritis Rheum.

    (1995)
  • E.J. Davies et al.

    A dysfunctional allele of the mannose binding protein gene associates with systemic lupus erythematosus in a Spanish population

    J. Rheumatol.

    (1997)
  • Y. Endo et al.

    Exon structure of the gene encoding the human mannose-binding protein-associated serine protease light chain: comparison with complement C1r and C1s genes

    Int. Immunol.

    (1996)
  • Y. Endo et al.

    Two lineages of mannose-binding lectin-associated serine protease (MASP) in vertebrates

    J. Immunol.

    (1998)
  • R.A. 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)
  • R.A. Ezekowitz et al.

    A human serum mannose-binding protein inhibits in vitro infection by the human immunodeficiency virus

    J. Exp. Med.

    (1989)
  • D.T. Fearon et al.

    The instructive role of innate immunity in the acquired immune response

    Science

    (1996)
  • T. Fujita et al.

    Mannose-binding protein recognizes glioma cells: in vitro analysis of complement activation on glioma cells via the lectin pathway

    Jpn. J. Cancer Res.

    (1995)
  • M. Gadjeva et al.

    The mannan-binding-lectin pathway of the innate immune response

    Curr. Opin. Immunol.

    (2001)
  • P. Garred et al.

    Diallelic polymorphism may explain variations of the 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)
  • P. Garred et al.

    Increased frequency of homozygosity of abnormal mannan-binding-protein alleles in patients with suspected immunodeficiency

    Lancet

    (1995)
  • 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)
  • P. Garred et al.

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

    Arthritis Rheum.

    (1999)
  • I. Ghiran et al.

    Complement receptor 1/CD35 is a receptor for mannan-binding lectin

    J. Exp. Med.

    (2000)
  • P.J. Green et al.

    Recognition of the major cell surface glycoconjugates of Leishmania parasites by the human serum mannan-binding protein

    Mol. Biochem. Parasitol.

    (1994)

    • Cited by (267)

    • Pulmonary surfactant-derived antiviral actions at the respiratory surface

      2023, Current Opinion in Colloid and Interface Science

    • Nanoparticle-induced immune response: Health risk versus treatment opportunity?

      2023, Immunobiology

    • Biomolecules capturing live bacteria from clinical samples

      2022, Trends in Biochemical Sciences
      Citation Excerpt :

      FcMBL comprises the human MBL carbohydrate recognition domain fused to the Fc region of human IgG [13] (Figure 1). Native MBL is an essential component of the innate immune system and acts as an opsonin to activate the complement system via the lectin pathway [14]. It binds carbohydrate PAMPs from a range of pathogens, including bacteria, viruses, fungi, parasites, and toxins.

    • Mannose-binding lectin levels and MBL2 gene polymorphisms are associated with dengue infection in Brazilian children at the early ages

      2022, International Journal of Infectious Diseases

    • Fucoidan for cardiovascular application and the factors mediating its activities

      2021, Carbohydrate Polymers

    • Toll-like receptor 2 and α-Smooth Muscle Actin expressed in the tunica of a urochordate, Styela plicata

      2021, Tissue and Cell
      Citation Excerpt :

      The genomes of C. intestinalis and Phallusa mammillata have since been completed (Dehal et al., 2002; Endo et al., 2010; McDougall et al., 2012). Ascidians pathogen recognition systems are: lectin-mediated complement activation (Vang Petersen et al., 2001), opsonization and activation of phagocytosis (Hajela et al., 2002), antimicrobial peptides and Toll-like receptors (TLRs) (Satake et al., 2019; Sasaki et al., 2009; Nonaka and Satake, 2010). TLRs playing a key role in the vertebrates innate immune system.

    View all citing articles on Scopus
    View full text
    Copyright © 2001 Elsevier Science Ltd. All rights reserved.