Integrated stress response in Behçet disease: expression analyses in peripheral blood and synovial monocytes

Abstract

Behçet disease (BD) is a chronic, relapsing inflammatory disorder, and human leukocyte antigen (HLA)-B*51 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-B*51 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.

Keywords: Behçet disease; Inflammation; Monocytes; Proteotoxic stress; Small heat-shock protein; eIF-2 kinase.