Bypassing complement: evolutionary lessons and future implications

Abstract

Lectins like mannan-binding protein are part of the innate immune system. They circulate in association with serine proteases. Upon binding oligosaccharides, they activate the complement cascade analogous to the more familiar but evolutionarily more recent classical pathway, which is triggered by antibody binding to antigen. In this issue of the JCI, Selander et al. developed a sensitive and specific ELISA employing Salmonella-specific sugars to assess the activity of the lectin pathway of complement activation (see the related article beginning on page 1425). This more physiologic assay system allowed the investigators to rigorously define the requirements for lectin pathway activation. Furthermore, they uncovered an unsuspected means for this pathway to reach the desired critical step of activation of the opsonin C3. These types of functional assays will eventually replace the more laborious, less physiologic, and less informative approaches currently in use to monitor complement activation.

Figure 1. Three pathways of complement activation.

Deposition of clusters of C3b on a target is the primary goal. The alternative pathway also serves as a feedback loop such that C3b deposition can be amplified (shown by broken line).

Figure 2. Lectin pathway.

This pathway, also called the MBL pathway, is activated by the binding of MBL and other lectins to sugar moieties on the surface of pathogens, which results in cleavage of C4 and C2 to produce the C3 convertase C4b2a. The convertase that is formed is the same as that in the classical pathway of complement activation.

Figure 3. Feedback loop of the alternative pathway.

C3b is formed by spontaneous C3 turnover in blood or generated by the lectin or classical pathways. C3b bound to a substrate binds the serine protease factor B (B). This low-affinity complex is converted by the serine protease factor D (D) to a C3-cleaving enzyme, C3bBb. This enzyme complex is stabilized by properdin (P). C3bBbP then cleaves C3 to C3a and C3b to complete the loop and lead to amplification.

Figure 4. Lectin pathway in normal versus C2-deficient serum.

In this issue of the JCI, Selander et al. (7) examined the mechanism of complement activation by MBL in the setting of C2 deficiency. Lectins bind sugar moieties on target pathogens and subsequently activate complement via MASPs. In normal human sera, MASPs cleave C4 and C2 to form the C3 convertase C4b2a. Surprisingly, Selander et al. found that in human sera from individuals deficient in C4 or C2, MBL is still capable of inducing substantial C3 deposition by engagement of the alternative pathway and formation of the C3 convertase C3bBb. This bypass pathway may be functioning in individuals with acquired or naturally occurring complement deficiencies.