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Title: Studies of the diagnosis and immunopathogenesis of Wegener's granulomatosis
Author: Harrison, David J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1990
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Wegener's Granulomatosis, classically, comprises a triad of granulomatous vasculitis in the upper and lower respiratory tracts, and a focal and segmental, necrotising glomerulonephritis in the kidney. In practice disease presentation and organ involvement is widespread and variable. The aetiology is unknown but an infectious aetiology has been proposed, based on the especial involvement of the respiratory tract in the disease process. The pathogenesis is also unclear but immune complex deposition leading to neutrophil chemotaxis and activation causing endothelial injury has been suggested. Recently antibodies against a component of neutrophil cytoplasm have been described in Wegener's Granulomatosis. This thesis records studies of the diagnosis and pathogenesis of Wegener's Granulomatosis. The first part of the study examined the problem of diagnosis using renal biopsy material. Renal biopsy is important because renal functional status is the major factor determining outcome, yet renal biopsy appearances are not specific for the condition and may be found in other vasculitides such as microscopic polyarteritis. Review of the histology, immunofluorescence studies and ultrastructure of renal biopsies from patients with Wegener's granulomatosis and microscopic polyarteritis revealed no diagnostically useful differences. In Wegener's Granulomatosis renal mast cells were frequently present unassociated with areas of active inflammation, whereas in microscopic polyarteritis they were predominantly present as part of an inflammatory infiltrate. In both conditions the number of mast cells was increased. The functional significance of this difference is unclear. The second part of the study examined the presence of autoantibodies against neutrophils. IgG antibodies giving coarse, granular, cytoplasmic fluorescence when incubated with cytospin preparations of normal neutrophils were found to be highly specific for Wegener's Granulomatosis. Diffuse cytoplasmic fluorescence was present in a wide variety of other diseases including some other forms of systemic vaculitis. By differential protein extraction of neutrophils and Western Blot analysis IgG antibodies which gave coarse fluorescence were found to react with 45 kDa 27-31 kDa proteins in the membrane-bound protein extract. This is consistent with the autoantibodies being directed against a component of neutrophil granules. An hypothesis is proposed. Wegener's Granulomatosis is the product of an immunological response to an antigen, possibly to an inhaled, exogenous pathogen. A predominantly cell-mediated response results in the typical lesions identified pathologically within the respiratory tract including granulomata. A humoral response also may occur, reflected by the presence of specific autoantibodies and this can lead to systemic imjury primarily by the formation and deposition of immune complexes. In other systemic vasculitides, such as microscopic polyarteritis, a variety of exogenous antigens result in humoral responses and immune complex formation and deposition leading to the same pattern of renal injury.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available