title: Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity.
abstract: Complement activation contributes to inflammation in many diseases, yet it also supports physiologic apoptotic cells (AC) clearance and its downstream immunosuppressive effects. The roles of individual complement components in AC phagocytosis have been difficult to dissect with artificially depleted sera. Using human in vitro systems and the novel antibody complement C1s inhibitor TNT003, we uncoupled the role of the enzymatic activation of the classical pathway from the opsonizing role of C1q in mediating a) the phagocytosis of early and late AC, and b) the immunosuppressive capacity of early AC. We found that C1s inhibition had a small impact on the physiologic clearance of early AC, leaving their immunosuppressive properties entirely unaffected, while mainly inhibiting the phagocytosis of late apoptotic/secondary necrotic cells. Our data suggest that C1s inhibition may represent a valuable therapeutic strategy to control classical pathway activation without causing significant AC accumulation in diseases without defects in AC phagocytosis.
authors.affiliation: University of Washington, Division of Rheumatology, 750 Republican Street, Box 358060, Seattle, WA 98109, USA. Electronic address: lcolonna@uw.edu.
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Colonna
authors.affiliation: True North Therapeutics, Inc, 951 Gateway Blvd, South San Francisco, CA 94080, USA. Electronic address: Graham@truenorthrx.com.
authors.forename: Graham C
authors.initials: GC
authors.lastname: Parry
authors.affiliation: True North Therapeutics, Inc, 951 Gateway Blvd, South San Francisco, CA 94080, USA. Electronic address: Sandip@truenorthrx.com.
authors.forename: Sandip
authors.initials: S
authors.lastname: Panicker
authors.affiliation: University of Washington, Division of Rheumatology, 750 Republican Street, Box 358060, Seattle, WA 98109, USA. Electronic address: elkon@uw.edu.
authors.forename: Keith B
authors.initials: KB
authors.lastname: Elkon
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D003167:Complement Activation / Q000187:drug effects* / Q000276:immunology; D015922:Complement C1q / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D003173:Complement C1s / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003179:Complement C3b / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects* / Q000276:immunology; D057899:Cytophagocytosis / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000187:drug effects / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D019169:Jurkat Cells; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; C439524:TNF protein, human; C000608635:TNT003; D014409:Tumor Necrosis Factor-alpha; D015922:Complement C1q; D003179:Complement C3b; D003173:Complement C1s
keywords: Apoptotic cells; C1q; C1s; Complement; Phagocytosis; Systemic lupus erythematosus