Department of Medical Sciences, Rheumatology and Science for Life Laboratories, Uppsala University, Uppsala, Sweden.
Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
Ann Rheum Dis. 2018 Jul;77(7):1070-1077. doi: 10.1136/annrheumdis-2017-212794. Epub 2018 Feb 23.
Genetic variants in the transcription factor are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic risk allele rs7574865[T] affects the function of immune cells in SLE.
Peripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-γ-induced activation of SLE PBMCs.
In resting PBMCs, the risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8 T cells from risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production in CD8 and CD4 T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-γ-induced activation of PBMCs from risk patients, respectively.
T cells from patients with SLE carrying the risk allele rs7574865[T] display an augmented response to IL-12 and IFN-α. This subset of patients may benefit from JAKi treatment.
转录因子 中的遗传变异与系统性红斑狼疮（SLE）易感性增加和更严重的疾病表型相关。本研究旨在阐明与 SLE 相关的内含子 风险等位基因 rs7574865[T] 如何影响 SLE 中免疫细胞的功能。
从 52 名经基因分型的 SLE 患者中分离外周血单核细胞（PBMC）。通过流式细胞术检测经植物血凝素（PHA）和白细胞介素（IL）-2 预激活后免疫细胞亚群中干扰素（IFN）-α、IFN-γ 或白细胞介素（IL）-12 刺激下 STAT4（pSTAT4）和 STAT1（pSTAT1）的磷酸化、STAT4、STAT1 和 T-bet 的总水平以及 IL-12 刺激下 IFN-γ 细胞的频率，并将细胞反应和表型与风险等位基因携带情况相关联。评估针对 TYK2（TYK2i）或 JAK2（JAK2i）的 Janus 激酶抑制剂（JAKi）对 IL-12 或 IFN-γ 诱导的 SLE PBMC 激活的抑制作用。
在静止的 PBMC 中，风险等位基因既与 STAT4 或 STAT1 的总水平无关，也与细胞因子诱导的 pSTAT4 或 pSTAT1 无关。在 PHA/IL-2 激活后，来自风险等位基因携带者的 CD8 T 细胞显示出 STAT4 水平升高，导致对 IL-12 和 IFN-α的 pSTAT4 增加，并在 CD8 和 CD4 T 细胞中增加 IL-12 诱导的 IFN-γ 产生。TYK2i 和 JAK2i 分别有效地阻断了来自风险患者的 PBMC 对 IL-12 和 IFN-γ 的诱导激活。
携带 rs7574865[T] 风险等位基因的 SLE 患者的 T 细胞对 IL-12 和 IFN-α 的反应增强。这部分患者可能受益于 JAKi 治疗。
