Article
Increased CD38 Expression Levels on immune cell subsets in systemic Lupus erythematosus
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Authors
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Lennard Ostendorf
- Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin; Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Rheumatologie und klinische Immunologie, Berlin
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Philipp Enghard
- Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin; Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Nephrologie und internistische Intensivmedizin, Berlin
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Pawel Durek
- Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
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Frederik Heinrich
- Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
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Mir-Farzin Mashereghi
- Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
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Gerd-Rüdiger Burmester
- Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Rheumatologie und klinische Immunologie, Berlin
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Andreas Radbruch
- Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
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Falk Hiepe
- Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin; Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Rheumatologie und klinische Immunologie, Berlin
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Tobias Alexander
- Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin; Charité – Universitätsmedizin Berlin, Med. Klinik m.S. Rheumatologie und klinische Immunologie, Berlin
| Published: | September 9, 2020 |
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Outline
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Introduction: Plasma cells (PCs) are implicated in the pathogenesis of systemic lupus erythematosus (SLE) and have been identified as promising therapeutic target. As there is a monoclonal therapeutic antibody targeting CD38 approved for clinical use in multiple myeloma, PC depletion targeting CD38 seems to represent a promising treatment modality for SLE. CD38 is highly expressed on PCs, but also present on the surface of subsets of T- and B-cells as well as myeloid cells. Here we aim to identify the differential expression of CD38 on peripheral blood leukocytes in SLE compared to healthy controls (HC) investigate the function of CD38+ T-cells.
Methods: We performed flow cytometry to investigate the expression of CD38 on peripheral blood mononuclear cells (PBMCs) of SLE patients (n=36) and HCs (n=20). We additionally analyzed the expression of T-cells isolated from the urine of patients with lupus nephritis. We investigated the cytokine-secreting potential of CD38+ memory T-cells after short-term stimulation and performed single-cell RNA sequencing analyses.
Results: When compared to samples from healty individuals, CD38 expression levels in SLE are increased on the following immune cell subsets: Plasmablasts, unswitched memory B-cells, plasmacytoid dendritic cells (pDCs) and CD16+ non-classical monocytes. Furthermore, we observed a drastic expansion of CD38-expressing memory CD4+ and CD8+ memory T-cells in SLE patients. These cells were predominantly conventional, not regulatory T-cells and expressed other markers of recent T-cell activation and proliferation. More strikingly, we identified an enrichment of CD38+ memory T-cells in the urine of patients with lupus nephritis. After short-term polyclonal stimulation ex vivo, CD38+ T-cells produced less inflammatory cytokines compared to their CD38- counterparts. Preliminary single-cell sequencing results indicate that CD38+ CD8+ T-cells have decreased clonal diversity and express genes associated with exhaustion and type-1 interferon (IFN) activity.
Conclusion: Increased CD38 expression on various lymphocyte subsets provides an additional rationale for investigating CD38-directed therapies in SLE. Therapeutic targeting CD38 could not only promote a depletion of long-lived PCs, which are refractory to immunosuppression and B-cell depleting therapies, but also has the potential to target IFN alpha producing plasmacytoid dendritic cells and modulate inflammatory T-cell functions.
Disclosures: None declared
