Kaan Ellen D, Brunekreef Tammo E, Drylewicz Julia, van den Hoogen Lucas L, van der Linden Maarten, Leavis Helen L, van Laar Jacob M, van der Vlist Michiel, Otten Henny G, Limper Maarten
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
J Transl Autoimmun. 2024 Jun 20;9:100246. doi: 10.1016/j.jtauto.2024.100246. eCollection 2024 Dec.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a variety of disease symptoms and an unpredictable clinical course. To improve treatment outcome, stratification based on immunological manifestations commonly seen in patients with SLE such as autoantibodies, type I interferon (IFN) signature and neutrophil extracellular trap (NET) release may help. It is assumed that there is an association between these immunological phenomena, since NET release induces IFN production and IFN induces autoantibody formation via B-cell activation. Here we studied the association between autoantibodies, the IFN signature, NET release, and clinical manifestations in patients with SLE.
We performed principal component analysis (PCA) and hierarchical clustering of 57 SLE-related autoantibodies in 25 patients with SLE. We correlated each autoantibody to the IFN signature and NET inducing capacity.
We observed two distinct clusters: one cluster contained mostly patients with a high IFN signature. Patients in this cluster often present with cutaneous lupus, and have higher anti-dsDNA concentrations. Another cluster contained a mix of patients with a high and low IFN signature. Patients with high and low NET inducing capacity were equally distributed between the clusters. Variance between the clusters is mainly driven by antibodies against histones, RibP2, RibP0, EphB2, RibP1, PCNA, dsDNA, and nucleosome. In addition, we found a trend towards increased concentrations of autoantibodies against EphB2, RibP1, and RNP70 in patients with an IFN signature. We found a negative correlation of NET inducing capacity with anti-FcER (r = -0.530; p = 0.007) and anti-PmScl100 (r = -0.445; p = 0.03).
We identified a subgroup of patients with an IFN signature that express increased concentrations of antibodies against DNA and RNA-binding proteins, which can be useful for further patient stratification and a more targeted therapy. We did not find positive associations between autoantibodies and NET inducing capacity. Our study further strengthens the evidence of a correlation between RNA-binding autoantibodies and the IFN signature.
系统性红斑狼疮（SLE）是一种自身免疫性疾病，具有多种疾病症状且临床病程不可预测。为改善治疗效果，基于SLE患者常见的免疫表现进行分层，如自身抗体、I型干扰素（IFN）特征和中性粒细胞胞外诱捕网（NET）释放，可能会有所帮助。由于NET释放诱导IFN产生，且IFN通过B细胞活化诱导自身抗体形成，因此假定这些免疫现象之间存在关联。在此，我们研究了SLE患者自身抗体、IFN特征、NET释放与临床表现之间的关联。
我们对25例SLE患者的57种SLE相关自身抗体进行了主成分分析（PCA）和层次聚类。我们将每种自身抗体与IFN特征和NET诱导能力进行关联分析。
我们观察到两个不同的聚类：一个聚类主要包含IFN特征较高的患者。该聚类中的患者常出现皮肤狼疮，且抗双链DNA（dsDNA）浓度较高。另一个聚类包含IFN特征高和低的患者混合。NET诱导能力高和低的患者在聚类中分布均匀。聚类之间的差异主要由针对组蛋白、RibP2、RibP0、EphB2、RibP1、增殖细胞核抗原（PCNA）、dsDNA和核小体的抗体驱动。此外，我们发现IFN特征患者中针对EphB2、RibP1和核糖核蛋白70（RNP70）的自身抗体浓度有升高趋势。我们发现NET诱导能力与抗Fcε受体（r = -0.530；p = 0.007）和抗PmScl100（r = -0.445；p = 0.03）呈负相关。
我们鉴定出一组具有IFN特征的患者亚群，其针对DNA和RNA结合蛋白的抗体浓度升高，这对于进一步的患者分层和更有针对性的治疗可能有用。我们未发现自身抗体与NET诱导能力之间存在正相关。我们的研究进一步加强了RNA结合自身抗体与IFN特征之间相关性的证据。
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