Overview

The Lectin pathway is initiated by mannan-binding lectin (MBL) which is a protein that binds specifically to mannose residues in bacterial cell walls. It is a phylogenetically ancient mechanism which was first shown to be activated by MBL when it interacts with repeating mannose residues on the surface of pathogens. Mannose is a monosaccharide isomer of glucose that is an integral part of the cell surface structure of potentially pathogenic bacteria. These sugars are usually absent from mammalian cells and thus provide a unique target for activaiton of the immune system. MBL is an oligomeric serum lectin that is associated with several homologus, modular lectin specific serine proteases (MASPs). The bining of MBL within this complex to microbial mannose residues activates MASP-1 and MASP-2. MASP-2 protease can hydrolyze circulating C4 and C2 proteins to produce the C4b2a complex (C3 convertase) as seen in the classical pathway. Unlike MASP-2, MASP-1 hydroyzes C3 directly. Two additional MASPs ahve been observed, an alternative spliced variant of MASP-1 called MASP-3 and a truncated form of MASP-2 called sMASP. (Pugsley, Cardiovascular Toxicology, 2003, pp. 43-69)

The binding of MBP to ther terminal mannose group I residue on the microbial cell surface is calcium dependent and serves the unique biological funciton of recognizing exogenous CHO moieties on cells. Thus, lectin binds these mannose or CHO ligands by the formation of a series of hydrogen and calcium coordinated bonds with the 2-OH groups of the terminal mannose residues. MBP binding then triggers an immune response that is mechanistically simlar to the classical pathway since C3 and C5 convertase are generated. (Pugsley, Cardiovascular Toxicology, 2003, pp. 43-69). 

Activation

Activation of the LP occurs through recognition of PAMPs by either MBL or ficolins in association with MBL-associated serine proteases (MASPs). MBL is a plasma protein belonging to a family of proteins known as the collectins. Collectins are oligomers of polypeptide chains containing a C type lectin carbohydrate recognition domain (CRD) attached to a collage like region. The overall structure of MBL resembles that of C1q. The PAMPs recognized by MBL comprise various simple and complex carbohydrate motifs. MBL does not selectively bind only mannose or its multimers as the name implies but rather in general recognizes sugars with 3- and 4-OH groups placed in the equatorial plae of the sugar ring structure. A group of proteins known as ficolins can also activate the LP. Ficolins are structurally similar to MBL and other collectins but instead of C-type lectin domains they possess fibrinogen like domain for PAMP recognition. Three ficolins are found in humans: H-ficolin, L-ficolin, and M-ficolin, while the mouse has only two. (Degn, Immunobiology 212, 2007, 301-311). Binding of MBL or serum ficolins indcues conformational changes in these complexes, leading to autoactivation of the MASPs, which in turn activate a downstream reaction cascade. 

With a prevalence of 5-10% in the Caucasian population, MBL deficiency is the most common imunodeficiency.  Functional MBL deficiency is explained largely by three single point mutations in codons 52, 54 and 57 of exon 1 in the MBL2 gene. 

Lectin Pathway 

Once MBL is bound to its target, MBL-associated proteins 1, 2, and 3 (MASP-1, MASP-2, MASP-3 and sMAP) are activated, resulting in the cleavage of C4 and C2, which is then followed by the assembly of the remainder of the complement pathway. MASPs are serine proteases. MASP-2 has been shown to be entirely associated with MBL, whereas MASP-1 cirulcates in both bound and in unbound forms. The overall structures of MASPs resemble C1r and C1s of the CP and mimic their activities. Upon bind of MBL to carbohydrate structures on teh surface of microbes, the proenzymes of MASPs are cleaved resulting in the active form. The activated MASPs are then  able to exert their proteolytic activites against complement components. MASP-2 activates C4 and C2, and form the C3 convertase (C4bC2a), an effect similar to the effect of CP C1s. 

The lectin pathway is particularly important in the recognition and clearance of pathogens, as deficiencies are strongly associated with recurrent infections and earlier death in patients with cystic fibrosis and recurrent pulmonary infection. MBL deficiency is the most common inherited immunodeficiency (MBL concentration <100 ng/ml) with a prevalence of 5-7% in the general population. It is alrgely explained by three single point mutations in codons 52, 54 and 57 of exon 1 of the MBL gene.