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

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 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 nephritis. In contrast, diminishing the burden IgG-ICs in MRL/lpr mice through deficiency in FcγRI markedly improves these lupus pathologies. Together, our findings reveal a previously unappreciated role for the cell surface accumulation of IgG-ICs in human and murine lupus.

Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

“…As a result, the IgG-ICs were not degraded and recycled back to the cell membrane. Hematopoietic cells from SLE patients have high levels of IgG and nuclear antigens (32), and they express LAMP1/2 on the cell surface (56). These findings support the idea that the lysosomal compartment has trafficked to the membrane and are consistent with our data showing that MFs from lupus-prone mice accumulated high levels of nuclear antigens (Fig.…”

“…1) (32). Similarly, SLE patients experiencing active disease accumulate nuclear antigens on peripheral blood mononuclear cells (32). Therefore, we assessed whether the accumulation of IgG-ICs occurs in other autoimmune models by quantifying the levels of surface IgG and nuclear antigen on MFs from murine models of diabetes (NOD) and rheumatoid arthritis (K/BxN).…”

“…Although this study focuses on defining how nuclear antigens accumulate on MFs, it is important to keep in mind that nuclear antigen accumulates on DCs and B and T cells (32). Thus, it is possible that other cells may harbor defects in lysosomal maturation, contributing other disease manifestations.…”

“…The IgG-ICs appeared to remain intact and bound by FcγRs, because both the antibody and apoptotic debris colocalized on the surface of the cell (Fig. S4), and the levels of surface FcγRI and IgG on MRL/lpr MFs increased proportionately (32 (Fig. 4 A and B), they remain impaired in lysosomal acidification and recycle internalized IgG-ICs.…”

The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis

“…Polymorphisms and/or copy number variants in multiple FcγR genes are linked to SLE susceptibility and associated with LN [23–27]. There is an accumulation of immune complexes bound to activating FcγRI and FcγRIV SLE-prone mice [28], and deletion of FcγRI in a murine model of SLE results in protection from immune complex accumulation in the kidney [28]. In contrast, FcγRIIB −/− mice develop severe SLE-like nephritis [29].…”