University of Thessaly, Larissa, Greece.
Arthritis Rheumatol. 2016 Feb;68(2):494-504. doi: 10.1002/art.39437.
Breg cells, a regulatory cell subset that produces interleukin-10 (IL-10), play a significant role in suppressing autoimmune responses and preventing autoimmunity. This study was undertaken to examine the number and function of Breg cells in patients with systemic sclerosis (SSc), a disease with many autoantibodies.
Forty-five patients with SSc (12 with early SSc, 33 with established disease including 16 with SSc-associated pulmonary fibrosis [PF]), 12 healthy control subjects, and 10 patients with rheumatoid arthritis (RA)-associated PF were studied. The phenotypes of immature/transitional Breg cells (CD19+CD24(high) CD38(high) ) and memory Breg cells (CD19+CD27+CD24(high) ) were evaluated by flow cytometry. The function of Breg cells was assessed by measuring the production of IL-10 after B cell activation. In addition, activation of p38 MAPK and STAT-3 was measured following stimulation of the cells with B cell receptor (BCR) and Toll-like receptor 9 (TLR-9).
Percentages of memory Breg cells were decreased in patients with early SSc (mean ± SEM 1.85 ± 0.38%), those with established SSc (1.6 ± 0.88%), those with SSc-associated PF (1.52 ± 0.17%), and those with RA-associated PF (1.58 ± 0.26%), compared to healthy controls (6.3 ± 0.49%; each P < 0.001). Percentages of transitional Breg cells were also decreased. Expression of IL-10 by Breg cells after stimulation with TLR-9 was impaired in patients with SSc, particularly those with SSc-associated PF. Activation of STAT-3 and p38 MAPK was impaired in naive and memory B cells from patients with SSc after stimulation with BCR and TLR-9. Expression of the stimulatory CD19 receptor was increased in B cells and also increased, to a lesser extent, in Breg cells from patients with SSc compared to healthy controls. Percentages of memory B cells were decreased in patients with SSc, particularly in those with SSc-associated PF.
This is the first study to demonstrate that Breg cells are phenotypically and functionally impaired in patients with SSc. Furthermore, in SSc, B cells exhibit impaired p38 MAPK and STAT-3 activation upon stimulation with BCR and TLR-9. The findings of decreased numbers of Breg cells along with increased expression of CD19 support the idea of B cell autoaggression acting as an immunopathogenic mediator in SSc.
Breg 细胞是一种产生白细胞介素-10（IL-10）的调节性细胞亚群，在抑制自身免疫反应和预防自身免疫方面发挥着重要作用。本研究旨在研究系统性硬化症（SSc）患者中 Breg 细胞的数量和功能，该疾病存在多种自身抗体。
研究了 45 名 SSc 患者（12 名早期 SSc 患者，33 名已确诊的患者，包括 16 名 SSc 相关肺纤维化[PF]患者）、12 名健康对照者和 10 名类风湿关节炎（RA）相关 PF 患者。通过流式细胞术评估未成熟/过渡性 Breg 细胞（CD19+CD24(high)CD38(high)）和记忆性 Breg 细胞（CD19+CD27+CD24(high)）的表型。通过测量 B 细胞激活后 IL-10 的产生来评估 Breg 细胞的功能。此外，通过刺激细胞的 B 细胞受体（BCR）和 Toll 样受体 9（TLR-9）来测量 p38 MAPK 和 STAT-3 的激活。
早期 SSc 患者（平均 ± SEM 1.85 ± 0.38%）、已确诊 SSc 患者（1.6 ± 0.88%）、SSc 相关 PF 患者（1.52 ± 0.17%）和 RA 相关 PF 患者（1.58 ± 0.26%）的记忆性 Breg 细胞比例均降低，与健康对照组（6.3 ± 0.49%；均 P < 0.001）相比。过渡性 Breg 细胞的比例也有所下降。SSc 患者刺激 TLR-9 后 Breg 细胞产生 IL-10 的能力受损，尤其是 SSc 相关 PF 患者。SSc 患者的 B 细胞在刺激 BCR 和 TLR-9 后，STAT-3 和 p38 MAPK 的激活受损。刺激 B 细胞后，B 细胞和 SSc 患者的 Breg 细胞上的刺激 CD19 受体表达增加，与健康对照组相比，SSc 患者的表达增加更多。SSc 患者的记忆性 B 细胞比例下降，尤其是 SSc 相关 PF 患者。
这是第一项证明 SSc 患者的 Breg 细胞在表型和功能上受损的研究。此外，在 SSc 中，BCR 和 TLR-9 刺激后 B 细胞的 p38 MAPK 和 STAT-3 激活受损。Breg 细胞数量减少以及 CD19 表达增加支持 B 细胞自身攻击作为 SSc 中免疫病理发病机制介质的观点。
