目的:自身反应性B细胞和干扰素(IFN)特征是原发性干燥综合征(pSS)的标志,但IFN信号通路如何影响自身抗体产生和临床表现仍不清楚.更详细的研究有望改善诊断方法和个性化治疗。
方法:我们分析了基线和刺激时来自34个pSS患者和38个健康供体(HD)的外周血T和B细胞亚群的I型和II型IFN信号分子(STAT1/2,IRF1,IRF9)的表达水平。此外,我们调查了这些分子水平与血清学和临床特征的相关性,并进行了ROC分析.
结果:患者显示IFN途径分子升高,在大多数T和B细胞亚群中包括STAT1、STAT2和IRF9。我们发现与HDs相比,患者磷酸化STAT1和STAT2的比例降低,尽管来自患者的B细胞通过IFN刺激后磷酸化增加而高度响应。相关性矩阵显示了pSS中STAT1,IRF1和IRF9之间的进一步相互关系。T和B细胞中STAT1和IRF9的水平与单核细胞上的IFN型I标志物Siglec-1(CD169)相关。pSSB细胞中高水平的STAT1和IRF9与高丙种球蛋白血症以及抗SSA/抗SSB自身抗体显着相关。在患有腺外疾病的患者中发现了升高的STAT1水平,并且可以作为该亚组的生物标志物(p<0.01)。值得注意的是,T和B细胞中IRF9水平与EULAR干燥综合征疾病活动指数(ESSDAI)相关。
结论:这里,我们提供的证据表明,在活动性PSS患者中,增强的IFN信号传导,包括。未磷酸化的STAT1和STAT2与IRFs引起慢性T和B细胞活化。此外,增加的STAT1水平候选作为颗粒外疾病的生物标志物,而IRF9水平可以作为疾病活动的生物标志物。
OBJECTIVE: Autoreactive B cells and interferon (IFN) signature are hallmarks of primary sjögren\'s syndrome (
pSS), but how IFN signaling pathways influence autoantibody production and clinical manifestations remain unclear. More detailed studies hold promise for improved diagnostic methodologies and personalized treatment.
METHODS: We analyzed peripheral blood T and B cell subsets from 34
pSS patients and 38 healthy donors (HDs) at baseline and upon stimulation regarding their expression levels of type I and II IFN signaling molecules (STAT1/2, IRF1, IRF9). Additionally, we investigated how the levels of these molecules correlated with serological and clinical characteristics and performed ROC analysis.
RESULTS: Patients showed elevated IFN pathway molecules, including STAT1, STAT2 and IRF9 among most T and B cell subsets. We found a reduced ratio of phosphorylated STAT1 and STAT2 in patients in comparison to HDs, although B cells from patients were highly responsive by increased phosphorylation upon IFN stimulation. Correlation matrices showed further interrelations between STAT1, IRF1 and IRF9 in
pSS. Levels of STAT1 and IRF9 in T and B cells correlated with the IFN type I marker Siglec-1 (CD169) on monocytes. High levels of STAT1 and IRF9 within
pSS B cells were significantly associated with hypergammaglobulinemia as well as anti-SSA/anti-SSB autoantibodies. Elevated STAT1 levels were found in patients with extraglandular disease and could serve as a biomarker for this subgroup (p < 0.01). Notably, IRF9 levels in T and B cells correlated with EULAR Sjögren\'s syndrome disease activity index (ESSDAI).
CONCLUSIONS: Here, we provide evidence that in active
pSS patients, enhanced IFN signaling incl. unphosphorylated STAT1 and STAT2 with IRFs entertain chronic T and B cell activation. Furthermore, increased STAT1 levels candidate as biomarker of extraglandular disease, while IRF9 levels can serve as biomarker for disease activity.