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

Abstract

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 Epstein–Barr virus (EBV) latency infection genes EBNA‐1 and LMP‐1 and EBV lytic infection BZLF‐1 and BRLF‐1 expression in the HIC bladders, indicating the coexistence of EBV persistence and reactivation in the B cells in HIC bladders. Upregulation of EBV‐associated inflammatory genes in HIC bladders, such as TNF‐α and IL‐6, suggests EBV infection is implicated in the pathogenesis of bladder inflammation. Nerve hyperplasia and upregulation of brain‐derived neurotrophic factor (BDNF) were noted in the HIC bladders. Double immunochemical staining and flow cytometry revealed the origin of BDNF to be EBV‐infected B cells. Inducible BDNF expression was noted in B cells upon EBV infection, but not in the T cells. A chromatin immunoprecipitation study revealed BDNF transcription could be promoted by cooperation between EBV nuclear antigens, chromatin modifiers, and B‐cell‐specific transcription. Knockdown of BDNF in EBV‐infected B cells resulted in the inhibition of cell 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 a 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. © 2022 The Pathological Society of Great Britain and Ireland.

Multimodal therapies and strategies for the treatment of interstitial cystitis/bladder pain syndrome in Taiwan

“…31 Jhang et al found that BDNF alteration in Epstein-Barr virus-infected B cells inhibits cell proliferation and viability in IC/BPS models. 32 Akiyama et al found defective umbrella cells with urothelial denudation, integrity defects, and pleomorphism in animal model with autoimmune cystitis. 29 These electron microscopic findings were also observed in human bladders and correlated with symptom severity in patients with HIC and NHIC.…”

“…Brain‐derived neurotrophic factor (BDNF) deficiency may cause dysregulated neuroinflammatory and metabolic responses 31 . Jhang et al found that BDNF alteration in Epstein–Barr virus‐infected B cells inhibits cell proliferation and viability in IC/BPS models 32 . Akiyama et al found defective umbrella cells with urothelial denudation, integrity defects, and pleomorphism in animal model with autoimmune cystitis 29 .…”

Urinary Viral Spectrum in Patients with Interstitial Cystitis/Bladder Pain Syndrome and the Clinical Efficacy of Valacyclovir Treatment

“…We used in situ hybridization and PCR to assess the presence of EBV, and EBV infection was identified in the bladder specimens of 87.5% and 17.4% of patients with HIC and NHIC, respectively [ 8 ]. In a subsequent study, we reported that both latent and lytic EBV infection were present in the bladders of patients with IC/BPS [ 9 ], suggesting EBV reactivation in the bladders. We also provided molecular evidence demonstrating that EBV infection is associated with the upregulation of brain-derived neurotrophic factor and EBV-associated inflammatory cytokines in the bladders of patients with IC/BPS [ 9 ].…”

“…In a subsequent study, we reported that both latent and lytic EBV infection were present in the bladders of patients with IC/BPS [ 9 ], suggesting EBV reactivation in the bladders. We also provided molecular evidence demonstrating that EBV infection is associated with the upregulation of brain-derived neurotrophic factor and EBV-associated inflammatory cytokines in the bladders of patients with IC/BPS [ 9 ]. Therefore, infection with EBV may be an etiology in some patients with IC/BPS.…”

“…Antiherpesvirus drugs, such as valacyclovir, have been widely used to treat patients with EBV infection because of their strong effects in eliminating herpes virus replication [ 13 , 14 , 15 ]. As suggested by the results of our previous study that EBV lytic infection in the bladder is associated with IC/BPS [ 9 ], valacyclovir may be useful for treating patients with IC/BPS. Hence, our present study first surveyed the types of urinary viruses in patients with IC/BPS.…”