Interstitial Cystitis/Painful Bladder Syndrome(IC/PBS) is a chronic inflammation of the urinary bladder, consisting of irritative voiding symptoms; frequent and urgent urination and pain referred to the pelvic region or the bladder upon filling, lack of other pathology. The pathophysiology of interstitial cystitis (IC) is enigmatic. The impaired urothelium of bladder and autoimmunity might lead the underlying pathology. One of the shortcomings in IC/PBS research has been the lack of an appropriate animal model.
In the current study, we show that the bladder specific Uroplakin 3A (UPK3A)-derived immunogenic UPK3A 65-84 peptide is capable of targeting experimental autoimmune cystitis (EAC) in BALB/c mice. We determined an immunogenic peptide from the known sequence of UPK3A based on having the binding motif for IAd MHC class II molecules expressed in BALB/c mice. The highly antigen-specific proliferative response to UPK3A 65-84 was determined by proliferation assays. Active immunization with the UPK3A 65-84 peptide resulted in increased micturition frequency and decreased urine output per micturition by FVC along with the increased pelvic pain response to von Frey Filaments, and decrease intercontractile intervals, bladder compliance and bladder capacity in CMG after 5 weeks of immunization compared to control group.
The recall responses of LNC to UPK3A 65-84 showed selectively activated CD4+ T-cells with a proinflammatory Th1-like phenotype. Immunocytochemical analysis showed that immunization with UPK3A 65-84 peptide resulted in T-cell infiltration of the bladder. The ratio of bladder weight to body weight was increased in EAC mice simply showing bladder inflammation. The elevated gene expression levels of TNF-α, IFN-γ, IL-17A, and IL-1β were confined to the bladder but not in other organs. T-cell induction of EAC was identified by showing significantly increased micturition frequency and decreased output per micturition by FVC along with the increased pelvic pain response to von Frey monofilament stimulus after adoptive transfer of peptide-activated CD4+ T-cells into naïve BALB/c hosts.
Our study provides the creation of an advanced and more specific EAC model manifesting all three major phenotypes of IC/PBS by inoculation of mice with, and eliciting an immune response to, tissue specific peptide derived from the Uroplakin of the bladder urothelium. These findings qualify this animal model as a contemporary model for future exploration of pathogenesis and therapeutic intervention of IC/PBS.