Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus
Abstract Background 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 daratumum...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-05-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13075-018-1578-z |
| _version_ | 1819028332334809088 |
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| author | Suzanne Cole Alice Walsh Xuefeng Yin Mihir D. Wechalekar Malcolm D. Smith Susanna M. Proudman Douglas J. Veale Ursula Fearon Costantino Pitzalis Frances Humby Michele Bombardieri Amy Axel Homer Adams Christopher Chiu Michael Sharp John Alvarez Ian Anderson Loui Madakamutil Sunil Nagpal Yanxia Guo |
| author_facet | Suzanne Cole Alice Walsh Xuefeng Yin Mihir D. Wechalekar Malcolm D. Smith Susanna M. Proudman Douglas J. Veale Ursula Fearon Costantino Pitzalis Frances Humby Michele Bombardieri Amy Axel Homer Adams Christopher Chiu Michael Sharp John Alvarez Ian Anderson Loui Madakamutil Sunil Nagpal Yanxia Guo |
| author_sort | Suzanne Cole |
| collection | DOAJ |
| description | Abstract Background 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. Methods RNA-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. Results We 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. Conclusion These 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. |
| first_indexed | 2024-12-21T05:56:41Z |
| format | Article |
| id | doaj.art-36023e7ad5564381815500c7e7f37e9e |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-21T05:56:41Z |
| publishDate | 2018-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-36023e7ad5564381815500c7e7f37e9e2022-12-21T19:13:50ZengBMCArthritis Research & Therapy1478-63622018-05-0120111410.1186/s13075-018-1578-zIntegrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosusSuzanne Cole0Alice Walsh1Xuefeng Yin2Mihir D. Wechalekar3Malcolm D. Smith4Susanna M. Proudman5Douglas J. Veale6Ursula Fearon7Costantino Pitzalis8Frances Humby9Michele Bombardieri10Amy Axel11Homer Adams12Christopher Chiu13Michael Sharp14John Alvarez15Ian Anderson16Loui Madakamutil17Sunil Nagpal18Yanxia Guo19Immunology, Janssen ResearchImmunology, Janssen ResearchImmunology, Janssen ResearchRheumatology Unit, Repatriation General Hospital and Flinders UniversityRheumatology Unit, Repatriation General Hospital and Flinders UniversityRheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia and Discipline of Medicine, University of AdelaideCenter for Arthritis and Rheuamatic Diseases, St. Vincent’s University Hospital, University College DublinMolecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Trinity College LondonQueen Mary University of LondonQueen Mary University of LondonQueen Mary University of LondonOncology, Janssen ResearchOncology, Janssen ResearchOncology, Janssen ResearchOncology, Janssen ResearchOncology, Janssen ResearchImmunology, Janssen ResearchImmunology, Janssen ResearchImmunology, Janssen ResearchImmunology, Janssen ResearchAbstract Background 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. Methods RNA-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. Results We 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. Conclusion These 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.http://link.springer.com/article/10.1186/s13075-018-1578-zCD38Plasma cellDaratumumabRheumatoid arthritisSystemic lupus erythematosus |
| spellingShingle | Suzanne Cole Alice Walsh Xuefeng Yin Mihir D. Wechalekar Malcolm D. Smith Susanna M. Proudman Douglas J. Veale Ursula Fearon Costantino Pitzalis Frances Humby Michele Bombardieri Amy Axel Homer Adams Christopher Chiu Michael Sharp John Alvarez Ian Anderson Loui Madakamutil Sunil Nagpal Yanxia Guo Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus Arthritis Research & Therapy CD38 Plasma cell Daratumumab Rheumatoid arthritis Systemic lupus erythematosus |
| title | Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus |
| title_full | Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus |
| title_fullStr | Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus |
| title_full_unstemmed | Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus |
| title_short | Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus |
| title_sort | integrative analysis reveals cd38 as a therapeutic target for plasma cell rich pre disease and established rheumatoid arthritis and systemic lupus erythematosus |
| topic | CD38 Plasma cell Daratumumab Rheumatoid arthritis Systemic lupus erythematosus |
| url | http://link.springer.com/article/10.1186/s13075-018-1578-z |
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