Christmas, Timothy John; (1992) The role of the immune system in the pathogenesis of interstitial cystitis. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Interstitial cystitis (IC) is a chronic debilitating condition predominantly affecting middle-aged females which presents with suprapubic pain and urinary frequency. At cystoscopy the bladder capacity is usually reduced and the urothelium may appear red and ulcerated - the Runner's ulcer. Chronic inflammatory cell infiltrate within bladder biopsies suggests an immunological aetiopathogenesis for IC but this has not previously been investigated in great detail. A series of 51 cases of IC, 48 female and 3 male have been studied. To determine if there is a genetic predisposition to IC ABO and rhesus blood groups and 102 different HLA tissue types were determined for IC cases and 140 normal controls. The incidence of ABO and rhesus blood groups were similar in the two groups but there was a significant association between HLA-DR6 and IC, with a relative risk factor of 4.91. The presence of chronic inflammation without evidence of an infective agent, the high incidence in middle-aged females and association with conditions such as Hashimoto's thyroiditis are features shared by IC and autoimmune diseases. The binding of IgA, IgG and IgM class antibodies from the serum of IC cases to bladder of normal controls of blood group O was examined and compared with serum from four female cases of chronic bacterial cystitis (BC) and eight normal female controls. Antibody binding to the urothelium was detected in 82% of IC, 75 % of BC and 13% of normal controls, and the titres were significantly higher in IC than in BC and normals. There was a similar prevalence of antibodies to detrusor sarcoplasm and sarcolemma in IC. In autoimmune diseases target cell destruction is initiated by abnormal surface expression of class II (HLA-DR) molecules with antigen which activates CD4+ T cells which in turn starts the cascade of immune autoreactivity, ultimately leading to destruction of target cells. Aberrant urothelial HLA-DR expression was found in all but one of the IC cases in which the urothelium was not denuded. Furthermore, the urothelium and submucosa in IC was infiltrated by CD4+, CD8+ and γδT cells, plasma cells, mast cells and macrophages. A search for infection with mycobacteria and viruses as an aetiological factor in IC using specific DNA probes produced negative results. Extra-vesical denervation (EVD) relieves pain in IC. Morphometric analysis of bladder wall PGP 9.5 immunoreactive nerve fibres has demonstrated nerve fibre proliferation in IC and depletion of nerve fibres within the submucosal plexus but not the detrusor muscle after EVD. This finding explains how EVD improves bladder pain without impairment of detrusor function, as demonstrated by urodynamic studies. The precise aetiology of IC remains obscure although this study has revealed a genetic predisposition to the development of IC and has demonstrated immunological autoreactive mechanisms in the pathogenesis of this condition.

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