The research, published in Frontiers in Molecular Medicine, focused on a subset of patients who carry visible regions of inflammation and ulceration on the bladder wall known as Hunner lesions. This form, called Hunner type interstitial cystitis, follows a more severe clinical course than the more common non-Hunner type, and the two forms rarely, if ever, interconvert. Using high-resolution sequencing of the human leukocyte antigen, or HLA, genes, the investigators identified two alleles that are significantly enriched in patients with Hunner lesions compared with healthy populations.

HLA association has long been considered the gold standard of evidence that a disease is autoimmune. These genes encode proteins that display fragments of antigens on the surface of immune cells, allowing T cells to survey the body for threats. When specific HLA variants recur in patients with a disorder far more often than in the general population, it strongly suggests that the adaptive immune system is responding to a particular antigen, whether that antigen is a self-protein or an external invader. In this study, half of the twelve patients with Hunner lesions carried a rare allele called HLA-DQB1*02:02, an allele so uncommon that it has no recorded frequency in the European population and is absent from the National Marrow Donor Program database.

Compared with reported healthy control genotype frequency, the HLA-DQB102:02 allele showed a significant association with Hunner type disease, with an odds ratio of 6.29 and a P-value of 0.0065. The researchers also found that the HLA-DRB107:01:01 allele had a significantly higher allele frequency in the Hunner cohort than in reference databases, with an odds ratio of 4.6 and a P-value of 0.0004. Notably, none of the seven patients with non-Hunner type disease carried HLA-DQB1*02:02, hinting that the two clinically defined forms of the syndrome may be biologically distinct entities rather than variations of a single disease.

The significance of these particular alleles extends beyond statistics. HLA-DQB1*02:02 has previously been associated with celiac disease, systemic lupus erythematosus, and type 1 diabetes mellitus, all conditions with well-established autoimmune mechanisms. In celiac disease, this allele forms part of an MHC class II heterodimer called HLA-DQ2.2 that presents gluten epitopes to the immune system. The structural details of how antigens bind within the pocket formed by the DQB1 protein are well characterized, and the researchers suggest that a similar antigen-presentation event may be occurring in the bladder lesions of affected patients.

Previous work by the same laboratory had already identified clonal proliferation of B cells within Hunner lesions, with different B cell clones from multiple patients sharing the same B cell receptor. That observation indicated the cells were responding to a specific, unidentified antigen in that location. The new HLA findings complement this picture, as the DQB1 and DQA genes encode a heterodimer expressed on antigen-presenting cells that presents antigens to immune cells, with the B1 allele specifically forming the binding pocket that complexes with the antigen. Together, the cellular and genetic evidence points toward a targeted adaptive immune response within the lesions.

The study has important limitations that the authors acknowledge. The cohort was small, reflecting the rarity of Hunner type disease, which represented approximately 25 percent of all cases seen at the clinic over two years. The sample size was determined by patient availability rather than a formal power calculation, consistent with exploratory genetic association studies of rare disorders. All patients analyzed were Americans of European descent, and the authors emphasize that the results must be reproduced in people of different origins to determine whether the HLA association is local or global. Autoimmune diseases can be associated with different HLA alleles in different populations, as demonstrated by neuromyelitis optica spectrum disorders, which show varying associations depending on geographic region.

If the autoimmune hypothesis is confirmed, the therapeutic implications could be substantial. Current treatments for the condition, including surgical fulguration of lesions, corticosteroids, and bladder hydrodistention, frequently offer limited efficacy. Targeted biologic therapies used to manage autoimmunity, such as anti-interleukin agents and TNF-alpha blockers, could potentially be delivered directly into the bladder. Prior randomized controlled trials with TNF-alpha blockers demonstrated statistically significant reductions in bladder pain and urinary frequency, though patients were not stratified by lesion type and a significant placebo effect was reported. Monoclonal antibodies against BAFF, which regulate clonal B-cell expansion, should also be considered given the evidence of B-cell proliferation within the lesions.

Beyond treatment, identifying the specific HLA alleles involved opens the door to locating the antigen that drives the immune response. Animal models of autoimmune cystitis, including those that induce immunity against bladder proteins called uroplakins, are available to explore disease mechanisms and test new therapies. A natural model also exists in domestic cats, which develop a disorder histologically similar to the non-Hunner form. As researchers work to confirm these genetic associations in larger and more diverse cohorts, the prospect of finally understanding the etiology of this debilitating syndrome moves from speculation toward testable science.

Subject of Research: Immunology

Article Title: Association of specific HLA alleles in patients with interstitial cystitis suggesting autoimmunity

Article References: Tabansky Stern, I., Wang, J., Moldwin, R. M., Kim, J. M., Singh, J. H., Tran, D. C., Najjar, S., Akinci, M., Howard, A., Duke-Cohan, J. E., Belhaj, M., Stevens, J., Lane, W. J., Birder, L. A., Jackson, E. K., Keskin, D. B., Zhang, G., & Stern, J. N. H. (2025). Association of specific HLA alleles in patients with interstitial cystitis suggesting autoimmunity. Frontiers in Molecular Medicine, 5, Article 1712660. https://doi.org/10.3389/fmmed.2025.1712660

Image Credits: AI Generated

DOI: 10.3389/fmmed.2025.1712660

Keywords: interstitial cystitis, bladder pain syndrome, HLA, autoimmunity, Hunner lesions, immunogenetics, Association, specific, alleles, patients, interstitial, cystitis