Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

Abstract

Interstitial cystitis/bladder pain syndrome is a debilitating condition of unknown etiology characterized by persistent pelvic pain with lower urinary tract symptoms and comprises a wide variety of potentially clinically useful phenotypes with different possible etiologies. Current clinicopathological and genomic evidence suggests that interstitial cystitis/bladder pain syndrome should be categorized by the presence or absence of Hunner lesions, rather than by clinical phenotyping based on symptomatology. The Hunner lesion subtype is a distinct inflammatory disease with proven bladder etiology characterized by epithelial denudation and enhanced immune responses frequently accompanied by clonal expansion of infiltrating B cells, with potential engagement of infection. Meanwhile, the non-Hunner lesion subtype is a non-inflammatory disorder with little evidence of bladder etiology. It is potentially associated with urothelial malfunction and neurophysiological dysfunction, and frequently presents with somatic and/or psychological symptoms, that commonly result in central nervous sensitization. Animal models of autoimmune cystitis and neurogenic sensitization might serve as disease models for the Hunner lesion and non-Hunner lesion subtypes, respectively. Here, we revisit the taxonomy of interstitial cystitis/bladder pain syndrome according to current research, and discuss its potential pathophysiology and representative animal models. Categorization of interstitial cystitis/bladder pain syndrome based on cystoscopy is mandatory to design optimized treatment and research strategies for each subtype. A tailored approach that specifically targets the characteristic inflammation and epithelial denudation for the Hunner lesion subtype, or the urothelial malfunction, sensitized/altered nervous system and psychosocial problems for the non-Hunner lesion subtype, is essential for better clinical management and research progress in this complex condition.

Keywords: animal model; autoimmune cystitis; bladder pain syndrome; interstitial cystitis; pathophysiology.

Fig. 1

A Hunner lesion. (a) A Hunner lesion is a reddish mucosal lesion lacking the normal capillary structure, frequently covered by fibrin clots. (b) Narrow-band imaging cystoscopy of the Hunner lesion emphasizes the abnormal capillary structure converging toward the lesion.

Fig. 2

Histological features of IC/BPS. (a) IC/BPS with Hunner lesions (lesion area). Dense subepithelial inflammatory infiltrates, epithelial denudation and increased neovascularization are observed, often accompanied by lymph follicles (magnification: ×100). (b) IC/BPS with Hunner lesions (non-lesion area). Note that similar inflammatory changes are observed in a non-lesion area (magnification: ×200). (c) IC/BPS without Hunner lesions. Few inflammatory changes with retained urothelium (magnification: ×200).

Fig. 3

Genomic landscape of IC/BPS, modified from the results of Akiyama et al. IC/BPS with Hunner lesions (red: lesion area, yellow: non-lesion area) shows a distinct gene expression pattern from IC/BPS without Hunner lesions (blue) and controls (green). The gene expression pattern of IC/BPS without Hunner lesions is similar to that of controls.

Fig. 4

Light chain-restricted B cells infiltrating in IC/BPS with Hunner lesions. (a–c) Light chain restriction in the infiltrating plasma cells in IC/BPS with Hunner lesions. (a) Hematoxylin–eosin staining shows dense plasma cell infiltration in the subepithelial layer. (b,c) In situ hybridization for the (b) kappa chain or (c) lambda chain. Most plasma cells are kappa chain-restricted (magnification: ×200).

Fig. 5

(a) Spontaneous autoimmune cystitis in a URO-OVA/OT-1 mouse at 20 weeks-of-age. Dense mononuclear cell infiltration, vasodilation, mucosal hyperemia and epithelial hyperplasia are observed in the bladder (magnification: ×200). (b) An enlargement of the area outlined by the rectangular dot box (magnification: ×400).

Fig. 6

(a) EAC in a URO-OVA mouse at 21 days after adoptive transfer of splenocytes from OVA-immunized C57BL/6 mice. Remarkable cellular infiltration, vascularity, mucosal hyperemia, stromal edema and epithelial hyperplasia are observed in the bladder (magnification: ×200). (b) An enlargement of the area outlined by the rectangular dot box (magnification: ×400).