The Role of Urinary Secretory Immunoglobulin A in the Pathophysiology of Interstitial Cystitis

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Int Neurourol J. 2025;29(3):181-187

Publication date (electronic) : 2025 September 30

doi : https://doi.org/10.5213/inj.2550048.024

Turan Ozdemir^,1, Bayram Aliyev¹, Kasim Emre Ergun¹, Serdar Kalemci¹, Fuat Kizilay¹, Elif Azarsiz², Adnan Simsir¹

¹Department of Urology, Faculty of Medicine, Ege University, Izmir, Turkey

²Department of Biochemistry, Faculty of Medicine, Ege University, Izmir, Turkey

Corresponding author: Turan Ozdemir Department of Urology, Faculty of Medicine, Ege University, Izmir, Turkey Email: drtrn_ozdemir18@hotmail.com

Received 2025 February 13; Accepted 2025 May 12.

Abstract

INTRODUCTION

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic and debilitating disorder defined by pelvic pain, pressure, or discomfort perceived to be related to the urinary bladder. It is typically accompanied by lower urinary tract symptoms such as urinary frequency and urgency, which often worsen with bladder filling and occur without identifiable infection or pathology [1]. The American Urological Association defines BPS/IC as symptoms persisting for more than 6 weeks in the absence of alternative explanations [2]. Prevalence estimates vary widely, from 0.01% to 6.5%, reflecting differences in diagnostic criteria and study populations [3].

The underlying pathophysiology of BPS/IC remains uncertain, but several mechanisms have been proposed. These include increased urothelial permeability, disruption of the glycosaminoglycan (GAG) layer, chronic inflammation, autoimmune activation, mast cell infiltration, and neurogenic dysfunction. Despite extensive research, no single unifying mechanism has been universally accepted [4].

Secretory immunoglobulin A (sIgA) plays a central role in mucosal immunity by protecting epithelial surfaces. It functions by neutralizing pathogens and preventing microbial adhesion, and is particularly important in mucosal tissues such as the respiratory, gastrointestinal, and urogenital tracts. Considering the hypothesized disruption of the bladder mucosal barrier in BPS/IC, sIgA may serve as an indicator of local immune response or barrier dysfunction [5].

We hypothesized that compromised mucosal immune integrity in BPS/IC may result in altered urinary sIgA levels. Thus, this study aimed to compare urinary sIgA levels between BPS/IC patients and healthy controls. Additionally, we sought to determine whether clinical variables, including comorbidities and lifestyle factors, were associated with changes in urinary sIgA levels within the BPS/IC population.

MATERIALS AND METHODS

Study Design

The study included 40 female patients diagnosed with BPS/IC (BPS/IC group) and 40 healthy female controls. Patients were selected according to the criteria outlined in the BPS/IC guidelines. Exclusion criteria were active urogenital tract infection, a history of bladder cancer, and prior pelvic radiotherapy. Symptom severity and overall condition in the BPS/IC group were assessed using the O’Leary-Sant Interstitial Cystitis Symptom and Problem Index (IC-SPI).

For all participants, a 10-mL urine sample was collected in a sterile container. Samples were centrifuged at 1,500×g at 4°C for 20 minutes and stored at -80°C for subsequent measurement of supernatant sIgA levels. A schematic overview of the study methodology is presented in Fig. 1.

Fig. 1.

Flowchart of study design and sample processing steps. sIgA, secretory immunoglobulin A; BPS/IC, bladder pain syndrome/ınterstitial cystitis; ELISA, enzyme-linked immunosorbent assay; OD, optical density.

Urinary sIgA concentrations were determined using a commercial ELISA kit (Abnova KA3980 Human Secretory IgA ELISA Kit, Taiwan). Urine samples were diluted 1:50 (10-μL sample+500-μL buffer) and applied to microplates coated with monoclonal anti-human sIgA antibodies. Following incubation, a peroxidase-conjugated secondary antibody was added, after which the plates were washed and substrate was applied. Optical density was measured at 450 nm, and sIgA concentrations were calculated using a 6-point standard curve ranging from 0 to 400 μg/mL.

RESULTS

The mean age of the BPS/IC group was significantly higher than that of the control group: 53.1±11.8 years versus 39.3±8.8 years (P=0.002).

No statistically significant differences were observed between the BPS/IC and control groups with respect to demographic variables, including body mass index (BMI), smoking status, prior surgical history, urinary incontinence, and comorbidities (all P>0.05), as summarized in Table 1.

Table 1.

