Lindblom Julius, Lagutkin Denis, Sherina Natalia, Idborg Helena, Beretta Lorenzo, Borghi Maria Orietta, Peyper Janique M, Barturen Guillermo, Jakobsson Per-Johan, Alarcón-Riquelme Marta E, Nikolopoulos Dionysis, Parodis Ioannis
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Stockholm, Sweden.
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Italy.
Ann Rheum Dis. 2025 Jul;84(7):1164-1179. doi: 10.1016/j.ard.2025.04.008. Epub 2025 May 9.
This study aimed to identify and validate novel autoantibodies that reflect global and organ-specific disease activity in systemic lupus erythematosus (SLE).
Plasma samples were screened for IgG and IgA seroreactivity against 1609 protein autoantigens using a microarray (i-Ome Discovery; Sengenics). We determined differentially abundant autoantibodies (daAAbs) in patients with SLE vs healthy controls within a discovery (n = 196 vs n = 110; NTC02890121) and an independent validation cohort (n = 30 vs n = 83; NCT02890134) from the European PRECISESADS project. Validated daAAbs were analysed in relation to global and organ-specific disease activity using linear and logistic regression, along with daAAb target pathway enrichment analysis.
We validated 89 IgG and 66 IgA daAAbs. IgG anti-LIN28A, IgG anti-HMGN5, and both isotypes for anti-IRF5 and anti-TGIF1 were associated with a SLE disease activity index 2000 score of ≥10, negatively associated with lupus low disease activity state, and highly prevalent in subgroups with active disease across organ manifestations. IgG anti-LIN28A levels exceeded the cutoff for positivity in 53% of patients with central nervous system (CNS) involvement, a prevalence higher than that observed for anti-double-stranded DNA (20%) and 47% of patients with renal activity. A cluster of IgG and IgA daAAbs against RNA-binding proteins, including anti-LIN28A, was linked to CNS involvement. IgA anti-FOSL2 was elevated uniquely in patients with musculoskeletal activity. Enriched pathways involving DNA binding and repair showed considerable overlap across manifestations.
Novel IgG and IgA autoantibodies, including IgG anti-LIN28A, IgG anti-HMGN5, IgG and IgA anti-IRF5, and IgG and IgA anti-TGIF1 were associated with SLE disease activity and highly abundant across organ manifestations.
本研究旨在鉴定和验证可反映系统性红斑狼疮（SLE）整体及器官特异性疾病活动的新型自身抗体。
使用微阵列（i - Ome Discovery；Sengenics）对血浆样本进行筛查，检测针对1609种蛋白质自身抗原的IgG和IgA血清反应性。我们在欧洲PRECISESADS项目的一个发现队列（n = 196 vs n = 110；NTC02890121）和一个独立验证队列（n = 30 vs n = 83；NCT02890134）中确定SLE患者与健康对照之间差异丰富的自身抗体（daAAbs）。使用线性和逻辑回归以及daAAb靶标通路富集分析，对验证后的daAAbs与整体及器官特异性疾病活动进行分析。
我们验证了89种IgG和66种IgA的daAAbs。IgG抗LIN28A、IgG抗HMGN5以及抗IRF5和抗TGIF1的两种亚型均与SLE疾病活动指数2000评分≥10相关，与狼疮低疾病活动状态呈负相关，且在各器官表现的活动性疾病亚组中高度流行。IgG抗LIN28A水平在53%的中枢神经系统（CNS）受累患者中超过阳性临界值，其患病率高于抗双链DNA（观察到为）20%以及47%有肾脏活动的患者。一组针对RNA结合蛋白的IgG和IgA daAAbs，包括抗LIN28A，与CNS受累相关。IgA抗FOSL2仅在有肌肉骨骼活动的患者中升高。涉及DNA结合和修复的富集通路在各表现中显示出相当大的重叠。
新型IgG和IgA自身抗体，包括IgG抗LIN28A、IgG抗HMGN5、IgG和IgA抗IRF5以及IgG和IgA抗TGIF1，与SLE疾病活动相关且在各器官表现中高度丰富。
