Background/Purpose: Systemic lupus erythematous (SLE) is a complex autoimmune disorder with heterogeneous disease presentation and a multi-pronged pathogenesis. Although autoreactive plasma cells (PC) play a key role in SLE, they are still elusive targets. In particular, bone marrow (BM) PC represent a long-lived (LL) pool that may be particularly difficult to eliminate. In order to define the signals that promote the survival of LLPCs in lupus BM, we performed transcriptomic analysis on sorted human BM populations.

Methods: Human CD19⁺CD27^hiCD38^hi blood plasmablasts (PB), CD19⁺CD27^hiCD38^hiCD138⁺ BM mature PCs and CD19^–CD27^hiCD38^hiCD138⁺ BM long-lived PCs (LLPC) were sorted for transcriptomic analysis (controls: n = 7 and SLE: n = 9). The impact of interferon (IFN-α2) on antibody secretion and PC survival was assessed by IgG ELISPOT, ELISA (n=5), and annexin V-propidium iodide flow cytometry-based apoptosis assay (n=3). STAT1 phosphorylation fold change (FC) after IFN-α2 stimulation was measured by flow cytometry median fluorescent intensity (n=3).

Results: In transcriptomic analysis, BM PCs showed up-regulation of NFkB signaling and extra-cellular matrix receptor interactions, and down-regulation of cell cycle signaling pathways, compared to blood PC (gene pathway enrichment analysis). Going along with this difference in transcriptomic profile, BM PCs had a higher survival in vitro compared to blood PB. PCs in the lupus BM, including the putative long-lived PC, had a prominent IFN signature compared to those of healthy controls. We next asked whether BM PC can respond to IFN. Indeed, both BM LLPCs (CD19- Ig+ CD27^hi CD38^hi) and PB/PC (CD19+ Ig+ CD27^hi CD38^hi) had increased STAT1 phosphorylation in response to IFN-α2 stimulation (FC for IgG+ BM LLPC: 5.07±0.97 in HD, 3.89±0.45 in SLE and for IgG+ BM PB/PC 4.35±0.86 in HD, 4.02±0.62 in SLE). However, IFN-α2 treatment did not alter IgG secretion or PC survival in in vitro culture experiments.

Conclusion: Our data highlights the importance of bone marrow microenvironment signals for PC survival. The pronounced IFN signature in the lupus BM suggests that IFN may be a key mediator of autoreactive PC longevity in SLE. We are currently investigating the impact of alternative interferons alone and in combination with other signals on PC survival and function.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/long-lived-plasma-cells-in-the-lupus-bone-marrow-are-imprinted-by-interferon/