Structural and Functional Overview of the Lectin Complement Pathway: Its Molecular Basis and Physiological Implication

Abstract

The complement system is an effector mechanism in immunity. It is activated in three ways, the classical, alternative and lectin pathways. The lectin pathway is initiated by the binding of mannose-binding lectin (MBL) or ficolins to carbohydrates on the surfaces of pathogens. In humans, MBL and three types of ficolins (L-ficolin, H-ficolin, and M-ficolin) are present in plasma. Of these lectins, at least, MBL, L-ficolin, and H-ficolin are complexed with three types of MBL-associated serine proteases (MASPs), MASP-1, MASP-2, and MASP-3 and their truncated proteins (MAp44 and sMAP). In the lectin pathway, the lectin-MASP complex (i.e., a complex of lectin, MASPs and their truncated proteins) binds to pathogens, resulting in the activation of C4 and C2 to generate a C3 convertase capable of activating C3. MASP-2 is involved in the activation of C4 and C2. MASP-1 activates C2 and MASP-2. The functions of MASP-3, sMAP, and MAp44 in the lectin pathway remain unknown. MASP-1 and MASP-3 also have a role in the alternative pathway. MBL and ficolins are able to bind to a variety of pathogens depending on their carbohydrate binding specificity, resulting in the activation of the lectin pathway. Deficiencies of the components of the lectin pathway are associated to susceptibility to infection, indicating an important role of the lectin pathway in innate immunity. The lectin-MASP complex is also involved in innate immunity by activating the coagulation system. Recent findings suggest a crucial role of MASP-3 in development.

Complement MASP-1 enhances adhesion between endothelial cells and neutrophils by up-regulating E‐selectin expression

“…Mannan-binding lectin (MBL)-associated serine protease-1 (MASP-1) is the primary enzyme of the lectin pathway [1][2][3]. MASP-1 is activated upon the recognition of special pathogen/danger-associated motifs by MBL, collectin-11 (CL-K1), or ficolins (1-, 2-, and 3-ficolin) [4,5]. Following its autoactivation, MASP-1 cleaves MASP-2 and C2, thereby ensuring further activation of the lectin pathway.…”

Distinct Longitudinal Associations of MBL, MASP-1, MASP-2, MASP-3, and MAp44 With Endothelial Dysfunction and Intima–Media Thickness

“…In contrast to the proteases MASP-1 and MASP-2, for whom the enzymatic activities are well described, much less is known about MASP-3. MASP-3 may not be primarily involved in the activation of any downstream complement proteases 17,18 but may rather be involved in developmental processes. 33,34 MAp44 has no catalytic activity at all and is thought to exert biological functions only via binding to other proteins.…”

“…MBL circulates in plasma as a complex with MBL-associated proteases (MASPs) and MBL-associated proteins (MAps) that mediate or regulate downstream complement activation. 7,17,18 In humans, MASPs and MAps have been measured in case-control studies or during acute cardiovascular events (CVEs), [19][20][21] but longitudinal studies on the role of MASPs and MAps in CVD are not yet available.…”

Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation

“…Microbial sugar motives are the targets of MBL, whereas DNA, modified lipids and sugars are recognized by CL-K1 and ficolins (Matsushita et al, 2013;Henriksen et al, 2013). These data together suggest that beside microbial components, necrotic debris and aberrantly modified self macromolecules may also trigger MASP-1 induced cell activation.…”