Uroplakin Peptide-Specific Autoimmunity Initiates Interstitial Cystitis/Painful Bladder Syndrome in Mice |
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Authors: | Kenan Izgi Cengiz Z. Altuntas Fuat Bicer Ahmet Ozer Cagri Sakalar Xiaoxia Li Vincent K. Tuohy Firouz Daneshgari |
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Affiliation: | 1. Department of Urology, Case Western Reserve University, Cleveland, Ohio, United States of America.; 2. Department of Clinical Chemistry, Cleveland State University, Cleveland,, Ohio, United States of America.; 3. Department of Genetics, Case Western Reserve University, Cleveland, Ohio, United States of America.; 4. Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.; University of Miami, United States of America, |
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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. |
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