Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus.
Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus.
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DOI：
10.1186/s13075-018-1578-z
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发表时间：
2018-05-02
影响因子：
4.9
通讯作者：
Guo Y
中科院分区：
文献类型：
--
作者：
Cole S;Walsh A;Yin X;Wechalekar MD;Smith MD;Proudman SM;Veale DJ;Fearon U;Pitzalis C;Humby F;Bombardieri M;Axel A;Adams H 3rd;Chiu C;Sharp M;Alvarez J;Anderson I;Madakamutil L;Nagpal S;Guo Y
浆母细胞和浆细胞在许多自身免疫性疾病中起着关键作用，如类风湿性关节炎(RA)和系统性红斑狼疮(SLE)。本研究旨在评价Daratumumab靶向CD38作为浆细胞/浆母细胞耗竭机制在RA和SLE患者治疗中的作用。对RA疾病进展不同阶段的滑膜组织进行RNA测序分析，对RA或SLE患者和健康献血者的外周血单个核细胞(PBMC)进行流式细胞术分析，对早期RA患者的滑膜组织进行免疫组织化学检测(IHC)，并使用抗CD38的单抗进行体外免疫细胞耗竭试验，以评估CD38作为治疗靶点的价值。我们发现，在关节痛、未分化关节炎(UA)、早期类风湿关节炎(RA)和已建立的类风湿关节炎(RA)患者的滑膜组织中，浆细胞/浆母细胞相关基因CD38、XBP1、IRF4、PRDM1、IGJ和TNFSF13B的表达显著上调。此外，在正常人、SLE和RA患者外周血中，CD38在浆细胞和浆母细胞上的表达高于自然杀伤细胞(NK)、经典树突状细胞(DC)、浆细胞样树突状细胞(PDC)和T细胞。此外，在早期类风湿关节炎患者的滑膜组织活检组织中，免疫组化显示CD38与CD3和CD138染色位于同一区域。最重要的是，我们的数据首次显示，Daratumab在体外以剂量依赖的方式有效地耗尽SLE和RA患者PBMC中的浆细胞/浆母细胞。这些结果表明，CD38可能是RA疾病阻断的潜在靶点，Daratumumab应在临床上评估其治疗RA和SLE的效果。本文的在线版本(10.1186/s13075-0181578-z)包含补充材料，授权用户可以使用。
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. 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. 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. 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. The online version of this article (10.1186/s13075-018-1578-z) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Khodadadi L;Cheng Q;Alexander T;Sercan-Alp Ö;Klotsche J;Radbruch A;Hiepe F;Hoyer BF;Taddeo A
通讯作者：
Taddeo A
影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
3.7
作者：
Della Beffa C;Slansky E;Pommerenke C;Klawonn F;Li J;Dai L;Schumacher HR Jr;Pessler F
通讯作者：
Pessler F
影响因子：
27.4
作者：
Doorenspleet, M. E.;Klarenbeek, P. L.;de Vries, N.
通讯作者：
de Vries, N.
影响因子：
2.6
作者：
Sjowall, C.;Hjorth, M.;Eriksson, P.
通讯作者：
Eriksson, P.