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Biomedical subjects

C D Pusey

Publications and source records attributed to C D Pusey.

At least 127 records · Page 7Linked to original sources
PubMed1988

Extraglomerular distribution of immunoreactive Goodpasture antigen.

The distribution of Goodpasture antigen (GA) was studied in a range of human tissues using indirect immunofluorescence and immunoperoxidase techniques. Frozen sections were stained using (1) a mouse monoclonal antibody (P1) raised against the autoantigenic component of human glomerular basement membrane, (2) autoantibodies eluted from the kidneys of patients with Goodpasture's syndrome, (3) antibodies eluted from the kidneys of a sheep with Steblay nephritis, and (4) mouse monoclonal and guinea pig polyclonal antibodies to human type IV collagen. The same pattern of staining was demonstrated using the eluted antibodies and monoclonal antibody P1. The presence of GA was confirmed in the lung and choroid plexus. GA was also detected in basement membranes at a number of previously unreported sites in the eye, thyroid, pituitary, adrenal, breast, and liver. GA was absent from other sites at which type IV collagen could be demonstrated. Direct immunofluorescence studies of tissue from a patient with Goodpasture's syndrome revealed deposition of IgG in the choroid plexus and eye, as well as in the kidney and lung.

Aged↗
PubMed1988

Fatal Stevens-Johnson syndrome following urography with iopamidol in systemic lupus erythematosus.

A 46 year old white woman with active systemic lupus erythematosus developed a skin rash 8 hours after intravenous urography with the non-ionic contrast medium iopamidol. Severe Stevens-Johnson syndrome with erythema multiforme, intrahepatic cholestasis, pulmonary infiltrates and acute renal failure ensued, leading to her death. Although non-ionic contrast media are generally less toxic than traditional ionic agents, their use in patients with immunological disease may be hazardous.

Female↗
PubMed1988

Therapeutic applications of plasma exchange.

Therapeutic plasma exchange has been used in a wide range of disorders in which circulatory macromolecules are thought to be pathogenic. In this review, we discuss briefly the practical aspects of the procedure, and consider the evidence for its benefit.

Blood Protein Disorders↗
PubMed1988

Minimal change nephropathy and pemphigus vulgaris associated with penicillamine treatment of rheumatoid arthritis.

A 51-year-old man developed pemphigus vulgaris, minimal change nephropathy and acute tubular necrosis after 11 months of treatment with penicillamine for rheumatoid arthritis associated with features of Reiter's syndrome. Penicillamine is a polyclonal B lymphocyte activator in animals and precipitates a variety of autoimmune reactions in man. The pathogenesis of minimal change nephropathy is obscure, but our observations support the possibility that autoimmune mechanisms play a role.

Acute Kidney Injury↗
PubMed1987

Specific immunoabsorption.

Rapidly progressive glomerulonephritis occurs in patients developing autoantibodies to the glomerular basement membrane (GBM) and in multisystem vasculitic syndromes such as Wegener's granulomatosis (WG) and microscopic polyarteritis (MPA). In anti-GBM disease the pathogenicity of the autoantibodies has been established by transfer experiments; new solid-phase radioimmunoassays (RIAs) for circulating autoantibodies allow early diagnosis and effective monitoring of treatment. Sequential measurements of antibody levels showed that their generation is self-limiting (even without treatment) and that their production can be arrested more quickly with immunosuppressive therapy (cyclophosphamide and high dose steroids) together with intensive plasma exchange. In systemic vasculitis, no pathogenic agent has been identified and the diseases are rarely self-remitting. In WG, antibodies to cytoplasmic components of normal human neutrophils (and monocytes) were reported to be detectable by indirect immunofluorescence, with titres correlating with disease activity. We confirmed this and showed that antigen can be extracted from normal human neutrophils and used as ligand in a solid-phase RIA. Sera from patients with other forms of systemic vasculitis, such as MPA, as well as WG, are positive in this assay. The antigens have been further characterized by HPLC fractionation on a Toyosoda TSK gel filtration column. In WG, antibodies were directed towards cytoplasmic fractions of 100, 6 and 2 kDa; in MPA, antibody reacted only with the 100 kDa fraction. These findings suggest a humoral pathogenesis in these disorders and indicate that this approach may be helpful in the classification, diagnosis and monitoring of therapy in the systemic vasculitides. Further characterization of the autoantigen and its potential use in specific immunoabsorption are discussed.

