Elsevier

Molecular Immunology

Volume 44, Issue 16, September 2007, Pages 3875-3888
Molecular Immunology

Review
Complement activating soluble pattern recognition molecules with collagen-like regions, mannan-binding lectin, ficolins and associated proteins

https://doi.org/10.1016/j.molimm.2007.06.005Get rights and content

Abstract

Mannan-binding lectin (MBL), L-ficolin, M-ficolin and H-ficolin are all complement activating soluble pattern recognition molecules with recognition domains linked to collagen-like regions. All four may form complexes with four structurally related proteins, the three MBL-associated serine proteases (MASPs), MASP-1, MASP-2 and MASP-3, and a smaller MBL-associated protein (MAp19). The four recognition molecules recognize patterns of carbohydrate or acetyl-group containing ligands. After binding to the relevant targets all four are able to activate the complement system. We thus have a system where four different and/or overlapping patterns of microbial origin or patterns of altered-self may be recognized, but in all cases the signalling molecules, the MASPs, are shared. MASP-1 and MASP-3 are formed from one gene, MASP1/3, by alternative splicing generating two different mRNAs from a single primary transcript. Similarly MASP-2 and MAp19 are both generated from one gene, MASP-2/MAp19, by alternative splicing. A number of non-synonymous polymorphisms of the four recognition molecules and of the MASPs are known, and the implications of these alterations are being studied. The clinical impact of deficiencies will be discussed.

Introduction

Immunology can be broadly defined as the study of anti-microbial defence mechanisms. A number of distinct components of the immune system interact in a balanced manner to create immunity. Anti-microbial defence is initiated by the innate immune system which respond to microbial non-self via the recognition of pathogen associated molecular patterns. The resulting effector functions may have different consequences, i.e., direct elimination of microorganisms or triggering of the adaptive immune system (Iwasaki and Medzhitov, 2004). However, immunology also involves the study of response to non-microbial components. Various components of the immune system recognize non-normal or altered-self surfaces and the body must also be able to distinguish between cells that are alive or dead (see Trouw et al., this issue). We have thus evolved a number of surveillance and repair mechanisms to sustain homeostasis. Despite the rapid pace of discovery in the field of immunology over the last decade, initiation and control of immune responses remain incompletely understood.

The recognition molecules of the innate immune system include cell-associated and soluble molecules. The cell bound receptors, e.g., toll-like receptors and scavenger receptors, have been discussed by others (Hoebe et al., 2004, Pluddemann et al., 2006). Here, I will present a group of soluble pattern recognition molecules and some associated proteins.

Complement is a central component of the innate immune system comprising at least 35 proteins which collaborate in an intricate manner in the elimination of microorganisms and in the removal of apoptotic cells, but also serves as a natural adjuvant, enhancing and directing the adaptive immune response (Walport, 2001). The initiation of the complement system may occur via three pathways, the classical, the alternative and the lectin pathway. The classical and lectin pathways are initiated by the recognition of ligands by complement activating soluble pattern recognition molecules with collagen-like regions (Table 1). Of these, C1q is primarily involved in the recognition of antibody molecules (IgG or IgM) deposited on patterns of antigens, but is also able to recognize other structures (reviewed in Kishore and Reid, 2000). The other members include mannan-binding lectin (MBL) and the three ficolins, L-ficolin, M-ficolin and H-ficolin (Table 1). Whereas C1q is found in plasma in complex with the serine proteases C1r and C1s, MBL and the ficolins may form complexes with MBL-associated serine proteases (MASPs) as well as a smaller molecule named MAp19 (Fig. 1).

Section snippets

The discovery of MBL, ficolins and associated proteins

The existence of a molecule with the ability to recognize the yeast cell surface component, mannan, was first reported by Kawasaki et al. (1978) who isolated a molecule from rabbit livers and named it mannan-binding protein. The human variant of this molecule is today known as mannan-binding lectin (MBL) or mannose-binding lectin. The first observation of activation of the complement system by MBL (rabbit) was made in 1987 by Ikeda and colleagues (Ikeda et al., 1987). A comprehensive historical

Structural overview

MBL and ficolins are built from polypeptide chains containing a collagen-like region linked to recognition domains. In the case of MBL, a C-type carbohydrate recognition domain (CRD) is the ligand-binding domain, whereas for the ficolins a fibrinogen-like domain recognizes ligands. Three identical polypeptide chains assemble into structural subunits (Fig. 2), which in turn associate into higher oligomeric forms (Fig. 3).

We find that all three ficolins bind to artificially acetylated surfaces,

Structure and ligand specificity

Starting from the N-terminal end, the MASPs are composed of a CUB domain (CUB1; CUB, acronym for a domain originally described in Complement subcomponents C1r/C1s, Uegf and Bone morphogenic protein-1), an EGF domain (EGF, acronym for epidermal growth factor), another CUB domain (CUB2), two CCP domains (CCP1 and CCP2; CCP, acronym for complement control protein), an activation peptide and a serine protease domain (SP) (Fig. 6, Fig. 7). MAp19 only comprises a CUB1 domain followed by an EGF

MBL deficiency and disease

The original finding of MBL deficiency as the cause of an opsonic defect in sick children (Super et al., 1989) spurred an increasing number of clinical studies. These may be divided into studies on the association between lack of MBL and infectious disease, on the association between MBL levels and autoimmune diseases, and of associations with other diseases. Some studies measure MBL levels, some determine the MBL genotypes and others do both. Thus, it is not always easy to compare the various

MASP-2 ā€“ clinical aspects

Since MASP-2 is involved in the biological activity of L-ficolin, M-ficolin, H-ficolin and MBL we would predict that MASP-2 deficiency would have a major impact on anti-microbial defence mechanisms of the innate immune system. A patient presenting with multiple infections and autoimmune manifestations was the first case of deficiency of MASP-2 (Stengaard-Pedersen et al., 2003). Only very low levels of MASP-2 and MAp19 were present in serum (Fig. 9), and despite sufficient MBL levels, no C4b

Concluding remarks

The proteins described above represent the youngest members of the complement family and as such there remain many uncertainties, particularly with regard to their roles in disease. The improved clinical assays, better understanding of regulation and increased awareness of the issues will ensure that the current rapid pace of progress to further elucidate the physiological and pathological roles of this important group of proteins continues.

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