Julius Lindblom, Denis Lagutkin, Natalia Sherina, Helena Idborg, Lorenzo Beretta, Maria Orietta Borghi, Janique M Peyper, Guillermo Barturen, Per-Johan Jakobsson, Marta E Alarcón-Riquelme, Dionysis Nikolopoulos, Ioannis Parodis
{"title":"在两个独立队列中验证的新型IgG和IgA自身抗体与系统性红斑狼疮的疾病活动性相关，并决定器官表现：抗lin28a、抗hmgn5、抗irf5和抗tgif1的意义。","authors":"Julius Lindblom, Denis Lagutkin, Natalia Sherina, Helena Idborg, Lorenzo Beretta, Maria Orietta Borghi, Janique M Peyper, Guillermo Barturen, Per-Johan Jakobsson, Marta E Alarcón-Riquelme, Dionysis Nikolopoulos, Ioannis Parodis","doi":"10.1016/j.ard.2025.04.008","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>This study aimed to identify and validate novel autoantibodies that reflect global and organ-specific disease activity in systemic lupus erythematosus (SLE).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1164-1179"},"PeriodicalIF":20.3000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Novel IgG and IgA autoantibodies validated in two independent cohorts are associated with disease activity and determine organ manifestations in systemic lupus erythematosus: implications for anti-LIN28A, anti-HMGN5, anti-IRF5, and anti-TGIF1.\",\"authors\":\"Julius Lindblom, Denis Lagutkin, Natalia Sherina, Helena Idborg, Lorenzo Beretta, Maria Orietta Borghi, Janique M Peyper, Guillermo Barturen, Per-Johan Jakobsson, Marta E Alarcón-Riquelme, Dionysis Nikolopoulos, Ioannis Parodis\",\"doi\":\"10.1016/j.ard.2025.04.008\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>This study aimed to identify and validate novel autoantibodies that reflect global and organ-specific disease activity in systemic lupus erythematosus (SLE).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":8087,\"journal\":{\"name\":\"Annals of the Rheumatic Diseases\",\"volume\":\" \",\"pages\":\"1164-1179\"},\"PeriodicalIF\":20.3000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of the Rheumatic Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ard.2025.04.008\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/5/9 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of the Rheumatic Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ard.2025.04.008","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/9 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的：本研究旨在鉴定和验证反映系统性红斑狼疮（SLE）全局和器官特异性疾病活动性的新型自身抗体。方法：采用微阵列（i-Ome Discovery）检测血浆样品对1609蛋白自身抗原的IgG和IgA血清反应性；Sengenics)。我们在一项研究中测定了SLE患者与健康对照者自身抗体（daAAbs）含量的差异(n = 196 vs n = 110；NTC02890121)和独立验证队列(n = 30 vs n = 83；NCT02890134)，来自欧洲PRECISESADS项目。使用线性和逻辑回归分析验证的daAAb与全局和器官特异性疾病活动的关系，以及daAAb靶标途径富集分析。结果：共验证了89个IgG抗体和66个IgA抗体。IgG抗lin28a、IgG抗hmgn5、IgG抗irf5和抗tgif1同型与SLE疾病活动性指数2000评分≥10相关，与狼疮低疾病活动性状态负相关，在跨器官表现活动性疾病亚组中高度流行。在中枢神经系统（CNS）受累的患者中，IgG抗lin28a水平超过了阳性临界值，高于抗双链DNA（20%）和肾活动患者的47%。一组针对rna结合蛋白（包括抗lin28a）的IgG和IgA daAAbs与中枢神经系统相关。IgA抗fosl2仅在肌肉骨骼活动患者中升高。涉及DNA结合和修复的富集途径在各种表现中显示出相当大的重叠。结论：新型IgG和IgA自身抗体，包括抗lin28a的IgG抗体、抗hmgn5的IgG抗体、抗irf5的IgG抗体和抗tgif1的IgG抗体和IgA抗体与SLE疾病活动性相关，且在各器官表现中高度丰富。
Novel IgG and IgA autoantibodies validated in two independent cohorts are associated with disease activity and determine organ manifestations in systemic lupus erythematosus: implications for anti-LIN28A, anti-HMGN5, anti-IRF5, and anti-TGIF1.
Objectives: This study aimed to identify and validate novel autoantibodies that reflect global and organ-specific disease activity in systemic lupus erythematosus (SLE).
Methods: 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.
Results: 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.
Conclusions: 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.
期刊介绍：
Annals of the Rheumatic Diseases (ARD) is an international peer-reviewed journal covering all aspects of rheumatology, which includes the full spectrum of musculoskeletal conditions, arthritic disease, and connective tissue disorders. ARD publishes basic, clinical, and translational scientific research, including the most important recommendations for the management of various conditions.
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