Dysregulated CD38 Expression on Peripheral Blood Immune Cell Subsets in SLE.

Marie Burns,Robert Biesen,Falk Hiepe,Andreas Grützkau,Tobias Alexander,Henrik E Mei,Lennard Ostendorf

doi:10.3390/ijms22052424

Abstract

Given its uniformly high expression on plasma cells, CD38 has been considered as a therapeutic target in patients with systemic lupus erythematosus (SLE). Herein, we investigate the distribution of CD38 expression by peripheral blood leukocyte lineages to evaluate the potential therapeutic effect of CD38-targeting antibodies on these immune cell subsets and to delineate the use of CD38 as a biomarker in SLE. We analyzed the expression of CD38 on peripheral blood leukocyte subsets by flow and mass cytometry in two different cohorts, comprising a total of 56 SLE patients. The CD38 expression levels were subsequently correlated across immune cell lineages and subsets, and with clinical and serologic disease parameters of SLE. Compared to healthy controls (HC), CD38 expression levels in SLE were significantly increased on circulating plasmacytoid dendritic cells, CD14++CD16+ monocytes, CD56+ CD16dim natural killer cells, marginal zone-like IgD+CD27+ B cells, and on CD4+ and CD8+ memory T cells. Correlation analyses revealed coordinated CD38 expression between individual innate and memory T cell subsets in SLE but not HC. However, CD38 expression levels were heterogeneous across patients, and no correlation was found between CD38 expression on immune cell subsets and the disease activity index SLEDAI-2K or established serologic and immunological markers of disease activity. In conclusion, we identified widespread changes in CD38 expression on SLE immune cells that highly correlated over different leukocyte subsets within individual patients, but was heterogenous within the population of SLE patients, regardless of disease severity or clinical manifestations. As anti-CD38 treatment is being investigated in SLE, our results may have important implications for the personalized targeting of pathogenic leukocytes by anti-CD38 monoclonal antibodies.

Highlights

To characterize CD38 expression across peripheral blood leukocyte subsets and identify potential dysregulation of CD38 in Systemic lupus erythematosus (SLE), we analyzed leukocytes isolated from cryopreserved whole blood samples of 20 SLE patients and 20 age- and gender-matched healthy controls (HC)
Leukocytes were subjected to dimension reduction by opt-SNE [19], and major cell subsets were annotated according to the expression of lineage-defining cell-surface markers on the resulting t-SNE map (Figure 1A and Supplementary Figure S1)
In accordance with previous reports [9,10,12], we found that CD38 was variably expressed on all immune cell types, with cell-type specific expression levels peaking in PB/plasma cells (PC)

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune responses against nuclear antigens. The immunopathogenesis of the disease is complex and involves genetic, environmental, hormonal, epigenetic, and immunoregulatory factors that may act either sequentially or simultaneously on the immune system [1]. It is assumed that a defect in the clearance of apoptotic cells with accumulation of undigested apoptotic remnants may provoke the first hit in the break of self-tolerance by activating otherwise quiescent autoreactive lymphocytes. The presence of extracellular DNA stimulates plasmacytoid dendritic cells (pDC) via Toll-like receptors, resulting in the production of type I interferons (IFN-I), some of the hallmark cytokines in SLE [1,2,3]

Methods

Results

Conclusion