Complement activation and disease: protective effects of hyperbilirubinaemia

Abstract

Complement, an important effector mechanism of the immune system, is an enzymatic cascade of approx. 30 serum proteins leading to the 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 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 complement system leads to diseases of variable severity, and pharmacological inhibition of the complement system is considered as a therapeutic strategy to ameliorate the inflammatory effects of exacerbated complement activation. Bilirubin is a product of haem degradation by the concerted action of haem oxygenase, which converts haem into biliverdin, and biliverdin reductase, which reduces biliverdin to UCB (unconjugated bilirubin). 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 the present review, we describe in detail the anti-complement 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 complement through the classical pathway. A molecular model is proposed for the interaction between UCB and C1q.

High sensitive C-reactive protein and serum amyloid A are inversely related to serum bilirubin: effect-modification by metabolic syndrome

“…In agreement with previous studies, we also found an inverse correlation of hs-CRP with bilirubin [9,10], which is clearly in line with allegedly anti-inflammatory properties of bilirubin. Bilirubin is known to interfere with expression of adhesion molecules VCAM-1 and ICAM-1 [1], with activity of the complement system [38] and with T cell differentiation [39]. Hence, it is conceivable that anti-inflammatory and anti-oxidative effects of bilirubin may both contribute to less low-grade chronic inflammation in MetS [3,15,18,25,26,40].…”

Decreased Serum Bilirubin Is Associated With Silent Cerebral Infarction

“…Recent studies have demonstrated that unconjugated bilirubin inhibits complement activation via interfering with the interaction between C1 component of complement and immunoglobulins. 19 Moreover, heme oxygenase 1 and heme degradation products could attenuate complement-mediated acute inflammation and protect human vascular endothelial cells against complement-mediated injury. 20 In addition, our previous studies have observed that serum bilirubin has a tight correlation with baPWV.…”

Circulating bilirubin and defense against kidney disease and cardiovascular mortality: mechanisms contributing to protection in clinical investigations

“…NO reacts with superoxide to form peroxynitrite (which can induce protein oxidation) and leads to vascular calcification (4). NO bioavailability is gradually reduced (5), leading to vasoconstriction (6) and vascular smooth muscle cell (VSMC) proliferation (7). Biliverdin reductase is expressed on the cell surface of leukocytes and catalyzes the conversion of biliverdin (BV) to bilirubin (UCB).…”