Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China; Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.
Mol Immunol. 2021 Dec;140:217-224. doi: 10.1016/j.molimm.2021.09.012. Epub 2021 Nov 5.
Granzyme B (GrB)-producing B cells are proposed to be a kind of regulatory B cells (Bregs) and have been revealed to be implicated in the pathogenesis of autoimmune diseases. Nevertheless, their role in SLE remains elusive. In this study, the frequencies of GrB-producing Bregs in peripheral blood of heathy control (HC) and systemic lupus erythematosus (SLE) were evaluated by flow cytometry, and their correlation with SLE patient clinical and immunological features were analyzed. The expression of GrB in HC and SLE B cells were also further detected by RT-qPCR analysis and ELISpot. The function of GrB-producing Bregs in HC and SLE patients was further investigated by in vitro CD4 effector T cells-B cells co-culture assays with GrB blockade. We found that GrB-producing Bregs were significantly decreased in SLE patients and correlated with the clinical and immunological features. Moreover, these cells were functionally impaired under SLE circumstance. The negative correlation between GrB-producing Bregs and CD4 T cells observed in healthy individuals disappeared in SLE patients. In vitro cell co-culture assay further showed that GrB-producing Bregs from SLE patients failed to suppress the Th1, Th2 and Th17 cell inflammatory responses, partially due to the dampened capacity of down-regulating TCR zeta and inducing T cell apoptosis. Taken together, these results revealed the disturbance of GrB-producing Bregs in SLE that might contribute to the disease initiation and progression.
颗粒酶 B（GrB）产生 B 细胞被认为是一种调节性 B 细胞（Bregs），并已被揭示与自身免疫性疾病的发病机制有关。然而，它们在系统性红斑狼疮（SLE）中的作用仍不清楚。在这项研究中，通过流式细胞术评估了健康对照组（HC）和系统性红斑狼疮患者外周血中 GrB 产生的 Bregs 的频率，并分析了它们与 SLE 患者临床和免疫特征的相关性。还通过 RT-qPCR 分析和 ELISpot 进一步检测了 HC 和 SLE B 细胞中 GrB 的表达。通过体外 CD4 效应 T 细胞-B 细胞共培养实验并用 GrB 阻断进一步研究了 GrB 产生的 Bregs 在 HC 和 SLE 患者中的功能。我们发现 SLE 患者中 GrB 产生的 Bregs 明显减少，与临床和免疫特征相关。此外，这些细胞在 SLE 情况下功能受损。在健康个体中观察到的 GrB 产生的 Bregs 与 CD4 T 细胞之间的负相关在 SLE 患者中消失。体外细胞共培养实验进一步表明，SLE 患者的 GrB 产生的 Bregs 未能抑制 Th1、Th2 和 Th17 细胞的炎症反应，部分原因是下调 TCR zeta 和诱导 T 细胞凋亡的能力减弱。总之，这些结果揭示了 SLE 中 GrB 产生的 Bregs 的紊乱，这可能有助于疾病的发生和进展。
