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

Determining disease activity in systemic lupus erythematosus (SLE) patients is challenging and limited by the lack of reliable biomarkers. Abnormally activated B cells play a key role in the pathogenesis of SLE, but their measure in clinical practice is currently not recommended. Here, we studied peripheral B cells to identify a valid biomarker. We analyzed peripheral B cells in a discovery cohort of 30 SLE patients compared to 30 healthy controls (HC) using mass cytometry and unsupervised clustering analysis. The relevant B cell populations were subsequently studied by flow cytometry in a validation cohort of 63 SLE patients, 28 autoimmune diseases controls and 39 HC. Our data show an increased frequency of B cell populations with activated phenotype in SLE compared to healthy and autoimmune diseases controls. These cells uniformly lacked the expression of CD21 and CD27. Measurement of CD21-CD27- B cells in the blood identified patients with active disease and their frequency correlated with disease severity. Interestingly, we did not observe an increase in the frequency of CD21-CD27- B cells in patients with clinically inactive disease but with elevated conventional biomarkers (anti-dsDNA and complement levels). Accordingly, measurement of CD21-CD27- B cells represents a robust and easily accessible biomarker to assess the activity of the disease in SLE patients.

SLAMF Receptor Expression Identifies an Immune Signature That Characterizes Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology, linked to alterations in both the innate and the adaptive immune system. Due to the heterogeneity of the clinical presentation, the diagnosis of SLE remains complicated and is often made years after the first symptoms manifest, delaying treatment, and worsening the prognosis. Several studies have shown that signaling lymphocytic activation molecule family (SLAMF) receptors are aberrantly expressed and dysfunctional in SLE immune cells, contributing to the altered cellular function observed in these patients. The aim of this study was to determine whether altered co-/expression of SLAMF receptors on peripheral blood mononuclear cells (PBMC) identifies SLE characteristic cell populations. To this end, single cell mass cytometry and bioinformatic analysis were exploited to compare SLE patients to healthy and autoimmune diseases controls. First, the expression of each SLAMF receptor on all PBMC populations was investigated. We observed that SLAMF1+ B cells (referred to as SLEB1) were increased in SLE compared to controls. Furthermore, the frequency of SLAMF4+ monocytes and SLAMF4+ NK were inversely correlated with disease activity, whereas the frequency SLAMF1+ CD4+ TDEM cells were directly correlated with disease activity. Consensus clustering analysis identified two cell clusters that presented significantly increased frequency in SLE compared to controls: switch memory B cells expressing SLAMF1, SLAMF3, SLAMF5, SLAMF6 (referred to as SLESMB) and circulating T follicular helper cells expressing the same SLAMF receptors (referred to as SLEcTFH). Finally, the robustness of the identified cell populations as biomarkers for SLE was evaluated through ROC curve analysis. The combined measurement of SLEcTFH and SLEB1 or SLESMB cells identified SLE patients in 90% of cases. In conclusion, this study identified an immune signature for SLE based on the expression of SLAMF receptors on PBMC, further highlighting the involvement of SLAMF receptors in the pathogenesis of SLE.

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

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.

Innate Lymphoid Cells in Autoimmune Diseases.

Innate lymphoid cells (ILC) are a heterogeneous group of immune cells characterized by lymphoid morphology and cytokine profile similar to T cells but which do not express clonally distributed diverse antigen receptors. These particular cells express transcription factors and cytokines reflecting their similarities to T helper (Th)1, Th2, and Th17 cells and are therefore referred to as ILC1, ILC2, and ILC3. Other members of the ILC subsets include lymphoid tissue inducer (LTi) and regulatory ILC (ILCreg). Natural killer (NK) cells share a common progenitor with ILC and also exhibit a lymphoid phenotype without antigen specificity. ILC are found in low numbers in peripheral blood but are much more abundant at barrier sites such as the skin, liver, airways, lymph nodes, and the gastrointestinal tract. They play an important role in innate immunity due to their capacity to respond rapidly to pathogens through the production of cytokines. Recent evidence has shown that ILC also play a key role in autoimmunity, as alterations in their number or function have been identified in systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Here, we review recent advances in the understanding of the role of ILC in the pathogenesis of autoimmune diseases, with particular emphasis on their role as a potential diagnostic biomarker and as therapeutic targets.