Complement activation and disease: protective effects of hyperbilirubinaemia

Abstract

The complement (C), an important effector mechanism of the immune system, is an enzymatic cascade of about 30 serum proteins leading to amplification of a specific humoral response. It can be activated through the classical or alternative pathways, or through the mannose-binding lectin pathway. The activation of the classical pathway (CP) is initiated by the binding of the C1 component to antigen-bound antibodies, known as immunocomplexes. C1 is a complex of one molecule of C1q, two molecules of C1r and two molecules of C1s. C1q contains three copies of a Y-shaped fundamental unit with globular heads included in its structure, which play a major role in the interaction with the Fc portion of immunoglobulins. Deficient or exacerbated activation of the C system leads to diseases of variable severity, and pharmacologic inhibition of the C system is considered as a therapeutic strategy to ameliorate the inflammatory effects of exacerbated C activation. Bilirubin is a product of heme degradation by the concerted action of heme oxygenase, which converts heme into biliverdin (BV), and biliverdin reductase, which reduces BV to unconjugated bilirubin (UCB). UCB exerts both cytoprotective and cytotoxic effects in a variety of tissues and cells, acting either as an antioxidant at low concentrations or as an oxidant at high concentrations. In this review we describe in detail the anti-C properties of bilirubin, occurring at levels above the UCB concentrations found in normal human serum, as a beneficial effect of potential clinical relevance. We provide evidence that UCB interferes with the interaction between C1q and immunoglobulins, thus inhibiting the initial step in the activation of C through the CP. A molecular model is proposed for the interaction between UCB and C1q.