Alkaline Phosphatase↗
PubMed1987

Protection from endotoxemia: a rat model of plasmapheresis and specific adsorption with polymyxin B.

Polymyxin B (PB), a cyclic polypeptide antibiotic, has potent antiendotoxin properties but is associated with significant toxicity when given parenterally. As an alternative, PB was immobilized on a solid phase (Sepharose 4B; Pharmacia, Uppsala, Sweden), and a system of plasmapheresis was developed in the conscious rat, with specific on-line plasma adsorption of endotoxin by a PB-Sepharose column. PB-Sepharose columns removed 94% of a challenge dose of 5 micrograms of endotoxin in vitro. Rats were pretreated with lead acetate so that they were sensitized to endotoxin and then given 10 micrograms of endotoxin/kg intraarterially. After 15 min plasmapheresis was begun and continued for 90 min. Animals whose plasma was perfused over PB-Sepharose were protected from endotoxin-induced leukopenia (P less than .01), thrombocytopenia (P less than .001), and death (four of four survivors compared with none of four controls). Thus plasmapheresis with on-line removal of endotoxin is a safe and highly effective means of protecting animals from the effects of endotoxemia.

Animals↗
PubMed1987

A single autoantigen in Goodpasture's syndrome identified by a monoclonal antibody to human glomerular basement membrane.

A mouse monoclonal antibody (P1) to the autoantigenic component of human glomerular basement membrane (GBM) was used to study the immunochemistry and tissue distribution of the Goodpasture antigen and the specificity of the human autoimmune response in Goodpasture's syndrome (anti-GBM disease). In solid phase assays, monoclonal antibody P1 bound to collagenase-solubilized human GBM (the ligand used in assays for human autoantibody), but not to other biochemically defined components of basement membrane. On Western blotting, P1 bound to the same 6 bands in solubilized GBM (between 26 and 58 kilodaltons with major bands at 26 and 54 kilodaltons) that were recognized by sera from all 42 patients studied with anti-GBM disease. Preincubation with sera from 8/8 patients blocked the subsequent binding of P1 from 83 to 89% on densitometer scanning of the Western blot; and preincubation with P1 blocked the binding of sera from 6/6 patients from 58 to 89%. Indirect immunofluorescence and immunoperoxidase studies revealed that the pattern of binding of P1 was identical to that of antibody eluted from the kidneys of a patient with Goodpasture's syndrome; there was linear binding to GBM, Bowman's capsule, and distal tubular basement membrane. In addition, P1 bound to basement membranes in lung and choroid plexus, and to membranes of the lens capsule, choroid, and retina of the eye and cochlea, but not to other organs studied. It is concluded that there is a single major autoantigenic component of human GBM (the Goodpasture antigen), which is present on fragments of different molecular weight in the collagenase digest. This antigen is distributed throughout well-defined basement membranes known to be involved in both Goodpasture's and Alport's syndromes. Human anti-GBM antibodies bind to the same (or closely related) determinants which are recognized by P1, demonstrating that the autoimmune response in Goodpasture's syndrome is of highly restricted specificity.

Anti-Glomerular Basement Membrane Disease↗
PubMed1987

Severe alveolar haemorrhage in Churg-Strauss syndrome.

We report two patients with Churg-Strauss syndrome (CSS), who presented with life-threatening alveolar haemorrhage as the major manifestation of their disease. One improved on high doses of steroids and cyclophosphamide; the other deteriorated on prednisolone alone, but responded rapidly to the addition of cyclophosphamide and plasma exchange. On follow-up, neither showed further evidence of lung disease except for well-controlled asthma. Pulmonary haemorrhage is a well-recognised phenomenon in patients with other forms of systemic vasculitis, and CSS must now be considered in the differential diagnosis of such cases.