Demographic characteristics of the patients

Mean urinary sIgA levels were 0.96±1.5 μg/mL in the BPS/IC group and 0.53±0.7 μg/mL in the control group. This difference was not statistically significant (P=0.173). Correlation analysis showed no significant association between age and urinary sIgA levels in either group (Spearman rho=0.029, P=0.801).

Table 2 presents intragroup comparisons of urinary sIgA levels across clinical variables, while Table 3 highlights intergroup comparisons between BPS/IC patients and controls using the same parameters. When comorbidity was evaluated, urinary sIgA levels were significantly higher in BPS/IC patients with cardiac disease (median, 0.82 μg/mL) compared to those without (P=0.015) (Table 2). Intergroup comparison further revealed that urinary sIgA levels were significantly higher in BPS/IC patients with cardiac disease (median, 0.82 μg/mL) compared with controls with cardiac disease (median, 0.13 μg/mL; P=0.003) (Table 3). This difference is also illustrated in Fig. 2.

Table 2.

Comparison of urinary sIgA levels within BPS/IC and control groups

Table 3.

Comparison of urinary sIgA levels between BPS/IC and Control groups

Fig. 2.

Comparison of urinary sIgA levels between BPS/IC patients with and without cardiac disease. sIgA, secretory immunoglobulin A; BPS/IC, bladder pain syndrome/ınterstitial cystitis.

Urinary sIgA levels were significantly lower in smokers with BPS/IC than in nonsmokers (P=0.004), whereas no significant differences were detected in the control group (Table 2).

No significant associations were found between urinary sIgA levels and hyaluronic acid (HA) plus chondroitin sulfate (CS) treatment (P=0.840) or treatment duration (P=0.399) (Table 4).

Table 4.

Comparison of urinary sIgA levels in the BPS/IC group

Previous surgical history (P=0.121) and BMI were not correlated with urinary sIgA levels in the BPS/IC group. Specifically, no significant differences were identified among BMI categories: <25 kg/m² (P=0.273), 25–29 kg/m² (P=0.258), and ≥30 kg/m² (P=0.221) (Table 3).

DISCUSSION

Given the critical role of mucosal immunity in maintaining epithelial integrity, investigating changes in urinary sIgA levels may provide important insights into disease mechanisms. By comparing urinary sIgA levels between BPS/IC patients and healthy controls, we aimed to identify potential immunological alterations associated with BPS/IC and to assess the influence of clinical factors such as smoking and comorbidities.

Although BPS/IC patients were older on average than controls, correlation analysis showed no significant association between age and urinary sIgA levels, suggesting that age alone does not account for the observed trends.

Previous studies have reported increased IgA levels following urinary tract infections, largely attributed to submucosal inflammation [6]. However, the dynamics of urinary sIgA in conditions characterized by disruption of the GAG layer, such as BPS/IC, remain unclear. The nonsignificant elevation of urinary sIgA observed in our BPS/IC cohort may reflect disease heterogeneity and variability in mucosal immune activation.

Hurst et al. [7] reported that CS, a natural GAG present in the bladder mucosal layer, plays an important role in the pathophysiology of interstitial cystitis when deficient. In another study, Porru et al. [8] demonstrated that a 6-month regimen of HA plus CS significantly reduced symptoms such as pain, frequency, and urgency in BPS/IC patients. Considering that HA and CS therapies support repair of the bladder GAG layer, the numerically higher urinary sIgA levels observed in patients receiving these therapies for 12 months or longer could be clinically relevant. However, this difference was not statistically significant and should be interpreted with caution. While GAG analogs may strengthen mucosal barrier integrity, our findings did not demonstrate a definitive impact on urinary sIgA levels.

The IC-SPI is a validated tool widely used to evaluate symptom severity and monitor treatment response in BPS/IC [9, 10]. In the present study, urinary sIgA levels did not correlate with IC-SPI scores. This suggests that urinary sIgA may reflect mucosal barrier integrity rather than patient-reported symptom severity.

Offiah et al. [11] suggested that factors such as childbirth, prior pelvic surgery, bacterial cystitis, urological instrumentation, and autoimmune activation may disrupt the GAG layer. In contrast, we observed no significant association between urinary sIgA levels and prior surgical history. This discrepancy may be related to differences in patient characteristics, surgical techniques, or the timing of mucosal injury relative to the measurement of sIgA levels.

It is well established that oxidative stress and bladder hypertrophy play central roles in bladder dysfunction in diabetes mellitus. Increased intravesical pressure contributes to hypertrophy, while oxidative stress accelerates mucosal injury. These mechanisms may lead to increased vascularization, thereby elevating IgA levels. Warren et al. [12] reported associations between interstitial cystitis and multiple systemic comorbidities, although the specific relationship with diabetes mellitus remains uncertain. In this context, diabetes-associated oxidative stress could plausibly affect urinary sIgA. Nonetheless, in our cohort, urinary sIgA levels did not differ significantly in patients with diabetes.

