Apoptotic debris accumulates on hematopoietic cells and promotes disease in murine and human systemic lupus erythematosus

SA Kang, JL Rogers, AJ Monteith, C Jiang… - The Journal of …, 2016 - journals.aai.org
The Journal of Immunology, 2016journals.aai.org
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 PBMCs 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 …
Abstract
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 PBMCs 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 wk 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 nephritis. In contrast, diminishing the burden IgG-ICs in MRL/lpr mice through deficiency in FcγRI markedly improves these lupus pathologies. Taken together, our findings reveal a previously unappreciated role for the cell surface accumulation of IgG-ICs in human and murine lupus.
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