Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
Hunan Clinical Research Center of Ophthalmic Disease, Changsha, 410011, Hunan, China.
J Transl Med. 2024 Mar 12;22(1):271. doi: 10.1186/s12967-024-05077-y.
Patients with spondyloarthritis (SpA)/HLA-B27-associated acute anterior uveitis (AAU) experience recurring acute flares, which pose significant visual and financial challenges. Despite established links between SpA and HLA-B27-associated AAU, the exact mechanism involved remains unclear, and further understanding is needed for effective prevention and treatment.
To investigate the acute pathogenesis of SpA/HLA-B27-associated AAU, Mendelian randomization (MR) and single-cell transcriptomic analyses were employed. The MR incorporated publicly available protein quantitative trait locus data from previous studies, along with genome-wide association study data from public databases. Causal relationships between plasma proteins and anterior uveitis were assessed using two-sample MR. Additionally, colocalization analysis was performed using Bayesian colocalization. Single-cell transcriptome analysis utilized the anterior uveitis dataset from the Gene Expression Omnibus (GEO) database. Dimensionality reduction, clustering, transcription factor analysis, pseudotime analysis, and cell communication analysis were subsequently conducted to explore the underlying mechanisms involved.
Mendelian randomization analysis revealed that circulating levels of AIF1 and VARS were significantly associated with a reduced risk of developing SpA/HLA-B27-associated AAU, with AIF1 showing a robust correlation with anterior uveitis onset. Colocalization analysis supported these findings. Single-cell transcriptome analysis showed predominant AIF1 expression in myeloid cells, which was notably lower in the HLA-B27-positive group. Pseudotime analysis revealed dendritic cell terminal positions in differentiation branches, accompanied by gradual decreases in AIF1 expression. Based on cell communication analysis, CD141CLEC9A classic dendritic cells (cDCs) and the APP pathway play crucial roles in cellular communication in the Spa/HLA-B27 group.
AIF1 is essential for the pathogenesis of SpA/HLA-B27-associated AAU. Myeloid cell differentiation into DCs and decreased AIF1 levels are also pivotal in this process.
患有脊椎关节炎（SpA）/HLA-B27 相关急性前葡萄膜炎（AAU）的患者会经历反复发作的急性发作，这给他们带来了重大的视力和经济挑战。尽管 SpA 和 HLA-B27 相关 AAU 之间存在明确的联系，但涉及的确切机制仍不清楚，需要进一步了解以进行有效的预防和治疗。
为了研究 SpA/HLA-B27 相关 AAU 的急性发病机制，采用了孟德尔随机化（MR）和单细胞转录组分析。MR 结合了先前研究中公开的蛋白质定量性状基因座数据，以及公共数据库中的全基因组关联研究数据。使用两样本 MR 评估了血浆蛋白与前葡萄膜炎之间的因果关系。此外，还使用贝叶斯共定位分析进行了共定位分析。单细胞转录组分析利用了 Gene Expression Omnibus（GEO）数据库中的前葡萄膜炎数据集。随后进行了降维、聚类、转录因子分析、伪时间分析和细胞通讯分析，以探索潜在的发病机制。
MR 分析表明，循环 AIF1 和 VARS 水平与降低 SpA/HLA-B27 相关 AAU 的发病风险显著相关，其中 AIF1 与前葡萄膜炎发病具有很强的相关性。共定位分析支持了这些发现。单细胞转录组分析显示，AIF1 在髓系细胞中表达为主，在 HLA-B27 阳性组中表达明显降低。伪时间分析显示，树突状细胞在分化分支中的末端位置，伴随着 AIF1 表达的逐渐降低。基于细胞通讯分析，CD141CLEC9A 经典树突状细胞（cDC）和 APP 途径在 Spa/HLA-B27 组中细胞通讯中发挥着关键作用。
AIF1 是 SpA/HLA-B27 相关 AAU 发病机制的关键。髓系细胞向 DC 分化和 AIF1 水平降低也是该过程的关键。
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