title: Functional complement C1q abnormality leads to impaired immune complexes and apoptotic cell clearance.
abstract: C1q plays a key role in apoptotic cell and immune complex removal. Its absence contributes to the loss of tolerance toward self structures and development of autoimmunity. C1q deficiencies are extremely rare and are associated with complete lack of C1q or with secretion of surrogate C1q fragments. To our knowledge, we report the first case of a functional C1q abnormality, associated with the presence of a normal C1q molecule. Homozygous GlyB63Ser mutation was found in a patient suffering from lupus with neurologic manifestations and multiple infections. The GlyB63Ser C1q bound to Igs, pentraxins, LPSs, and apoptotic cells, similarly to C1q from healthy donors. However, the interaction of C1r(2)C1s(2) and C1 complex formation was abolished, preventing further complement activation and opsonization by C3. The mutation is located between LysB(61) and LysB(65) of C1q, suggested to form the C1r binding site. Our data infer that the binding of C1q to apoptotic cells in humans is insufficient to assure self-tolerance. The opsonization capacity of C4 and C3 fragments has to be intact to fight infections and to prevent autoimmunity.
authors.affiliation: Centre de Recherche des Cordeliers, INSERM Unité Mixte de Recherche en Santé 872, 75006 Paris, France. lubka.roumenina@crc.jussieu.fr
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
authors.forename: Damien
authors.initials: D
authors.lastname: Sène
authors.forename: Maria
authors.initials: M
authors.lastname: Radanova
authors.forename: Jacques
authors.initials: J
authors.lastname: Blouin
authors.forename: Lise
authors.initials: L
authors.lastname: Halbwachs-Mecarelli
authors.forename: Marie-Agnes
authors.initials: MA
authors.lastname: Dragon-Durey
authors.forename: Wolf H
authors.initials: WH
authors.lastname: Fridman
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
mesh_terms: D000328:Adult; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D003167:Complement Activation / Q000235:genetics* / Q000276:immunology; D015922:Complement C1q / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004252:DNA Mutational Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D017354:Point Mutation; D017634:Self Tolerance / Q000235:genetics* / Q000276:immunology
chemical_list: D000936:Antigen-Antibody Complex; D015922:Complement C1q