A Novel Mechanism for Generating the Interferon Signature in Lupus: Opsonization of Dead Cells by Complement and IgM.
In vitro studies suggest that the type I interferon (IFN) signature seen in most lupus patients results from Fcγ receptor-mediated uptake of nucleic acid-containing immune complexes by plasmacytoid dendritic cells and engagement of endosomal Toll-like receptors. The aim of this study was to reexamine the pathogenesis of the IFN signature in vivo.



Lupus was induced in mice by injecting pristane. Some mice were treated with normal immunoglobulin or with cobra venom factor to deplete complement. The IFN signature was evaluated by polymerase chain reaction. The IFN signature also was determined in C4-deficient patients and control subjects.



Wild-type C57BL/6 mice with pristane-induced lupus developed a strong IFN signature, which was absent in immunoglobulin-deficient (μMT), C3-/-, and CD18-/-mice. Intravenous infusion of normal IgM, but not IgG, restored the IFN signature in μMT mice, and the IFN signature in wild-type mice was inhibited by depleting complement, suggesting that opsonization by IgM and complement is involved in IFN production. Consistent with that possibility, the levels of "natural" IgM antibodies reactive with dead cells were increased in pristane-treated wild-type mice compared with untreated controls, and in vivo phagocytosis of dead cells was impaired in C3-deficient mice. To examine the clinical relevance of these findings, we identified 10 C4-deficient patients with lupus-like disease and compared them with 152 C4-intact patients and 21 healthy controls. In comparison with C4-intact patients, C4-deficient patients had a different clinical/serologic phenotype and lacked the IFN signature.



These studies define previously unrecognized roles of natural IgM, complement, and complement receptors in generating the IFN signature in lupus.
University of Florida, Gainesville.
Haoyang
H
Zhuang
University of Florida, Gainesville.
Shuhong
S
Han
University of Florida, Gainesville.
Yi
Y
Li
Universitätsklinikum Erlangen, Erlangen, Germany.
Deborah
D
Kienhöfer
Boston Children's Hospital, Boston, Massachusetts.
Pui
P
Lee
University of Florida, Gainesville.
Stepan
S
Shumyak
University of Florida, Gainesville.
Richard
R
Meyerholz
University of Florida, Gainesville.
Krzysztof
K
Rosadzinski
University of Florida, Gainesville.
Danielle
D
Rosner
University of Florida, Gainesville.
Annie
A
Chan
University of Florida, Gainesville.
Yuan
Y
Xu
University of Florida, Gainesville.
Mark
M
Segal
University of Florida, Gainesville.
Eric
E
Sobel
University of Florida, Gainesville.
Li-Jun
LJ
Yang
Universitätsklinikum Erlangen, Erlangen, Germany.
Markus H
MH
Hoffmann
University of Florida, Gainesville.
Westley H
WH
Reeves
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D018821:CD18 Antigens / Q000235:genetics; D016022:Case-Control Studies; D003176:Complement C3 / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D003181:Complement C4 / Q000172:deficiency; D051056:Complement Inactivating Agents / Q000494:pharmacology; D003165:Complement System Proteins / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004546:Elapid Venoms / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007075:Immunoglobulin M / Q000276:immunology* / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000633:toxicity; D007370:Interferon Type I / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009895:Opsonin Proteins / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013729:Terpenes / Q000633:toxicity
D001323:Autoantibodies; D018821:CD18 Antigens; D003176:Complement C3; D003181:Complement C4; D051056:Complement Inactivating Agents; D016207:Cytokines; D004546:Elapid Venoms; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D007370:Interferon Type I; D009895:Opsonin Proteins; D013729:Terpenes; C016310:cobra venom factor; C009042:pristane; D003165:Complement System Proteins