EBV infection mediated BDNF expression is associated with bladder inflammation in interstitial cystitis/bladder pain syndrome with Hunner's lesion.

Interstitial cystitis/bladder pain syndrome with Hunner's lesion (HIC) is characterized by chronic inflammation and nerve hyperplasia; however, the pathogenesis of HIC remains a mystery. In this study, we detected both EBV latency infection genes EBNA-1, LMP-1, and EBV lytic infection BZLF-1 and BRLF-1 expression in the HIC bladders, indicating coexistence of EBV persistence and reactivation in the B cells in HIC bladders. Upregulation of EBV-associated inflammatory genes in the HIC bladders, such as TNF-α and IL-6, suggests EBV infection is implicated in the pathogenesis of bladder inflammation. Nerve hyperplasia and up-regulation of brain-derived neurotrophic factor (BDNF) were noted in the HIC bladders. Double immunochemical staining and flow cytometry revealed the origin of BDNF should be the EBV infected B cells. Inducible BDNF expression was noted in B cells upon EBV infection, but not in the T cells. Chromatin immunoprecipitation study revealed BDNF transcription could be promoted by a cooperation between EBV nuclear antigens, chromatin modifiers, and B cell specific transcription. Knockdown of BDNF in EBV infected B cells resulted in inhibition of cells proliferation and viability. Downregulation of phosphorylated SMAD2 and STAT3 after BDNF knockdown may play a role in the mechanism. Implantation of latent EBV infected B cells into rat bladder walls resulted in higher expression level of CD45 and PGP9.5, suggesting tissue inflammation and nerve hyperplasia. In contrast, implantation of BDNF depleted EBV infected B cells abrogated these effects. This is the first study to provide insights into the mechanisms underlying the involvement of EBV infected B cells in HIC pathogenesis. This article is protected by copyright. All rights reserved.

The Journal of pathology. 2022 Nov 28 [Epub ahead of print]

Jia-Fong Jhang, Cheng-Der Liu, Yung-Hsiang Hsu, Chien-Chin Chen, Hsiang-Chin Chen, Yuan-Hong Jiang, Wan-Chen Wu, Chih-Wen Peng, Hann-Chorng Kuo

Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan., Department of Life Science, National Donghwa University, Shoufeng, Taiwan., Department of Pathology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan., Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.