Uroplakin Peptide-Specific Autoimmunity Initiates Interstitial Cystitis/Painful Bladder Syndrome in Mice

Kenan Izgi,Ahmet Ozer,Fuat Bicer,Cagri Sakalar,Firouz Daneshgari,Cengiz Z. Altuntas,Xiaoxia Li,Vincent K. Tuohy,Wasif N. Khan

doi:10.1371/journal.pone.0072067

Abstract

The pathophysiology of interstitial cystitis/painful bladder syndrome (IC/PBS) is enigmatic. Autoimmunity and impaired urothelium might lead the underlying pathology. A major shortcoming in IC/PBS research has been the lack of an appropriate animal model. In this study, we show that the bladder specific uroplakin 3A-derived immunogenic peptide UPK3A 65–84, which contains the binding motif for IAd MHC class II molecules expressed in BALB/c mice, is capable of inducing experimental autoimmune cystitis in female mice of that strain. A highly antigen-specific recall proliferative response of lymph node cells to UPK3A 65–84 was observed, characterized by selectively activated CD4+ T cells with a proinflammatory Th1-like phenotype, including enhanced production of interferon γ and interleukin-2. T cell infiltration of the bladder and bladder-specific increased gene expression of inflammatory cytokines were observed. Either active immunization with UPK3A 65–84 or adoptive transfer of peptide-activated CD4+ T cells induced all of the predominant IC/PBS phenotypic characteristics, including increased micturition frequency, decreased urine output per micturition, and increased pelvic pain responses to stimulation with von Frey filaments. Our study demonstrates the creation of a more specific experimental autoimmune cystitis model that is the first inducible model for IC/PBS that manifests all of the major symptoms of this debilitating condition.

Highlights

Interstitial cystitis (IC) is a chronic sterile inflammation of the bladder, inducing pain in the pelvic region and in the bladder [1]
The 20-mer UPK3A 65–84 peptide derived from the mouse bladder specific protein uroplakin 3A was predicted by the SYFPEITHI program and database to be highly immunogenic in BALB/c mice, due to its inclusion of the -SXXVXV- binding motif for IAd MHC class II molecules expressed in those mice
lymph node cells (LNC) obtained from female SWXJ mice immunized with peptide UPK2 115–134 exhibited a negligible recall response to the UPK2 peptide (Figure 1A,B), suggesting either that other peptide sequences of uroplakin 2 were responsible for its immunogenicity in our previous study, or additional native UPK2 amino acid residues are required in order for the –KXXS- motif to be properly processed and presented by MHC

Summary

Introduction

Interstitial cystitis (IC) is a chronic sterile inflammation of the bladder, inducing pain in the pelvic region and in the bladder [1]. The most recent NIH-funded epidemiological study of IC/PBS in women in the U.S (Rand IC Epidemiology or RICE Study) identified a prevalence of 6.5% and 2.7% based on high sensitivity and high specificity criteria, respectively, for diagnosing IC/PBS [4]. Those percentages translated into 3.3 to 7.9 million women 18 years old or older with IC/PBS symptoms [4]. Chronic pain, urinary frequency and urgency, and sleep deprivation associated with IC/PBS may contribute to psychological distress. Advancement in addressing this disease has been slow due to its uncertain etiology and a lack of understanding of the underlying pathophysiology

Methods

Results

Conclusion