Autoimmunity to urothelial antigen causes bladder inflammation, pelvic pain, and voiding dysfunction: a novel animal model for Hunner-type interstitial cystitis

Yoshiyuki Akiyama; Jian-Rong Yao; Karl J Kreder; Michael A O'Donnell; Susan K Lutgendorf; Dan Lyu; Daichi Maeda; Haruki Kume; Yukio Homma; Yi Luo

doi:10.1152/ajprenal.00290.2020

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Autoimmunity to urothelial antigen causes bladder inflammation, pelvic pain, and voiding dysfunction: a novel animal model for Hunner-type interstitial cystitis

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Autoimmunity to urothelial antigen causes bladder inflammation, pelvic pain, and voiding dysfunction: a novel animal model for Hunner-type interstitial cystitis

Yoshiyuki Akiyama, Jian-Rong Yao, Karl J Kreder, Michael A O'Donnell, Susan K Lutgendorf, Dan Lyu, Daichi Maeda, Haruki Kume, Yukio Homma and Yi Luo

American journal of physiology. Renal physiology, Vol.320(2), pp.F174-F182

02/01/2021

DOI: 10.1152/ajprenal.00290.2020

PMCID: PMC7948122

PMID: 33308017

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Abstract

Recent evidence revealed that Hunner-type interstitial cystitis (HIC) is a robust inflammatory disease potentially associated with enhanced immune responses and histologically characterized by epithelial denudation and lymphoplasmacytic infiltration with frequent clonal expansion of infiltrating B cells. To date, few animal models that reproduce the histological and clinical correlates of HIC have yet been established. In the present study, we aimed to develop a novel animal model for HIC via autoimmunity to the bladder urothelium using the transgenic mouse model (URO-OVA) that expresses the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the bladder urothelium. OVA-specific lymphocytes (splenocytes) were generated by immunization of C57BL/6 mice with OVA protein and injected intravenously into URO-OVA mice. The splenocytes from OVA-immunized C57BL/6 mice showed increased interferon (IFN)-γ production in response to OVA stimulation in vitro. URO-OVA mice adoptively transferred with OVA-primed splenocytes developed cystitis exhibiting histological chronic inflammatory changes such as remarkable mononuclear cell infiltration predominantly composed of T and B lymphocytes, increased vascularity, and mucosal hyperemia in the bladder at - with a peak at tested. No systemic inflammation was found in cystitis-induced URO-OVA mice, nor was any inflammation found in wild-type C57BL/6 mice adoptively transferred with OVA-primed splenocytes. Along with bladder inflammation, URO-OVA mice demonstrated significantly increased pelvic nociceptive responses, voiding dysfunction, and upregulated mRNA expression levels for IFN-γ, tumor necrosis factor-α (TNF-α), and substance P precursor in the bladder. This model reproduces the histological and clinical features of human HIC, providing a novel model for HIC research.

Cytokines - metabolism

Ovalbumin - immunology

Gene Expression Regulation - immunology

Mice, Transgenic

Urinary Bladder - pathology

Cystitis - pathology

Animals

Pelvic Pain - pathology

Pelvic Pain - etiology

Cystitis, Interstitial - pathology

Urination Disorders - etiology

Urothelium - immunology

Antigens - immunology

Mice

Urination Disorders - pathology

Autoimmune Diseases - pathology

Cytokines - genetics

Cystitis - etiology

Disease Models, Animal

Details

Title: Subtitle: Autoimmunity to urothelial antigen causes bladder inflammation, pelvic pain, and voiding dysfunction: a novel animal model for Hunner-type interstitial cystitis
Creators: Yoshiyuki Akiyama - Department of Urology, University of Iowa, Iowa City, Iowa
Jian-Rong Yao - Department of Urology, University of Iowa, Iowa City, Iowa
Karl J Kreder - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa
Michael A O'Donnell - Department of Urology, University of Iowa, Iowa City, Iowa
Susan K Lutgendorf - Department of Psychological and Brain Sciences, University of Iowa, Iowa City, Iowa
Dan Lyu - Department of Anesthesia, University of Iowa, Iowa City, Iowa
Daichi Maeda - Department of Clinical Genomics, Graduate School of Medicine, Osaka University, Osaka, Japan
Haruki Kume - Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Yukio Homma - Japanese Red Cross Medical Center, Tokyo, Japan
Yi Luo - Department of Urology, University of Iowa, Iowa City, Iowa
Resource Type: Journal article
Publication Details: American journal of physiology. Renal physiology, Vol.320(2), pp.F174-F182
DOI: 10.1152/ajprenal.00290.2020
PMID: 33308017
PMCID: PMC7948122
NLM abbreviation: Am J Physiol Renal Physiol
ISSN: 1931-857X
eISSN: 1522-1466
Publisher: United States
Grant note: R01 DK111396 / NIDDK NIH HHS
Language: English
Date published: 02/01/2021
Academic Unit: Psychological and Brain Sciences; Iowa Neuroscience Institute; Obstetrics and Gynecology; Urology
Record Identifier: 9984065881902771

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