The alternative complement pathway revisited

Abstract

Alternative pathway amplification plays a major role for the final effect of initial specific activation of the classical and lectin complement pathways, but the quantitative role of the amplification is insufficiently investigated. In experimental models of human diseases in which a direct activation of alternative pathway has been assumed, this interpretation needs revision placing a greater role on alternative amplification. We recently documented that the alternative amplification contributed to 80-90% of C5 activation when the initial activation was highly specific for the classical pathway. The recent identification of properdin as a recognition factor directly initiating alternative pathway activation, like C1q in the classical and mannose-binding lectin in the lectin pathway initiates a renewed interest in the reaction mechanisms of complement. Complement and Toll-like receptors, including the CD14 molecule, are two main upstream recognition systems of innate immunity, contributing to the inflammatory reaction in a number of conditions including ischemia-reperfusion injury and sepsis. These systems act as "double-edged swords", being protective against microbial invasion, but harmful to the host when activated improperly or uncontrolled. Combined inhibition of complement and Toll-like receptors/CD14 should be explored as a treatment regimen to reduce the overwhelming damaging inflammatory response during sepsis. The alternative pathway should be particularly considered in this regard, due to its uncontrolled amplification in sepsis. The alternative pathway should be regarded as a dual system, namely a recognition pathway principally similar to the classical and lectin pathways, and an amplification mechanism, well known, but quantitatively probably more important than generally recognized.

Fig. 1

Complement activation proceeds through three distinct initial pathways. Patterns for recognition are indicated in red and recognition molecules in green. Properdin has a dual role in the alternative pathway. Activation is induced on a foreign surface favouring binding of factor B instead of factor H as indicated in the upper right. The proposed mechanism for reaction of properdin with a target on the foreign surface recruits fluid-phase C3b inducing assembly of AP C3 convertase [27] is indicated with a blue line pointing to C3. Amplification mechanisms are indicated in thick red lines: The slow spontaneous activation involving C3(H₂O) reacting with factor B, ‘tick-over’, is controlled and inhibited by factor H. The second function of properdin is to stabilize the C3bBb complex promoting self-amplification in the other loop. These C3-directed reactions all promote C5 convertase amplification indicated with the third, circular loop. Direct C5 activation [16] is indicated in the red square. Formation of C5b initiates assembly of the components of the common terminal pathway with formation of the terminal complement complex TCC forming sC5b-9 in the fluid phase or C5b-9(m), when incorporated into a nearby membrane, leading to sub-lytic attack or lysis.