title: Complement activation by phospholipids: the interplay of factor H and C1q.
abstract: Complement proteins in blood recognize charged particles. The anionic phospholipid (aPL) cardiolipin binds both complement proteins C1q and factor H. C1q is an activator of the complement classical pathway, while factor H is an inhibitor of the alternative pathway. To examine opposing effects of C1q and factor H on complement activation by aPL, we surveyed C1q and factor H binding, and complement activation by aPL, either coated on microtitre plates or in liposomes. Both C1q and factor H bound to all aPL tested, and competed directly with each other for binding. All the aPL activated the complement classical pathway, but negligibly the alternative pathway, consistent with accepted roles of C1q and factor H. However, in this system, factor H, by competing directly with C1q for binding to aPL, acts as a direct regulator of the complement classical pathway. This regulatory mechanism is distinct from its action on the alternative pathway. Regulation of classical pathway activation by factor H was confirmed by measuring C4 activation by aPL in human sera in which the C1q:factor H molar ratio was adjusted over a wide range. Thus factor H, which is regarded as a down-regulator only of the alternative pathway, has a distinct role in downregulating activation of the classical complement pathway by aPL. A factor H homologue, β2-glycoprotein-1, also strongly inhibits C1q binding to cardiolipin. Recombinant globular domains of C1q A, B and C chains bound aPL similarly to native C1q, confirming that C1q binds aPL via its globular heads.
authors.affiliation: MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Rd, Oxford OX13QU, UK.
authors.forename: Lee Aun
authors.initials: LA
authors.lastname: Tan
authors.forename: Bingbin
authors.initials: B
authors.lastname: Yu
authors.forename: Francis C J
authors.initials: FC
authors.lastname: Sim
authors.forename: Uday
authors.initials: U
authors.lastname: Kishore
authors.forename: Robert B
authors.initials: RB
authors.lastname: Sim
mesh_terms: D000818:Animals; D003167:Complement Activation; D015922:Complement C1q / Q000737:chemistry / Q000378:metabolism*; D017242:Complement Factor H / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D007074:Immunoglobulin G; D010743:Phospholipids; D015922:Complement C1q; D017242:Complement Factor H