Abstract
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 vasculitis. By differential protein extraction of
neutrophils and Western Blot analysis IgG antibodies which
gave coarse fluorescence were found to react with 4 5 kDa
and 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
ii
occur, reflected by the presence of specific autoantibodies
and this can lead to systemic injury 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.
