Studies of antibody, complement and immune complexes as mediators of immune-injury

Show simple item record Simpson, Ian James en 2009-11-19T03:36:20Z en 2009-11-19T03:36:20Z en 1984 en
dc.identifier.citation Thesis (MD)--University of Auckland, 1984. en
dc.identifier.uri en
dc.description.abstract In guinea-pig nephrotoxic nephritis (NTN) induced by a sheep antibody there was minimal glomerular capillary deposition of C3 or accumulation of polymorphonuclear leucocytes (PMN) in the heterologous phase. The C4 deficient (C4d) strain developed the same injury as normal Dunkin-Hartley animals. Complement depletion with cobra venom factor, PMN depletion with nitrogen mustard or anti-PMN serum and treatment with antihistamines, aprotinin and indomethacin provided no protection. The relationship between the dose of nephrotoxic antibody and the proteinuria was similar for the γ1 and γ2 subclasses and the F(ab’)2 fragment of γ1 antibody. However, the F(ab’) and the F(ab) antibody fragments, though fixing on the GBM did not cause proteinuria. It is Concluded that the development of proteinuria in this system: is largely independent of the C/PMN system; is due to the fixation of the F(ab’)2 fragment of the antibody molecule; and does not depend on an intact Fc piece. In the autologous phase of NTN induced by sheep antibody to GBM in DH and C4d strain gp, <50% of animals developed proteinuria at the height of the autologous antibody response despite high anti-sheep immunoglobulin titres and fixation of the gp IgG and complement in the kidneys. Only 2 of 37 animals (5.4%) developed progressive disease. In a passive model of autologous phase injury using high titre rabbit antibody to sheep IgG, proteinuria failed to occur despite fixation of up to 95µg of rabbit antibody per kidney. Repeated injection of sheep nephrotoxic antibody caused a persisting nephritic syndrome but not the characteristic proliferative lesion of anti-GBM diseases in other species. Because antibody responses to the alternative complement pathway activator cobra venom factor, are T-dependent and B-mice therefore do not develop resistance to its action it was possible to examine whether renal injury occured under circumstances of protracted alternative pathway activation. After periods of up to three months, no evidence from measurements of blood urea or proteinuria or from examination with light microscopy, immunofluorescent or electron microscopy was obtained to indicate a direct nephrotoxic effect of this type of complement activation. These studies do not support the concept that glomerular injury in patients with mesangiocapillary glomerulonephritis and hypocomplementaemia from C3 nephritic factor are due to the continued activation of the alternative pathway. The clinical course and levels of anti-GBM antibody were compared in 20 patients with Goodpasture’s syndrome treated with plasma exchange and immunosuppression (8 patients), immunosuppression alone (4patients) or no specific therapy (8 patients). There was a more rapid fall in the level of anti-GBM antibody and pulmonary haemorrhage was less protracted in the patients treated with plasma exchange and immunosuppression. In this group, one patient who presented with severe renal failure showed a marked improvement in renal function and there was no progression of disease in the four with milder renal involvement. Two of the four patients treated with immunosuppression alone and only two of the eight patients who received no specific therapy maintained normal renal function. In the group which received no specific therapy, one of the six patients who progressed to renal failure had mild renal involvement initially. There was a significant correlation between the level of anti-GBM antibody and the severity of the morphological changes seen at renal biopsy but not between the level of anti-GBM antibody and the severity of lung haemorrhage. The course and outcome of the disease in these patients not treated or treated with immunosuppression alone was better than that described in earlier reports of this disease, while those patients with plasma exchange and immunosuppression fared even better. An adequately stratified controled trial of immunosuppression in plasma exchange versus immunsuppression alone is justified. Immune complex (IC) levels were measured in normal subjects using the C1q solid phase, C1q deviation, C1q binding and polyethylene glycol precipitation assays. Significant changes in IC levels were seen in normals with each of the assays but the pattern of variation was not consistent between assays or subjects or in the same subject from day to day. There were no consistent changes with meals, time of day, exercise or the prior administration of prednisone. Low levels of IC appeared to be normal in plasma, but the variation in IC levels was not explained. Normal IC may well comprise mixtures of non-specific immunoglobulin aggregates, rheumatoid factor-immunoglobulin complexes, idiotype anti-idiotype complexes as well as specific antibody complexes with antigens from food, infective agents and other sources. Eighty-six patients with primary glomerulonephritis had circulating IC levels measured in 4 IC assays at the time of percutaneous renal biopsy. Patients with acute glomerulonephritis and type 1 mesangiocapillary glomerulonephritis showed the greatest positivity rate overall while patients with membranous glomerulonephritis had the lowest rate. overall, just over half the patients with primary glomerulonephritis were positive in any one assay and <5% in any three assays. Repeat samples taken from the same patients after an interval of some months often showed the same pattern of reactivity in the 4 assays or a return towards lower values. Thirty-one patients with proven acute myocardial infarction (MI) were studied prospectively at the time of admission to hospital and at 3, 7, and 18 days using 4 IC assays. Each assay showed an increased incidence of IC activity in MI with 76% of patients being Positive in at least one assay on one or more of the sampling days. A positive IC assay did not show a significant correlation with cardiac failure, pericarditis, post MI syndrome or previous infarction. The presence of IC was found to correlate with serum C-reactive protein (CRP), serum enzymes and ESR and suggested that complexed CRP or other acute phase proteins may account for some of the IC activity found with less specific assays. The measurement of IC levels in MI has not proved helpful in the diagnosis, management or prediction of outcome in this disorder. In recipients of cadaveric renal transplants circulating IC as detected by the C1q deviation test were found in more than two thirds of patients with recent graft. IC levels were found to rise after rejection episodes and also after episodes of infection. Low or rapidly falling IC levels soon after transplantation were associated with good graft function. Sera from 4 patients with systemic lupus erythematosis (SLE) were shown to contain abnormal lipoproteins which behaved as IC. One IC lipoprotein (ICVLDL) had the density in ultracentrifugation of very low density lipoprotein, but a markedly altered electrophoretic mobility. A second IC lipoprotein (ICIDL) had the electrophoretic mobility of very low density lipoprotein but was slightly denser than low density lipoprotein on ultracentrifugation. Both the ICVLDL and ICLDL contained IgG and behaved as IC in the C1q deviation test, platelet aggregation and rheumatoid factor inhibition assays, but not in the conglutinin and C1q binding assays and the C1q solid phase assays. These differences could be due to the low densities of the ICVLDL and ICLDL. The abnormal lipoprotein IC disappeared with clinical remission in two patients and were not present in the sera of other patients with inactive or mild SLE, type 4 hyperlipidaemia or during prednisone therapy or plasma exchange for other conditions. These IC appeared to be markers of severe and active SLE. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA777267 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. en
dc.rights.uri en
dc.title Studies of antibody, complement and immune complexes as mediators of immune-injury en
dc.type Thesis en Medicine en The University of Auckland en Doctoral en MD en
dc.subject.marsden Fields of Research::320000 Medical and Health Sciences::320100 Medicine-General en
dc.rights.holder Copyright: the author en
pubs.local.anzsrc 11 - Medical and Health Sciences en Faculty of Medical & Hlth Sci en

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