Abstract
BackgroundPlasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE.MethodsRNA-sequencing analysis of synovial biopsies from various stages of RA disease progression, flow cytometry analysis of peripheral blood mononuclear cells (PBMC) from patients with RA or SLE and healthy donors, immunohistochemistry assessment (IHC) of synovial biopsies from patients with early RA, and ex vivo immune cell depletion assays using daratumumab (an anti-CD38 monoclonal antibody) were used to assess CD38 as a therapeutic target.ResultsWe demonstrated that the plasma cell/plasmablast-related genes CD38, XBP1, IRF4, PRDM1, IGJ and TNFSF13B are significantly up-regulated in synovial biopsies from patients with arthralgia, undifferentiated arthritis (UA), early RA and established RA as compared to healthy controls and control patients with osteoarthritis. In addition, the highest CD38 expression was observed on plasma cells and plasmablasts compared to natural killer (NK) cells, classical dendritic cells (DCs), plasmacytoid DCs (pDCs) and T cells, in blood from healthy controls and patients with SLE and RA. Furthermore, IHC showed CD38 staining in the same region as CD3 and CD138 staining in synovial tissue biopsies from patients with early RA. Most importantly, our data show for the first time that daratumumab effectively depletes plasma cells/plasmablasts in PBMC from patients with SLE and RA in a dose-dependent manner ex vivo.ConclusionThese results indicate that CD38 may be a potential target for RA disease interception and daratumumab should be evaluated clinically for the treatment of both RA and SLE.
Highlights
Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)
The expression of plasma cell/plasmablast differentiation and survival-related genes is increased in synovial biopsies from various stages during RA progression The involvement of CD38 and plasma cell/plasmablast-related genes in RA disease progression was evaluated by obtaining synovial tissue biopsies from patients with arthralgia, undifferentiated arthritis (UA) and early and established RA
Since specific transcription factors are essential for plasma cell differentiation, high antibody production and plasma cell homing to the bone marrow, we examined the expression of X-box binding protein 1 (XBP1), interferon regulatory factor 4 (IRF4) and PR domain zinc finger protein 1 (PRDM1)
Summary
Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE. Long-lived plasma cells reside in bone marrow and inflammatory tissue niches and produce copious amounts of autoantibodies independent of B cell activation. The bone marrow provides the survival niche for long-lived plasma cells [5, 6], inflammatory tissues bear high B cellactivating factor (BAFF) and a proliferation-inducing ligand (APRIL), maintain long-lived plasma cell survival, and contribute to the autoantibody secretion in inflammatory joints in patients with RA [7] and nephritic kidneys in NZB/W mice [8]. Aside from the strategies mentioned above, it is worthwhile to determine if plasma-cell-specific targets may prove more efficacious in the treatment of autoimmune diseases, such as RA and SLE
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