title: Complement 1 inhibitor is a regulator of the alternative complement pathway.
abstract: We studied complement 1 inhibitor (C1-INH) as an inhibitor of the alternative complement pathway. C1-INH prevented lysis, induced by the alternative complement pathway, of paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes in human serum. It inhibited the binding of both factors B and C3 to PNH and rabbit erythrocytes and blocked the ability of factor B to restore alternative-pathway function in factor B-depleted serum. C1-INH did not bind to factors B or D but did bind to immobilized C3b and cobra venom factor (CVF), a C3b analogue. C1-INH prevented factor B from binding to CVF-coated beads and dissociated bound factor B from such beads. Factor B and C1-INH showed cross competition in binding to CVF-coated beads. Factor D cleaved factor B into Bb and Ba in the presence of C3b. Cleavage was markedly inhibited when C3b was preincubated with C1-INH. C1-INH inhibited the formation of CVFBb and decreased the C3 cleavage. Removal of C1-INH from serum, in the presence of Mg-EGTA with an anti-C1-INH immunoabsorbant, markedly increased alternative-pathway lysis. C1-INH interacts with C3b to inhibit binding of factor B to C3b. At physiologic concentrations, it is a downregulator of the alternative pathway convertase.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.forename: E
authors.initials: E
authors.lastname: Wagner
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: M M
authors.initials: MM
authors.lastname: Frank
mesh_terms: D000042:Absorption; D000818:Animals; D003174:Complement C1 Inactivator Proteins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D051561:Complement C3 Convertase, Alternative Pathway; D003179:Complement C3b / Q000276:immunology* / Q000378:metabolism; D011415:Complement Factor B / Q000276:immunology* / Q000378:metabolism; D011416:Complement Factor D / Q000276:immunology* / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000276:immunology / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000276:immunology*; D004533:Egtazic Acid / Q000494:pharmacology; D004546:Elapid Venoms / Q000276:immunology / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006023:Glycoproteins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood / Q000276:immunology*; D006461:Hemolysis / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008863:Microspheres; D010446:Peptide Fragments / Q000378:metabolism; D011817:Rabbits; D012685:Sepharose
chemical_list: D003174:Complement C1 Inactivator Proteins; D003169:Complement Inactivator Proteins; D004546:Elapid Venoms; D006023:Glycoproteins; D010446:Peptide Fragments; C016310:cobra venom factor; C051367:complement C3bBa complex; D004533:Egtazic Acid; D003179:Complement C3b; D012685:Sepharose; C493488:CFD protein, human; D011416:Complement Factor D; D051561:Complement C3 Convertase, Alternative Pathway; D011415:Complement Factor B