Hamilton, M. I R; (1996) The parthogenesis of ulcerative colitis: The role of autoimmunity and microvascular injury. Doctoral thesis (M.D.), University College London.

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Abstract

Aims: To investigate the roles of autoimmunity and microvascular injury in the pathogenesis of ulcerative colitis. Background: The aetiology of ulcerative colitis is unknown. A putative mucosal autoantigen, (UCAg), had been identified as tropomyosin, the presence of ANCA in ulcerative colitis suggested involvement of vascular factors; and disease demarcation suggested vascular anatomical distribution of disease. Methods: Using the monoclonal antibody 7E12H12, cellular localisation of the target antigen, UCAg, was studied. Comparative immunohistochemical studies were made of the staining patterns of 7E12H12 and anti-tropomyosin antibodies. The nature of the UCAg was examined further using SDS-PAGE and Western blotting. A novel dot-blot technique examined potential binding between tropomyosin and 7E12H12. In-vitro angiography examined the relation between vascular factors and the distribution of disease. The frequency of ANCA and the target antigen(s) was examined in patients with inflammatory bowel disease. Results: Immunohistochemistry demonstrated plasma membrane localisation of UCAg and revealed additional supranuclear staining. Comparative immunostaining experiments failed to show a similar localisation pattern for tropomyosin. There was no relation between UCAg expression and disease activity. SDS-PAGE, Western blotting and dot-blot experiments confirmed the presence of UCAg and tropomyosin in colon protein extracts, but no reactivity between 7E12H12 and tropomyosin. In-vitro angiography of resected ulcerative colitis colon specimens revealed a consistent relationship between the marginal artery of the colon and disease extent. ANCA were found in 57% of patients with ulcerative colitis. Novel antigenic targets for ANCA were identified: ANCA directed against bactericidal/permeability increasing protein were found in 27% of patients. Conclusions: UCAg is not tropomyosin, but the nature of this antigen remains to be determined. Novel target antigens for ANCA, present in vasculitis, have been identified in ulcerative colitis. The extent of disease appears to be determined by the anatomy of the marginal artery. These data suggest a microvascular pathogenesis for ulcerative colitis.

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