Adult↗
PubMed1986

Use of a monoclonal antibody in differential diagnosis of children with haematuria and hereditary nephritis.

In a retrospective, double-blind study, paraffin-embedded renal biopsy sections from 44 children with haematuria were examined to see whether a mouse monoclonal antibody (MCA-P1) against glomerular basement membrane (GBM) could identify a subgroup of patients with hereditary glomerulonephritis (Alport's syndrome) in whom the Goodpasture antigen was abnormal. There was strong linear binding of MCA-P1 to GBM in all of 29 patients with no evidence of hereditary nephritis and in 2 patients in whom the diagnosis of hereditary nephritis was thought possible but not definite on available clinicopathological evidence. In contrast, 12 of 13 patients with strong evidence of hereditary nephritis showed no binding (9) or greatly reduced binding (3). These findings suggest that a major subgroup of patients with hereditary glomerulonephritis have biochemical abnormalities of the GBM involving Goodpasture antigen and that MCA-P1 is useful in the differential diagnosis of children with haematuria.

Adolescent↗
PubMed1986

Antiglomerular basement membrane antibody mediated disease in the British Isles 1980-4.

Clinical and pathological data on 71 patients from throughout the British Isles who developed antiglomerular basement membrane antibody mediated nephritis in the period 1980-4 were studied. Two principle patterns of disease were recognised: young men presenting in their 20s with Goodpasture's syndrome (glomerulonephritis and lung haemorrhage) and women presenting in their 60s with glomerulonephritis alone. The effect of treatment on prognosis of a total of 108 patients was also reviewed (the 71 patients plus patients seen before 1980 at Hammersmith Hospital). Treatment with prednisolone, cytotoxic drugs, and plasma exchange hastened the time to clearance of autoantibody and improved the outlook of patients who were not dependent on dialysis and those with lung haemorrhage.

Adolescent↗
PubMed1986

The Goodpasture antigen in Alport's syndrome: studies with a monoclonal antibody.

A mouse monoclonal antibody (MCA-P1), which recognizes an antigenic determinant in human glomerular basement membrane against which autoantibodies are directed in Goodpasture's syndrome, was used in indirect immunofluorescence studies to investigate glomerular basement membrane structure in Alport's syndrome. We found reduced or absent binding of MCA-P1 to glomerular and distal tubular basement membranes in renal biopsy tissue from ten patients with Alport's syndrome. Antiglomerular basement membrane antibody eluted from the kidneys of a patient who had died from Goodpasture's syndrome was used to confirm these findings. In contrast, there was bright linear fluorescence of MCA-P1 on glomerular and tubular basement membranes of normal renal material and renal biopsy tissue obtained from patients with a variety of glomerulonephritides. These results suggest an abnormality or a variable quantity of the immunoreactive autoantigen in the glomerular basement membrane of patients with Alport's syndrome. Furthermore, MCA-P1 may be of value in the diagnostic interpretation of renal biopsies from patients with familial nephritis.

Anti-Glomerular Basement Membrane Disease↗
PubMed1986

Repeated membrane plasma separation with on-line sorbent treatment of plasma in the conscious rat.

Repeated membrane plasma separation with on-line sorbent treatment of plasma was performed in unrestrained and conscious rats, thus avoiding the possible effects of repeated stress and exposure to anesthetic agents. The procedure was well tolerated, even after four consecutive perfusions. Blood flow was 0.7 ml/min, with a transmembrane pressure of 18.6 mm Hg and plasma filtration rate of 0.21 ml/min. This allowed 12 ml of plasma (greater than 1 plasma volume) to be treated within 1 h. Levels of albumin, immunoglobulin G, and C3 remained constant during each perfusion and were not significantly different from those of animals subjected to control procedures. Results obtained from filtrate were comparable at 15 and 60 min with values obtained from whole blood, with sieving coefficients of approximately 1. Leukocyte, erythrocyte, and thrombocyte counts remained unchanged during each plasma perfusion. A progressive rise in leukocyte counts occurred following successive perfusions, but this was true also of animals subjected to control procedures.

