Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus

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 p...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2016-05, Vol.196 (10), p.4030-4039
Main Authors: Kang, SunAh, Rogers, Jennifer L, Monteith, Andrew J, Jiang, Chuancang, Schmitz, John, Clarke, Stephen H, Tarrant, Teresa K, Truong, Young K, Diaz, Marilyn, Fedoriw, Yuri, Vilen, Barbara J
Format: Article
Language:English
Subjects:
Adult
Animals
Apoptosis
Autoantigens - immunology
Autoantigens - metabolism
B-Cell Activating Factor - metabolism
Blood Cells - immunology
Dendritic Cells - immunology
Female
Humans
Lupus Erythematosus, Systemic - immunology
Macrophages - immunology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred MRL lpr
Mice, Knockout
Middle Aged
Receptors, IgG - genetics
Young Adult
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1500418