Apoptotic debris accumulates on hematopoietic cells and promotes disease in murine and human SLE 1

Apoptotic debris, autoantibody, and IgG-immune complexes (ICs) have long been implicated in the inflammation associated with systemic lupus erythematosus (SLE); however, it remains unclear whether they initiate immune-mediated events that promote disease. In this study, we show that peripheral blood mononuclear cells from SLE patients experiencing active disease, and hematopoietic cells from lupus-prone MRL/lpr and NZM2410 mice accumulate markedly elevated levels of surface-bound nuclear self-antigens. On dendritic cells (DCs) and macrophages (MFs), the self-antigens are part of IgG-ICs that promote FcγRI-mediated signal transduction. Accumulation of IgG-ICs is evident on ex vivo myeloid cells from MRL/lpr mice by 10 weeks of age, and steadily increases prior to lupus nephritis. IgG and FcγRI play a critical role in disease pathology. Passive transfer of pathogenic IgG into IgG-deficient MRL/lpr mice promotes the accumulation of IgG-ICs prior to significant B cell expansion, BAFF secretion, and lupus 1This work was supported by NIH R01AI070984, NIH R21AI105613, Alliance for Lupus Research, and the National Center for Advancing Translational Sciences (NCATS; National Institutes of Health) through Grant Award Number 1UL1TR001111. A.J.M. was supported by 5T32AI07273-27. Corresponding author: Barbara Vilen Ph.D., Department of Microbiology and Immunology, CB# 7290, University of North Carolina, Chapel Hill, NC 27599, Phone: 919-966-5436, FAX: 919-962-8103, barb_vilen@med.unc.edu. 2To whom correspondence should be sent: 125 Mason Farm Road, Chapel Hill, North Carolina 27599-7290 Author Contributions: S-A. K. directed and performed experiments, analyzed data, and wrote the manuscript; A.J.M. performed experiments and analyzed data; J.L.R performed experiments and analyzed data; S.H.C analyzed data, C.J. and M.D. provided mice; T.K.T, J.L.R and J.S. provided patient samples; Y.F. analyzed kidney pathology; Y.K.T. performed statistical analysis; B.J.V. codirected experiments and wrote the manuscript. The authors declare no competing financial interests. HHS Public Access Author manuscript J Immunol. Author manuscript; available in PMC 2017 May 15. Published in final edited form as: J Immunol. 2016 May 15; 196(10): 4030–4039. doi:10.4049/jimmunol.1500418. A uhor M anscript