title: 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.
authors.affiliation: Institute of Experimental Physiology (CONICET), National University of Rosario, S2002LRL-Rosario, Argentina.
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: Basiglio
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Arriaga
authors.forename: Fabián
authors.initials: F
authors.lastname: Pelusa
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Almará
authors.forename: Jaime
authors.initials: J
authors.lastname: Kapitulnik
authors.forename: Aldo D
authors.initials: AD
authors.lastname: Mottino
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D001663:Bilirubin / Q000494:pharmacology / Q000502:physiology; D015922:Complement C1q / Q000378:metabolism; D051056:Complement Inactivating Agents / Q000494:pharmacology; D003171:Complement Pathway, Classical / Q000187:drug effects / Q000276:immunology*; D019610:Cytoprotection / Q000502:physiology; D006801:Humans; D006932:Hyperbilirubinemia / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000276:immunology
chemical_list: D000975:Antioxidants; D051056:Complement Inactivating Agents; D015922:Complement C1q; D001663:Bilirubin