Protection of host cells by complement regulators

Abstract

Summary The complement cascade is an ancient immune-surveillance system that not only provides protection from pathogen invasion but has also evolved to participate in physiological processes to maintain tissue homeostasis. The alternative pathway (AP) of complement activation is the evolutionarily oldest part of this innate immune cascade. It is unique in that it is continuously activated at a low level and arbitrarily probes foreign, modified-self, and also unaltered self-structures. This indiscriminate activation necessitates the presence of preformed regulators on autologous surfaces to spare self-cells from the undirected nature of AP activation. Although the other two canonical complement activation routes, the classical and lectin pathways, initiate the cascade more specifically through pattern recognition, their activity still needs to be tightly controlled to avoid excessive reactivity. It is the perpetual duty of complement regulators to protect the self from damage inflicted by inadequate complement activation. Here, we review the role of complement regulators as preformed mediators of defense, explain their common and specialized functions, and discuss selected cases in which alterations in complement regulators lead to disease. Finally, rational engineering approaches using natural complement inhibitors as potential therapeutics are highlighted.

The renaissance of complement therapeutics

“…In principle, complement can be triggered by any foreign, diseased or otherwise altered surface, and host cells are occasionally opsonized owing to bystander activation or low background turnover (tick-over). A panel of potent complement regulators, both in the circulation and tethered to host cell surfaces, normally controls complement activation at the level of initiation, convertase-mediated opsonization and MAC formation 27 (FIG. 1b).…”

Complement in cancer: untangling an intricate relationship

“…Such an array of interactions between complement proteins and cell-surface receptors not only guarantees immune surveillance but also determines the outcome of immune responses, metabolic pathways and developmental processes. Proper control of the activation signals described above is required to prevent excessive activation that can lead to tissue damage and is achieved by an assortment of complement regulators (TABLE 1) that restrain certain steps of the complement cascade 133 .…”

Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery

“…Surface-directed C3 convertase inhibitors that fuse complement-modulatory domains of endogenous C3 regulators with unique targeting moieties that bind to opsonized host cells (e.g., CR2-FH/TT30, mini-FH) offer other viable alternatives to C5-targeted intervention that warrant investigation [23]. Notably, a series of preclinical studies targeting C3 in primate models has strongly attested to the clinical potential of C3 intervention for a number of inflammatory diseases with distinct complement-driven etiologies [21].…”

“…The rational design of chimeric C3 regulators that direct C3 inhibitory modules to C3b-opsonized surfaces has expanded the therapeutic arsenal [23,44]. It is conceivable that these surface-directed approaches may offer a plausible strategy for increasing the efficacy of complement modulation in cases in which renal pathology is mainly driven by local complement imbalance on the GBM (e.g.…”