University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Erasmus University Medical Center, Rotterdam, The Netherlands.
Arthritis Rheumatol. 2017 Sep;69(9):1850-1861. doi: 10.1002/art.40165. Epub 2017 Aug 13.
To assess the effect of abatacept (CTLA-4Ig), which limits T cell activation, on homeostasis of CD4+ T cell subsets and T cell-dependent B cell hyperactivity in patients with primary Sjögren's syndrome (SS).
Fifteen patients with primary SS treated with abatacept were included. Circulating CD4+ T cell and B cell subsets were analyzed by flow cytometry at baseline, during the treatment course, and after treatment was completed. CD4+ effector T cell subsets and Treg cells were identified based on expression of CD45RA, CXCR3, CCR6, CCR4, CXCR5, programmed death 1, inducible costimulator (ICOS), and FoxP3. Serum levels of anti-SSA/anti-SSB and several T cell-related cytokines were measured. Expression of ICOS and interleukin-21 (IL-21) protein was examined in parotid gland tissue at baseline and after treatment. Changes in laboratory parameters and associations with systemic disease activity (EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI]) over time were analyzed using generalized estimating equations.
Abatacept selectively reduced percentages and numbers of circulating follicular helper T (Tfh) cells and Treg cells. Other CD4+ effector T cell subsets were unaffected. Furthermore, expression of the activation marker ICOS by circulating CD4+ T cells and expression of ICOS protein in parotid gland tissue declined. Reduced ICOS expression on circulating Tfh cells correlated significantly with lower ESSDAI scores during treatment. Serum levels of IL-21, CXCL13, anti-SSA, and anti-SSB decreased. Among circulating B cells, plasmablasts were decreased by treatment. After cessation of treatment, all parameters gradually returned to baseline.
Abatacept treatment in patients with primary SS reduces circulating Tfh cell numbers and expression of the activation marker ICOS on T cells. Lower numbers of activated circulating Tfh cells contribute to attenuated Tfh cell-dependent B cell hyperactivity and may underlie the efficacy of abatacept.
评估 CTLA-4Ig（abatacept）对原发性干燥综合征（pSS）患者 CD4+T 细胞亚群稳态和 T 细胞依赖性 B 细胞过度活跃的影响。
纳入 15 例接受 abatacept 治疗的 pSS 患者。在基线、治疗过程中和治疗结束后，通过流式细胞术分析循环 CD4+T 细胞和 B 细胞亚群。根据 CD45RA、CXCR3、CCR6、CCR4、CXCR5、程序性死亡受体 1、诱导共刺激因子（ICOS）和 FoxP3 的表达，鉴定 CD4+效应 T 细胞亚群和 Treg 细胞。测量血清抗 SSA/抗 SSB 水平和几种 T 细胞相关细胞因子。在基线和治疗后，检查腮腺组织中 ICOS 和白细胞介素 21（IL-21）蛋白的表达。使用广义估计方程分析实验室参数随时间的变化及其与全身疾病活动度（EULAR 干燥综合征疾病活动指数[ESSDAI]）的关系。
abatacept 选择性降低了循环滤泡辅助 T（Tfh）细胞和 Treg 细胞的百分比和数量。其他 CD4+效应 T 细胞亚群不受影响。此外，循环 CD4+T 细胞上的激活标志物 ICOS 表达和腮腺组织中 ICOS 蛋白表达下降。循环 Tfh 细胞上 ICOS 表达减少与治疗期间 ESSDAI 评分降低显著相关。血清 IL-21、CXCL13、抗 SSA 和抗 SSB 水平降低。治疗后循环 B 细胞中的浆母细胞减少。停药后，所有参数逐渐恢复基线。
在 pSS 患者中，abatacept 治疗可降低循环 Tfh 细胞数量和 T 细胞上的激活标志物 ICOS 表达。循环中活化 Tfh 细胞数量减少有助于减弱 Tfh 细胞依赖性 B 细胞过度活跃，这可能是 abatacept 疗效的基础。
