Coşkuntan İrem, Paçal Ferda, Coşan Fulya, Aktaş Esin Çetin, Deniz Günnur, Üstek Duran, Ekmekci Sema Sırma, Abacı Neslihan, Gül Ahmet
Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Fatih, 34093, Istanbul, Turkey.
Health Sciences Institute, Istanbul University, Istanbul, Turkey.
Rheumatol Int. 2025 Sep 6;45(9):219. doi: 10.1007/s00296-025-05972-7.
Behçet disease (BD) is a chronic, relapsing inflammatory disorder, and human leukocyte antigen (HLA)-B51 is considered to be the strongest genetic susceptibility factor. The integrated stress response (ISR), defined by the eIF2α/ATF4 axis, is a signaling network that maintains protein homeostasis and regulates innate immunity in eukaryotic cells; pathological activation of this pathway can affect the immune response and cause various diseases. In this study, we aimed to investigate the role of the ISR signaling pathway in the pathogenesis of BD. The study group comprised 83 BD patients and 33 matched healthy controls. eIF2α, PERK, HRI, HSPB8, and ATF4 mRNA expression analysis was performed by real-time quantitative polymerase chain reaction (RTq-PCR) using cDNA prepared from monocytes isolated from peripheral blood and synovial fluid. HLA-B51 status was available for 73 BD patients. ISR analysis revealed decreased expression of eIF2α and increased expression of PERK, HRI, HSPB8, and ATF4 genes in BD compared to controls (all p < 0.05). Findings of synovial fluid monocytes of active BD patients with arthritis showed a consistent (p = 0.0417, one-tailed) increase in HSPB8 expression and strong correlation with those in corresponding blood monocytes. BD patients exhibit dysregulated ISR signatures regardless of HLA-B*51 status. Despite limitations in sample size and in vivo validation, our findings implicate these signaling pathways as potential contributors to the pathogenesis of BD and possibly other the major histocompatibility complex (MHC) class I-associated diseases.
白塞病（BD）是一种慢性复发性炎症性疾病，人类白细胞抗原（HLA）-B51被认为是最强的遗传易感性因素。由eIF2α/ATF4轴定义的综合应激反应（ISR）是一个信号网络，可维持真核细胞中的蛋白质稳态并调节先天免疫；该通路的病理激活可影响免疫反应并导致各种疾病。在本研究中，我们旨在探讨ISR信号通路在BD发病机制中的作用。研究组包括83例BD患者和33例匹配的健康对照。使用从外周血和滑液中分离的单核细胞制备的cDNA，通过实时定量聚合酶链反应（RTq-PCR）进行eIF2α、PERK、HRI、HSPB8和ATF4 mRNA表达分析。73例BD患者可获得HLA-B51状态。ISR分析显示，与对照组相比，BD患者中eIF2α表达降低，PERK、HRI、HSPB8和ATF4基因表达增加（所有p<0.05）。活动性BD关节炎患者滑液单核细胞的研究结果显示，HSPB8表达一致（p=0.0417，单尾）增加，且与相应血液单核细胞中的表达高度相关。无论HLA-B*51状态如何，BD患者均表现出ISR特征失调。尽管样本量和体内验证存在局限性，但我们的研究结果表明，这些信号通路可能是BD以及可能其他主要组织相容性复合体（MHC）I类相关疾病发病机制的潜在因素。
