Parodis Ioannis, Lagutkin Denis, Lindblom Julius, Idborg Helena, Beretta Lorenzo, Borghi Maria Orietta, Peyper Janique M, Barturen Guillermo, Jakobsson Per-Johan, Alarcón-Riquelme Marta E, Sherina Natalia, Nikolopoulos Dionysis
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Stockholm, Sweden; Department of Rheumatology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Stockholm, Sweden.
Ann Rheum Dis. 2025 Jul;84(7):1180-1194. doi: 10.1016/j.ard.2025.04.003. Epub 2025 May 14.
In response to the urgent unmet needs of heterogeneity, unpredictability, and diagnostic delay in systemic lupus erythematosus (SLE), we aimed to identify and validate new immunoglobulin (Ig)G and IgA autoantibody specificities.
Using a KoRectly EXpressed technology-based microarrays (i-Ome Discovery; Sengenics), we screened for circulating IgG and IgA autoantibodies against 1609 proteins in 2 independent cohorts (discovery: NTC02890121; validation: NCT02890134) comprising patients with SLE (n = 199 and n = 30), primary Sjögren's disease (n = 115 and n = 31), and systemic sclerosis (n = 115 and n = 24), and healthy controls (HCs; n = 111 and n = 84), respectively.
We identified and validated 5 IgG (anti-Lin-28 homolog A [LIN28A], anti-HNRNPA2B1, anti-HMG20B, anti-HMGB2, and anti-alpha-globin transcription factor CP2 [TFCP2]) and 4 IgA (anti-LIN28A, anti-HMG20B, anti-SUB1, and anti-TFCP2) autoantibodies that demonstrated high specificity for SLE (0.91-0.94), along with consistent and robust positivity (0.22-0.69) in differentially abundant autoantibody (daAAb) analysis between SLE and comparator groups. IgG and IgA anti-LIN28A levels varied over a 14-month follow-up in the validation cohort of newly diagnosed patients with SLE and exhibited metrics that outperformed those of traditional autoantibody markers such as anti-double-stranded DNA. Clustering of patients with SLE based on autoantibody positivity (levels above the HC median plus 2 IQRs in the discovery cohort) status revealed 1 subgroup demonstrating seroreactivity against multiple antigens, 3 exhibiting varying reactivity, and 1 showing no reactivity. In pathway analysis, daAAb targets pointed to DNA-binding and RNA-binding and transcription functions.
Novel autoantibodies validated in this study may enhance diagnostics and molecular characterisation in SLE. The prominent IgA seroreactivity implicates important roles of mucosal tissues in SLE autoimmunity, warranting further investigation.
为应对系统性红斑狼疮（SLE）在异质性、不可预测性和诊断延迟方面迫切未得到满足的需求，我们旨在鉴定和验证新的免疫球蛋白（Ig）G和IgA自身抗体特异性。
我们使用基于KoRectly EXpressed技术的微阵列（i - Ome Discovery；Sengenics），针对1609种蛋白质筛选循环IgG和IgA自身抗体，研究对象为2个独立队列（发现队列：NTC02890121；验证队列：NCT02890134），分别包括SLE患者（n = 199和n = 30）、原发性干燥综合征患者（n = 115和n = 31）、系统性硬化症患者（n = 115和n = 24）以及健康对照（HCs；n = 111和n = 84）。
我们鉴定并验证了5种IgG自身抗体（抗Lin - 28同源物A [LIN28A]、抗HNRNPA2B1、抗HMG20B、抗HMGB2和抗α - 珠蛋白转录因子CP2 [TFCP2]）和4种IgA自身抗体（抗LIN28A、抗HMG20B、抗SUB1和抗TFCP2），这些自身抗体对SLE具有高特异性（0.91 - 0.94），并且在SLE与对照群体之间的差异丰富自身抗体（daAAb）分析中呈现出一致且强烈的阳性反应（0.22 - 0.69）。在新诊断的SLE患者验证队列中，IgG和IgA抗LIN28A水平在14个月的随访期间有所变化，并且其指标优于传统自身抗体标志物如抗双链DNA。基于自身抗体阳性（发现队列中高于HC中位数加2个四分位距的水平）状态对SLE患者进行聚类分析，发现1个亚组对多种抗原具有血清反应性，3个亚组表现出不同的反应性，1个亚组无反应性。在通路分析中，daAAb靶点指向DNA结合、RNA结合和转录功能。
本研究中验证的新型自身抗体可能会增强SLE的诊断和分子特征分析。显著的IgA血清反应性表明黏膜组织在SLE自身免疫中起重要作用，值得进一步研究。
