Background/Purpose: Systemic lupus erythematous (SLE) is a complex autoimmune disorder with heterogeneous disease presentation and a multi-pronged pathogenesis. Although autoreactive plasma cells play a key role in SLE, they are still elusive targets. Selective inhibitors of nuclear export (SINE) were recently approved by the FDA for treatment of refractory multiple myeloma (selinexor). Our lab has demonstrated that SINE abrogate lupus nephritis and significantly reduce autoreactive plasma cells in lupus prone NZBW/F1 mice. Here we investigated the impact of SINE on In vitro survival and antibody secretion of human plasma cells (PC) and how these classic PC functions are modulated by the bone marrow (BM) microenvironment.

Methods: Peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) from healthy (n = 4) and SLE donors (n = 4), cultured in the presence of mesenchymal stromal cell secretome, were treated with KPT-335 for different periods of time. Number of antibody secreting cells (ASC) and PC survival were assessed by IgG ELISPOT and annexin V-propidium iodide flow based apoptosis assay, respectively. CD19⁺CD27^hiCD38^hi blood plasmablasts, CD19⁺CD27^hiCD38^hiCD138⁺ BM mature PCs and CD19^–CD27^hiCD38^hiCD138⁺ BM long-lived PCs were sorted for transcriptomic analysis (controls: n = 7 and SLE: n = 9).

Results: Blood ASC were significantly reduced (IC50= 0.1uM) compared to BM ASC (IC50 = 10uM) after short-term ex vivo treatment with KPT-335 (24 hours). In long-term cultures (120 hours), there was a greater impact on BM PCs (IC50=0.1uM). We also examined the capacity of SINEs to induce apoptosis in different PC subsets. Blood plasmablasts from both healthy and SLE donors were reduced by 30-70% after SINE treatment for 48 hours. Of note, SINE treatment did not affect BM mature and long-lived PC. In transcriptomic analysis, BM PCs showed up-regulation of NFkB signaling and extra-cellular matrix receptor interactions (gene pathway analysis), and experienced down-regulation of cell cycle signaling pathways, compared to blood PC. Mature and long-lived PC in lupus BM had a prominent interferon (IFN) signature compared to controls. We are currently investigating the impact of type I IFN on PC survival and function.

Conclusion: SINEs represent a novel treatment approach for SLE. These results support the hypothesis that the effect of SINEs on PC depends upon the dose and duration of treatment, and is modulated by BM microenvironmental signals that orchestrate PC survival.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impact-of-selective-inhibitors-of-nuclear-export-on-sle-plasma-cells-is-modulated-by-the-bm-microenvironment/