Case reports of immune-related cystitis and the antibody combination hypothesis

Immune-related cystitis is a rare condition, and its diagnostic criteria and pathogenesis are not yet fully understood. Here, we report two cases of immune-related cystitis. Both patients were previously diagnosed with lung squamous cell carcinoma and received combined treatment with immune checkpoint inhibitors and chemotherapy, leading to hemorrhagic cystitis. We reviewed the cystoscopic images and pathological features of previous cases and found that autoantibodies against hemidesmosomes may be the cause of immune-related cystitis, proposing the “antibody combination” hypothesis to explain the tissue specificity of the condition. Lung squamous cell carcinoma can produce certain proteins called autoantigens. Some patients treated with immune checkpoint inhibitors might develop antibodies against these autoantigens. A specific combination of these antibodies may cause the bladder lining to slough, leading to immune-related cystitis. Symptoms of this condition include frequent urination, urgent need to urinate, painful urination and blood in the urine. These patients typically require treatment with steroids. PD-L1 staining was not positive in the urothelium of all cases of immune-related cystitis. Our cases of immune-related cystitis both showed floating bladder mucosa on cystoscopy and urothelial desquamation on pathological slides. Elevated serum levels of autoantibodies against BP180, integrin α6 and β4 were observed during both onset and recovery phases. BP180, integrin α6 and β4 were all significantly overexpressed in lung squamous cell carcinoma compared with normal lung tissue. The different distribution of BP180, integrin α6 and β4 in various tissues may contribute to the tissue-specific immune reactions observed in the urothelium. Immune-related cystitis could theoretically coexist with urinary tract infection due to the vulnerability caused by urothelium desquamation.