The complement and contact activation systems: partnership in pathogenesis beyond angioedema

Abstract

The blood plasma contains four biologically important proteolytic cascades, which probably evolved from the same ancestral gene. This in part may explain why each cascade has very similar "initiating trigger" followed by sequential and cascade-like downstream enzymatic activation pattern. The four cascades are: the complement system, the blood clotting cascade, the fibrinolytic system, and the kallikrein-kinin system. Although much has been written about the interplay between all these enzymatic cascades, the cross-talk between the complement and the kinin generating systems has become particularly relevant as this interaction results in the generation of nascent molecules that have significant impact in various inflammatory diseases including angioedema and cancer. In this review, we will focus on the consequences of the interplay between the two systems by highlighting the role of a novel molecular link called gC1qR. Although this protein was first identified as a receptor for C1q, it is now recognized as a multiligand binding cellular protein, which serves not only as C1q receptor, but also as high affinity (K ≤ 0.8 nM) binding site for both high molecular weight kininogen (HK) and factor XII (FXII). At inflammatory sites, where atherogenic factors such as immune complexes and/or pathogens can activate the endothelial cell into a procoagulant and proinflammatory surface, the two pathways are activated to generate vasoactive peptides that contribute in various ways to the inflammatory processes associated with numerous diseases. More importantly, since recent observations strongly suggest an important role for both pathways in cancer, we will focus on how a growing tumor cluster can employ the byproducts derived from the two activation systems to ensure not only its survival and growth, but also its escape into distal sites of colonization.

C1q as an autocrine and paracrine regulator of cellular functions

“…More importantly however, recent experiments especially in the area of cancer pathology, are also revealing that the role of membrane-anchored C1q and soluble C1q my have diametrically opposing roles. While membrane-bound or released into the pericellular milieu is pro-proliferative (Bulla et al, 2016; Ghebrehiwet et al 2016), soluble C1q is antiproliferative since addition of C1q to proliferating cells inhibits cell growth, and the receptors for C1q, gC1qR and cC1qR as well as adaptive or signal transducing molecules such as ADAM 28 are shown to be involved (Ghebrehiwet et al, 1990; Miayamae et al, 2016). …”

Production of complement components by cells of the immune system

“…Several receptors have also been described for C1q; however, the relative contributions of these receptors and their functions is not yet resolved [15][16][17][18]. Next to receptors for the complement opsonins, a set of receptors can also be triggered by the anaphylatoxins, C3a and C5a.…”

Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits

“…It circulates in the plasma at the concentration of 0.15–0.3 mg/mL and is mainly produced by the liver. It inhibits the activation of the complement system (Ziccardi & Cooper, ) and the kallikrein–kinin system (KKS) (Schapira, Scott, & Colman, ), which share many inflammatory features mediated by the vascular system (Bossi, Peerschke, Ghebrehiwet, & Tedesco, ; Ghebrehiwet, Kaplan, Joseph, & Peerschke, ). Activation of the KKS through plasma kallikrein and high molecular weight kininogen (HK) induces secretion of a potent 9‐amino acid peptide, bradykinin (Thompson, Mandle, & Kaplan, ).…”