The mannose-binding lectin: a prototypic pattern recognition molecule

Abstract

The innate immune system is comprised of a sophisticated network of recognition and effector molecules that act together to protect the host in the first minutes or hours of exposure to an infectious challenge. The mannose-binding lectin (MBL) is an evolutionary conserved circulating host defense protein that acts as a broad-spectrum recognition molecule against a wide variety of infectious agents. Target binding triggers the MBL pathway of complement activation. MBL can be considered conceptually as an 'ante-antibody' because it has a role in mammals during the lag period that is required to develop an antibody response against infectious agents. Additionally, there are MBL-like homologues in animals that lack adaptive immunity that activate a primitive complement system, and under these circumstances these MBL-like molecules play an analogous role to antibodies in higher animals. These molecules might be considered to be functional antecedents of antibodies. Recent work also indicates that MBL recognizes altered self-antigens, and as such MBL has a role that extends beyond a traditional role in first line host defense as it appears to play a role as a modulator of inflammation.

Figure 1

(a) A schematic diagram of proposed binding of MBL to hexose sugars that have hydroxyl groups in the equatorial position and are thereby accommodated in the binding pocket that is stabilized by calcium ions. Also depicted is a model of MBL binding to complex ligands that require interactions of multiple binding pockets with ligand, which results in high affinity binding. (b) A model of the interactions of MBL with MASPs. Engagement of ligand by MBL activates MASP2, which then cleaves the C2C4 convertase and results in the cleavage of C3 and the generation of C3b. It has also been proposed that MASP1 can directly cleave C3; what is not known is whether this requires an MBL interaction with ligand. Our model proposes that this might be a prerequisite for this reaction to occur and that this in turn would activate the alternative complement pathway. Adapted from [1].