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

Authors :
Yuri Fedoriw
Stephen H. Clarke
Barbara J. Vilen
John L. Schmitz
Jennifer L. Rogers
SunAh Kang
Andrew J. Monteith
Marilyn Diaz
Chuancang Jiang
Young K. Truong
Teresa K. Tarrant
Publication Year :
2016
Publisher :
The University of North Carolina at Chapel Hill University Libraries, 2016.

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.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....50d5188d0e261aeb90fa30ec9ccb4621
Full Text :
https://doi.org/10.17615/xwve-c619