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* Division of Rheumatology, Department of Medicine, University of Pennsylvania, and
Department of Microbiology and Immunology, and Division of Nephrology, Temple University School of Medicine, Philadelphia, PA 19140; and
Division of Rheumatology and Clinical Immunology, Department of Medicine, and Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
Nuclear autoantigens in systemic lupus erythematosus are thought to derive primarily from apoptotic cells, yet there is no direct evidence that interfering with apoptosis impairs the generation of lupus autoantibodies. Here we use a mouse model that lacks the endonuclease caspase-activated DNase (CAD), resulting in an absence of chromatin and nuclear fragmentation during apoptotic cell death. We show that in this mouse, production and release into circulation of chromatin is impaired after exposure to several apoptotic triggers, but that the absence of CAD does not interfere with upstream steps of apoptosis or immune system function. Finally we show that in CAD-mutant mice, impaired lupus autoimmunity is skewed toward known cytoplasmic components, and autoimmunity toward membrane autoantigens is preserved, while autoimmunity toward chromatin and other lupus nuclear targets is severely impaired or absent. We also show, as control, that the induction of experimental autoimmune encephalomyelitis is not affected by the absence of CAD. Thus, our work in vivo strongly suggests that apoptotic molecular steps during cell death generate nuclear autoantigens to sustain the specific autoimmune response in systemic lupus erythematosus.
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1 This work was supported by the Lupus Research Institute (R.C.), the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (R.C), and the American Heart Association (M.M).
2 Address correspondence and reprint requests to Dr. Roberto Caricchio, Division of Rheumatology, University of Pennsylvania, 751 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, PA 19104. E-mail address: rocarri2{at}mail.med.upenn.edu
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; aCL, anti-cardiolipin; CAD, caspase-activated DNase; EAE, experimental autoimmune encephalomyelitis; NP40, Nonidet P-40; ANA, anti-nuclear Abs; snRNP, small nuclear ribonucleoproteins; MRL/lpr, MRL/Mp-lpr/lpr; IP, immunoprecipitation technique; pristane, 2,6,10,14-tetramethylpentadecane; RT, room temperature; CL, chemiluminescence.
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