Article
CD38 is up-regulated on plasmablasts and memory T-Lymphocytes and in SLE and may represent a promising future therapeutic target
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Authors
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Lennard Ostendorf
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Deutsches Rheumaforschungszentrum (DRFZ), Berlin
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Philipp Enghard
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Nephrologie und internistische Intensivmedizin, Berlin
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Ulrich Richter
- Charité Universitätsmedizin Berlin – Medizinische Klinik m.S. Hämatologie, Stammzelltransplantation, Onkologie und Palliativmedizin, Berlin
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Falk Hiepe
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
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Tobias Alexander
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
| Published: | October 8, 2019 |
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Outline
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Background: Long-Lived plasmacells (PCs) contribute to immunopathology in systemic lupus erythematosus (SLE), but their targeting represents a therapeutic challenge as they are resistant to conventional immunosuppressive or B-cell depleting therapies. Novel PC-directed therapies have therefore emerged, e.g. with CD38-targeting antibodies, which are already in clinical use for the treatment of multiple myeloma.
Methods: We performed multicolor flow cytometry to investigate CD38-expression levels on peripheral blood mononuclear cells (PBMCs) from SLE patients (n=36) compared to multiple myeloma patients (MM, n=12) and healthy controls (HC, n=20). For analysis of kidney-infiltrating T-cells in lupus nephritis (LN), we analyzed paired samples of urine and blood. To investigate the cytokine secreting potential of CD38+ T-cells, PBMCs were stimulated in vitro with PMA/Ionomycin for 5h.
Results: Among PBMCs, CD38-expression was highest in CD19+CD24- CD27high plasmablasts, with significantly increased expression levels (MFI) in SLE and MM compared to HC. In SLE, co-expression of CD38 was significantly increased in all CD4 and CD8 memory T cell subsets (CCR7+CD45RA- central memory, CCR7-CD45RA- effector memory and CCR7-CD45RA+ terminal effector). Compared their CD38- counterparts, such cells co-expressed higher markers of recent activation (HLA-DR) and proliferative history (Ki-67), yet with no difference between SLE and HC. Counterintuitively, secretion of effector cytokines (IFN-g, TNF-a, IL-2, IL-17) after polyclonal stimulation was most exclusively restricted to CD38- T-cell subsets. CD38-expression was equally distributed between FoxP3+Helios+ T regulatory (Treg) and conventional cells in HC, but found significantly reduced in SLE Tregs compared to their counterparts in HC. Virtually all CD4 and CD8 T cells isolated from urine of LN patients co-expressed CD38+ and were confined to CXCR3+ memory subsets.
Conclusion: Our data confirm previous observations on increased CD38-expression levels on peripheral blood lymphocytes in SLE. More precisely, we now demonstrate that up-regulation of CD38 is restricted to plasmablasts and memory T cell subsets, the latter being characterized by a chronically activated phenotype and presence in lupus nephritis urine samples, suggesting their role in disease pathology and tissue inflammation. Together, these data identify CD38 as promising future therapeutic target in SLE given its potential to deplete PCs and pre-activated memory T cells.
