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Traditionally, HL has been used as a clinical diagnostic tool for a subset of patients with interstitial cystitis\/bladder pain syndrome (IC\/BPS); however, emerging evidence supports a unique pathophysiology for IC\/BPS with HL (HIC) that is distinct from IC\/BPS without HL (NHIC). This review is aimed at synthesizing current literature on the etiology of HL\/HIC and evaluate whether HIC and NHIC warrant classification as separate clinical conditions with distinct management strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A comprehensive literature review using PubMed was conducted to identify literature surrounding HL etiology and pathophysiology. Case\u2013control studies, cohort studies, experimental studies, case reports, and animal studies were included; editorial comments and literature reviews were excluded from this review.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Emerging data suggest that a subset of patients might be predisposed to HIC, including alteration in major histocompatibility complex (MHC) molecules, HLA amino acid positions, and additional protein expression alterations detected by RNA sequencing. Hypoxia-inducible factor activation and chronic ischemia have also been shown to play a role in HL development. Both local and systemic inflammation are seen in HIC, with clonal B-cell expansion influencing the upregulation of inflammatory cytokines, chemokines, and lymphoplasmacytic cells. With additional validation these biomarkers have the potential to serve as a diagnostic tool.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Hunner lesion with IC\/BPS is a chronic condition likely caused by an upregulation of humoral immunity leading to an overexpression of inflammatory markers within the urothelium, suggesting an autoimmune-mediated pathology for this patient subgroup.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00192-026-06739-9","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T13:58:23Z","timestamp":1781963903000},"page":"3597-3609","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Etiology of Hunner Lesions: Linking Immune Dysregulation and Chronic Inflammation in Interstitial Cystitis\/Bladder Pain Syndrome"],"prefix":"10.1007","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3365-886X","authenticated-orcid":false,"given":"Eboni T.","family":"Acoff","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9079-0091","authenticated-orcid":false,"given":"Kaylee","family":"Ferrara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6263-6221","authenticated-orcid":false,"given":"Hannah","family":"Ruetten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3158-8092","authenticated-orcid":false,"given":"Gopal","family":"Badlani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8191-5549","authenticated-orcid":false,"given":"Robert J.","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8412-5967","authenticated-orcid":false,"given":"Amr","family":"El Haraki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0732-2366","authenticated-orcid":false,"given":"Stephen J.","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"issue":"18","key":"6739_CR1","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1056\/NEJM191505061721802","volume":"172","author":"GL Hunner","year":"1915","unstructured":"Hunner GL. 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