Factors such as hypertension, hyperlipidemia, sex, age, and obesity play a role in the development of cardiovascular diseases by triggering endothelial dysfunction, which is the main pathogenic mechanism. Endothelial tissue regulates coagulation factors and vascular tone, while long-term injury promotes vascular inflammation, cell migration, and proliferation. Lynes et al. [13] demonstrated a strong correlation between endothelial dysfunction, bladder epithelial ulceration, epithelial loss from submucosal inflammation, and increased detrusor mast cells. Another study found endothelial damage in 70% of interstitial cystitis patients on electron microscopy [14]. Moreover, submucosal bleeding and mucosal destruction have been correlated with pain complaints, though not with cystoscopic findings [15]. Electron microscopy has also shown that uroepithelial destruction increases IgA transfer to the interstitium by enhancing intercellular permeability [16]. Taken together, these mechanisms suggest that the elevated urinary sIgA observed in BPS/IC patients with cardiac comorbidities may reflect underlying endothelial dysfunction and mucosal barrier compromise. However, because these differences were not consistently statistically significant, they should be interpreted cautiously. Further studies are needed to clarify the role of mucosal immune activation in this subgroup.

Smoking is another important factor contributing to mucosal injury. Hypoxia-induced oxidative stress, coupled with increased secretion of platelet-activating factor, exacerbates the effects of inflammatory cytokines and reactive oxygen species [17]. Reduced cell proliferation also delays mucosal repair [18, 19]. These smoking-related changes may worsen BPS/IC symptoms, although our study did not evaluate this association directly. They may also alter urinary immune markers, including sIgA. Chronic oxidative stress, combined with prolonged exposure to urinary toxins, may lead to fibrotic remodeling of the interstitium. Such remodeling could impair local mucosal immunity, providing a plausible explanation for the significantly lower urinary sIgA levels observed in smokers with BPS/IC.

Obesity is an increasingly prevalent condition worldwide and is associated with heightened morbidity and mortality. Several studies have demonstrated a relationship between obesity and urinary incontinence [20]. Proposed mechanisms include increased intra-abdominal and intravesical pressure, vascular injury due to hyperlipidemia and endothelial dysfunction, heightened oxidative stress, weakening of pelvic floor muscles from neurogenic factors, involvement of both smooth and striated muscles, and impaired sphincter function [21]. These mechanisms contribute to mucosal destruction, while the same factors also delay mucosal regeneration. Prolonged obesity or elevated BMI further slows mucosal repair. Variations in urinary sIgA levels across BMI categories in BPS/IC patients may therefore reflect the differential effects of obesity-related tissue stress and mucosal injury, although no statistically significant differences were observed in this study.

Anionic polysaccharide components such as the GAG layer are critical for the urothelium’s barrier function. One of the most widely accepted hypotheses for BPS/IC pathogenesis is that damage to the bladder GAG layer disrupts barrier integrity. van Ophoven et al. [22] reported that oral pentosan polysulfate sodium (PPS) therapy was not dose-dependent but was influenced by treatment duration, with at least 32 weeks required for clinical effect. Approximately half of the patients responded to this treatment. In this context, prolonged PPS use may support mucosal barrier restoration and potentially influence urinary immune markers such as sIgA. The variations in urinary sIgA levels we observed according to PPS treatment duration may reflect underlying mucosal repair mechanisms, but the lack of statistically significant differences requires cautious interpretation.

This study has several limitations. Its single-center design and inclusion of only female participants may restrict the generalizability of findings. Future multicenter studies including both male and female participants are warranted for a broader understanding.

Another limitation is the absence of detailed subclassification of cardiac comorbidities, which limited our ability to distinguish the specific effects of different cardiovascular conditions on urinary sIgA levels. Subgroup analyses focusing on individual metabolic syndrome components may provide deeper insight into these interactions.

In conclusion, to the best of our knowledge, this is the first study to comprehensively evaluate the effects of demographic and clinical factors on urinary sIgA levels in BPS/IC patients. Elevated urinary sIgA levels observed in patients with cardiac comorbidities may reflect underlying uroepithelial dysfunction, while reduced levels in smokers may be associated with mucosal alterations caused by chronic bladder irritation and fibrosis. Given the potential association between smoking and decreased sIgA levels, smoking cessation may represent a beneficial adjunct in the management of BPS/IC. However, current evidence remains limited, and prospective, randomized, controlled studies with larger cohorts are needed to more definitively establish the role of urinary sIgA in BPS/IC pathophysiology.

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