Weinhaeusel Andreas, Huber Jasmin, Schoenthaler Silvia, Beigel Florian, Noehammer Christa, Vierlinger Klemens, Siebeck Matthias, Gropp Roswitha
Austrian Institute of Technology GmbH (AIT), Giefinggasse, 1210 Vienna, Austria.
Department of Medicine II, Hospital of the Ludwig-Maximilian University Munich, 81377 Munich, Germany.
Int J Mol Sci. 2025 Apr 25;26(9):4086. doi: 10.3390/ijms26094086.
Ulcerative colitis (UC) is a major form of inflammatory bowel disease (IBD) characterised by chronic immune-mediated inflammation. While serological biomarkers for IBD diagnosis and differentiation have been explored, autoantibody-based profiling remains underdeveloped. This study aimed to elucidate antibody signatures in manifested and pre-diagnostic UC patients compared to controls using a high-content protein microarray. Serum and plasma samples from manifested and pre-diagnostic UC cohorts were analysed using AIT's 16k protein microarray, presenting 6369 human proteins. The pre-diagnostic cohort, consisting of 33 UC cases and 33 controls, included longitudinal samples collected before diagnosis, while the severe UC cohort, comprising 49 severe UC patients and 23 controls, included individuals undergoing treatment. Immunoglobulin G (IgG) autoantibody reactivity was assessed to identify differentially reactive antigens (DIRAGs) linked to UC onset, disease progression, and activity. In manifested UC, 691 DIRAGs showed higher reactivity in cases. In the pre-diagnostic cohort, 966 DIRAGs were identified, with 803 antigens exhibiting increased reactivity in cases. Longitudinal analysis revealed 1371 DIRAGs, with 1185 showing increased reactivity closer to diagnosis when comparing samples collected 4-11 months before UC diagnosis to earlier time points 9-24 months prior, highlighting potential early biomarkers. A significant overlap of 286 antigens, corresponding to 41 percent of identified DIRAGs, was observed between severe and pre-diagnostic UC datasets, with an odds ratio of 3.8 and a -value below 2.2 × 10, confirming reliability and biological relevance. Additionally, 21 antigens correlated with simple clinical colitis activity index (SCCAI) scores. Reactome pathway analysis identified 49 pathways associated with DIRAGs in pre-diagnostic UC, distinct from 24 pathways in manifested UC, with an overlap of five key pathways related to protein folding, immune regulation, and viral infection, reflecting differences in disease onset and manifestation. Autoantibody profiling reveals early immune signatures in UC, offering novel biomarkers for preclinical diagnosis and disease monitoring. The overlap between pre-diagnostic and manifested UC antigenic profiles reinforces their biological relevance, linking them to molecular pathology. These findings highlight antibody profiling as an additional omics layer, paving the way for new diagnostic and therapeutic strategies in UC management.
溃疡性结肠炎（UC）是炎症性肠病（IBD）的一种主要形式，其特征为慢性免疫介导的炎症。虽然已经探索了用于IBD诊断和鉴别的血清生物标志物，但基于自身抗体的分析仍未充分发展。本研究旨在使用高内涵蛋白质微阵列，阐明已确诊和诊断前UC患者与对照组相比的抗体特征。使用AIT的16k蛋白质微阵列分析已确诊和诊断前UC队列的血清和血浆样本，该微阵列展示了6369种人类蛋白质。诊断前队列由33例UC病例和33例对照组成，包括诊断前采集的纵向样本，而重度UC队列由49例重度UC患者和23例对照组成，包括正在接受治疗的个体。评估免疫球蛋白G（IgG）自身抗体反应性，以识别与UC发病、疾病进展和活动相关的差异反应性抗原（DIRAG）。在已确诊的UC中，691种DIRAG在病例中显示出更高的反应性。在诊断前队列中，鉴定出966种DIRAG，其中803种抗原在病例中反应性增加。纵向分析揭示了1371种DIRAG，当将UC诊断前4 - 11个月采集的样本与更早的9 - 24个月的时间点采集的样本进行比较时，1185种DIRAG在接近诊断时反应性增加，突出了潜在的早期生物标志物。在重度和诊断前UC数据集之间观察到286种抗原的显著重叠，占已鉴定DIRAG的41%，优势比为3.8，P值低于2.2×10，证实了可靠性和生物学相关性。此外，21种抗原与简单临床结肠炎活动指数（SCCAI）评分相关。Reactome通路分析确定了诊断前UC中与DIRAG相关的49条通路，与已确诊UC中的24条通路不同，有5条关键通路重叠，涉及蛋白质折叠、免疫调节和病毒感染，反映了疾病发病和表现的差异。自身抗体分析揭示了UC中的早期免疫特征，为临床前诊断和疾病监测提供了新的生物标志物。诊断前和已确诊UC抗原谱之间的重叠强化了它们的生物学相关性，将它们与分子病理学联系起来。这些发现突出了抗体分析作为另一个组学层面，为UC管理中的新诊断和治疗策略铺平了道路。
