Restoration of NK Cell Cytotoxic Function With Elotuzumab and Daratumumab Promotes Elimination of Circulating Plasma Cells in Patients With SLE

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by multiple cellular and molecular dysfunctions of the innate and adaptive immunity. Cytotoxic function of NK cells is compromised in patients with SLE. Herein, we characterized the phenotypic alterations of SLE NK cells in a comprehensive manner to further delineate the mechanisms underlying the cytotoxic dysfunction of SLE NK cells and identify novel potential therapeutic targets. Therefore, we examined PBMC from SLE patients and matched healthy controls by single-cell mass cytometry to assess the phenotype of NK cells. In addition, we evaluated the cell function of NK cells (degranulation and cytokine production) and the killing of B cell subpopulations in a B cell-NK cell in vitro co-culture model. We found that SLE NK cells expressed higher levels of CD38 and were not able to adequately upregulate SLAMF1 and SLAMF7 following activation. In addition, ligation of SLAMF7 with elotuzumab or of CD38 with daratumumab on SLE NK cells enhanced degranulation of both healthy and SLE NK cells and primed them to kill circulating plasma cells in an in vitro co-culture system. Overall, our data indicated that dysregulated expression of CD38, SLAMF1 and SLAMF7 on SLE NK cells is associated with an altered interplay between SLE NK cells and plasma cells, thus suggesting their contribution to the accumulation of (auto)antibody producing cells. Accordingly, targeting SLAMF7 and CD38 may represent novel therapeutic approaches in SLE by enhancing NK cell function and promoting elimination of circulating plasma cell.

Peripheral blood lymphocytes and monocytes heterogeneity in SLE patients treated by Belimumab

“…NK cells in SLE exhibit an impairment with cytotoxic function. Increasing studies have suggested that restoration of NK cell cytotoxic function by regulating SLAMF7 and CD38 can promote plasma cell deletion and contribute to SLE improvement [35]. Our data has implicated a declined level of NK cells in SLE patients, which is consistent with ndings in a previous study [32].…”

Measurement of circulating CD21−CD27− B lymphocytes in SLE patients is associated with disease activity independently of conventional serological biomarkers

“…Disease activity was assessed using the Safety of Estrogens in Lupus Erythematosus National Assessment modification (SELENA)-SLEDAI and the Physician's Global Assessment score (PGA) 33 . We categorized SLE patients into three groups of disease activity: inactive (SELENA-SLEDAI 0–3), moderate (SELENA-SLEDAI 4–10) and active (SELENA-SLEDAI > 10) 58 . Clinical SELENA-SLEDAI was used to evaluate disease activity, while excluding complement and anti-dsDNA from the score.…”

“…Cryopreserved PBMC from SLE and matched HC were processed and analyzed as previously published 58 . Lists of mass cytometry antibodies are provided in the Supplementary Table 2 and were previously described 58 .…”

Increased CD21-CD27- atypical memory B cells as a biomarker of clinical disease activity in patients with systemic lupus erythematosus

“…Cryopreserved PBMC from SLE and matched HC were processed and analyzed as previously published (5). Lists of mass cytometry antibodies are provided in the Supplementary Table 3 and were previously described (5). To avoid batch effect, PBMCs of SLE and matched HC were barcoded, processed, and examined at the same time.…”

“…Cryopreserved PBMC from SLE and matched HC were processed and analyzed as previously published (5). Lists of mass cytometry antibodies are provided in the Supplementary Table 3 and were previously described (5).…”