Abnormal urothelial HLA-DR expression in interstitial cystitis

Abstract

SUMMARY Interstitial cystitis is a chronic inflammatory disorder of the urinary bladder that predominantly afflicts middle‐age women. The end stage of the disease is ulceration of the urothelium, the so‐called Hunner's ulcer. The aetiology of interstitial cystitis remains obscure. We have studied bladder biopsies from 22 cases of interstitial cystitis and control groups consisting of six cases of bacterial cystitis and eight healthy women. Indirect immunofluorescence was performed on the biopsies using murine MoAbs to human HLA class I molecules, and class II molecules, HLA‐DP, HLA‐DQ and HLA‐DR. In interstitial cystitis, bacterial cystitis and normal controls most cells expressed HLA class I products. In six cases of interstitial cystitis and one case of bacterial cystitis there was evidence of HLA class I hyperexpression. In normal bladder and bacterial cystitis HLA class II expression was restricted to submucosal dendritic cells. Langerhans cells macrophages, vascular endothelial cells and activated lymphocytes. All but two cases of interstitial cystitis showed surface expression of HLA‐DR (but not HLA‐DP or DQ). In all cases of interstitial cystitis there was an increase in the numbers of macrophages, activated lymphocytes and vascular endothelial cells expressing HLA class II molecules within the submucosa. These findings provide further evidence fofthe importance of inappropriate HLA molecule expression in a disease suspected of having an autoimmune pathogenesis and where cellular autoimmune mechanisms play a decisive role in the destruction of the target cells ‐ the bladder urothelium.

Uroplakin Peptide-Specific Autoimmunity Initiates Interstitial Cystitis/Painful Bladder Syndrome in Mice

“…With regard to the reported association of IC/PBS with the HLA DR6 allele of MHC class II [14], we found it interesting that the extracellular domains of human uroplakins 1A and 2, though not uroplakin 3A, contain potential HLA-DR6 binding sites, according to the published HLA-DR6 binding motifs [53]. Those sequences (human UPK1A 171–179, sequence F TS A F R AA T , and human UPK2 117–125, sequence I SY L V K KG T ) suggest that uroplakins 1A and 2 are possible targets for T cell-mediated autoimmunity leading to IC/PBS in humans.…”

“…Higher numbers of CD4+, CD8+ and γδ T cells, as well as IgA, IgG and IgM plasma cells were found in the urothelium and submucosa of human IC bladder biopsies compared with normal bladder biopsies [12], [13]. IC also has been associated with the HLA DR6 allele of MHC class II as a relative risk factor [14].…”

Urothelial antigen-specific CD4+ T cells function as direct effector cells and induce bladder autoimmune inflammation independent of CD8+ T cells

“…For example, interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic inflammatory condition of the urinary bladder characterized by pelvic pain, irritative voiding symptoms (frequency, urgency and nocturia), and sterile and cytologically normal urine 1,2. Although the etiology of IC/PBS remains unknown, the immune/autoimmune mechanisms are thought to play at least a partial role in the pathophysiology of this painful condition 3-8…”

RDP58 inhibits T cell-mediated bladder inflammation in an autoimmune cystitis model

“…Antinuclear IgG and anti-epithelial cell autoantibodies have been found in the majority of IC patients [10][11][12][13][14]. Abnormal urothelial HLA-DR expression has also been reported in IC patients [15,16]. Autoimmune disorders such as bronchial asthma, systemic lupus erythematosus, Sjogren's syndrome and rheumatoid arthritis have been found to coexist in some IC patients [8,9,[17][18][19][20][21][22][23].…”