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,
,¶
* Department of Medicine,
Department of Cell Biology, and
Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21224;
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; and
¶ Department of Pathology, Uniformed Services University, Bethesda, MD 20814
Although defects in apoptosis have been linked to both human and murine lupus, the exact mechanisms remain unknown. Moreover, it is not clear whether such defects are primary or secondary events in disease pathogenesis. To address these issues, we used an induced model of murine lupus, the parent-into-F1 model of chronic graft-versus-host disease (cGVHD) in which a lupus-like phenotype highly similar to human systemic lupus erythematosus is reliably induced in normal F1 mice. We addressed the role of nuclear Ags modified by caspases during apoptosis as potential targets of the autoantibody response and our results identify poly(ADP-ribose) polymerase 1 (PARP-1) as a frequently targeted autoantigen. Additional proteins cleaved during apoptosis were also targeted by the immune response. Importantly, female mice exhibited significantly greater numbers of apoptotic cells in germinal centers and higher serum anti-PARP-1 Ab levels compared with male cGVHD mice. Serum anti-PARP-1 levels in male cGVHD mice could be elevated to levels comparable to those of female cGVHD mice by the injection of apoptotic syngeneic F1 splenocytes early in the disease course. These results provide a mechanism by which lupus autoantibodies target apoptotic molecules. Specifically, T cell-driven polyclonal B cell activation characteristic of systemic lupus erythematosus is sufficient to saturate otherwise normal apoptotic clearance mechanisms, permitting apoptotic material to accumulate, serve as autoantigens, and drive autoantibody production.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 These studies were supported by National Institutes of Health Grants AR 44684 (to L.C.R.), DE 12354 (to A.R.), AI 47466 (to C.S.V.), AR 48522-01 (to T.G.B.), a Maryland Chapter Arthritis Foundation Institutional Grant, and a Maryland Chapter Arthritis Foundation Maryland Arthritis Research Center Award.
2 Address correspondence and reprint requests to Dr. Charles S. Via, Department of Pathology, Uniformed Services University of Health Sciences, Room B3-100, 4301 Jones Bridge Road, Bethesda, MD 20814. E-mail address: cvia{at}usuhs.mil
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; cGVHD, chronic graft-versus-host disease; IVTT, in vitro transcription/translation; P
F1, parent-into-F1; PARP-1, poly(ADP-ribose) polymerase 1; AU, arbitrary unit.
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