Elevated levels of endogenous apoptotic DNA and IFN-alpha in complement C4-deficient mice: implications for induction of systemic lupus erythematosus.
Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis and dermatitis, and the presence of antinuclear autoantibodies, is associated with complement factor deficiencies in the classical activation pathway. In addition, IFN-alpha seems to be a key cytokine in SLE as an activated IFN-alpha system is regularly observed in patients with SLE. Here, we demonstrate that in lupus-susceptible, complement C4-deficient mice the lack of complement results in elevated intravascular levels of apoptotic DNA. The apoptotic DNA is targeted to the splenic marginal zone where it accumulates and induces IFN-alpha. As such, we present here a unifying hypothesis for the induction of SLE that incorporates the role of complement deficiency and elevated levels of IFN-alpha.
Finke
Doreen
D
Institute of Immunology and Transfusion Medicine, University of Lübeck, Lübeck, Germany.
Randers
Katharina
K
Hoerster
Robert
R
Hennig
Holger
H
Zawatzky
Rainer
R
Marion
Tony
T
Brockmann
Christian
C
Klempt-Giessing
Katja
K
Jacobsen
Kirsten
K
Kirchner
Holger
H
Goerg
Siegfried
S
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000032:analysis / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D039481:CD11b Antigen / Q000032:analysis; D003181:Complement C4 / Q000172:deficiency / Q000235:genetics*; D004247:DNA / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D016898:Interferon-alpha / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000032:analysis; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; C016759:C4b protein, mouse; D039481:CD11b Antigen; D003181:Complement C4; D007075:Immunoglobulin M; D016898:Interferon-alpha; D012333:RNA, Messenger; D007371:Interferon-gamma; D004247:DNA; D017493:Leukocyte Common Antigens