Department of Rheumatology and Clinical Immunology, The Ministry of Education Key Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing , 100730, China.
Clinical Immunology Centre, Medical Epigenetics Research Centre, The Ministry of Education Key Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
Clin Rev Allergy Immunol. 2022 Apr;62(2):301-323. doi: 10.1007/s12016-020-08820-7. Epub 2021 Feb 3.
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with high heterogeneity but the common characterization of numerous autoantibodies and systemic inflammation which lead to the damage of multiple organs. Aberrance of B cells plays a pivotal role in the immunopathogenesis of SLE via both antibody-dependent and antibody-independent manners. Escape of autoreactive B cells from the central and peripheral tolerance checkpoints, over-activation of B cells and their excessive cytokines release which drive T cells and dendritic cells stimulation, and dysregulated surface molecules, as well as intracellular signal pathways involved in B cell biology, are all contributing to B cell aberrance and participating in the pathogenesis of SLE. Based on that rationale, targeting aberrance of B cells and relevant molecules and pathways is expected to be a promising strategy for lupus control. Multiple approaches targeting B cells through different mechanisms have been attempted, including B-cell depletion via monoclonal antibodies against B-cell-specific molecules, blockade of B-cell survival and activation factors, suppressing T-B crosstalk by interrupting costimulatory molecules and inhibiting intracellular activation signaling cascade by targeting pathway molecules in B cells. Though most attempts ended in failure, the efficacy of B-cell targeting has been encouraged by the FDA approval of belimumab that blocks B cell-activating factor (BAFF) and the recommended use of anti-CD20 as a remedial therapy in refractory lupus. Still, quantities of clinical trials targeting B cells or relevant molecules are ongoing and some of them have displayed promising preliminary results. Additionally, advances in multi-omics studies help deepen our understandings of B cell biology in lupus and may promote the discovery of novel potential therapeutic targets. The combination of real-world data with basic research achievements may pave the road to conquering lupus.
系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病，具有高度异质性，但具有许多自身抗体和全身炎症的共同特征，导致多个器官受损。B 细胞的失常在 SLE 的免疫发病机制中起着关键作用，通过抗体依赖和非抗体依赖的方式。自身反应性 B 细胞逃避中枢和外周耐受检查点、B 细胞过度激活及其过度细胞因子释放，驱动 T 细胞和树突状细胞的刺激以及失调的表面分子和参与 B 细胞生物学的细胞内信号通路，都导致了 B 细胞的失常，并参与了 SLE 的发病机制。基于这一原理，针对 B 细胞和相关分子及通路的失常，有望成为狼疮控制的一种有前途的策略。通过不同机制针对 B 细胞的多种方法已被尝试，包括通过针对 B 细胞特异性分子的单克隆抗体来耗尽 B 细胞、阻断 B 细胞存活和激活因子、通过阻断共刺激分子来抑制 T-B 细胞串扰以及通过靶向 B 细胞内激活信号级联来抑制细胞内激活信号级联。尽管大多数尝试都以失败告终，但 belimumab（一种阻断 B 细胞激活因子（BAFF）的药物）获得 FDA 批准以及抗 CD20 被推荐作为难治性狼疮的补救疗法，这都为 B 细胞靶向治疗的疗效提供了鼓舞。目前仍有大量针对 B 细胞或相关分子的临床试验正在进行，其中一些已显示出有希望的初步结果。此外，多组学研究的进展有助于加深我们对狼疮中 B 细胞生物学的理解，并可能促进新的潜在治疗靶点的发现。将真实世界的数据与基础研究成果相结合，可能为攻克狼疮铺平道路。