Animals↗
PubMed1986

Cryoglobulinaemia: clinical features and response to treatment.

We report the clinical features and outcome of 16 patients with cryoglobulinaemia. Two patients with Type I cryoglobulinaemia both had IgG kappa monoclonal paraproteins. Nine of 10 with Type II disease had monoclonal IgM kappa and polyclonal IgG; one had monoclonal IgG kappa and polyclonal IgG in the cryoglobulin. Underlying disorders identified in 3 of the 4 Type III patients were Sjogren's syndrome, infective endocarditis, and non-A non-B hepatitis and HTLV III infection. The commonest presenting features were rash in 94 p. 100 (ulceration 25 p. 100), arthralgia in 63 p. 100 (erosive arthritis 32 p. 100), renal disease in 63 p. 100, neurological involvement in 56 p. 100, hepatomegaly in 32 p. 100 and splenomegaly in 32 p. 100. Major associated conditions were progressive bronchiectasis in one case, and severe peripheral vascular disease in another; underlying malignancy was found in 2 cases (lymphoma and malignant melanoma). Treatment was with plasma exchange (PE) and immunosuppressive drugs (ID) in 10, PE alone in 3, ID alone in 2 and antibiotics [corrected] in 1. Fourteen of 16 patients showed an initial clinical response and fall in cryoglobulin levels. Four patients have died, one each from gastro-intestinal haemorrhage, sepsis, pulmonary embolism and lymphoma. Of the remaining 12 patients, all are symptomatically controlled and 10 have persisting cryoglobulinaemia (3 on PE and ID, 2 on PE, 2 on ID and 3 on no treatment). Of the two cases in whom cryoglobulinaemia resolved, one (Type II) had received PE and ID and the other (Type III) had been treated with antibiotics and surgery for infective endocarditis.

Adult↗
PubMed1985

The splenic extraction ratio of antibody-coated erythrocytes and its response to plasma exchange and pulse methylprednisolone.

Splenic blood flow was measured in a series of normal subjects and patients with connective tissue diseases by measuring the rate of equilibration and the partition of 111In-labelled autologous platelets between blood and spleen. These data were used to quantify the role of splenic blood flow in determining the splenic clearance of IgG coated erythrocytes (IgG-RBC) from the circulation. Previous studies have interpreted the clearance rates of IgG-RBC only in terms of splenic reticuloendothelial function. Splenic blood flow was increased in seven of eight patients with systemic lupus erythematosus (SLE), six of 10 patients with rheumatoid arthritis (RA) and in all five patients with essential mixed cryoglobulinaemia (EMC) compared with a series of thirteen normal subjects. Expressing the rate constant of clearance of IgG-RBC as a fraction of splenic blood flow gave a value for the 'extraction ratio' of IgG-RBC (a specific measurement of reticuloendothelial function, corrected for splenic blood flow). Normal splenic extraction ratio of IgG-RBC was calculated to be 32%. All the patients with SLE and with EMC had reduced extraction ratios (in seven out of 13 patients less than 10%). In RA the extraction ratio tended to be normal (average 27.3%) but variable (9-59%). Following plasma exchange in nine patients, a significant increase in IgG-RBC extraction ratio (average of 39% with respect to pre-exchange values, P less than 0.05) was found. In contrast there was no significant change in extraction ratio following pulse methylprednisolone therapy in a further nine patients. Although the rate constant of clearance of IgG-RBC decreased by an average of 33% (P less than 0.01) in the latter group, it was matched by an equal decrease of splenic blood flow (average 37%, P less than 0.01) and so extraction ratio showed no change. These data indicate that quantification of splenic reticuloendothelial function requires measurement of both IgG-RBC clearance and of splenic blood flow.

Adolescent↗
PubMed1984

Autoregulation of autoantibody synthesis in mercuric chloride nephritis in the Brown Norway rat. I. A role for T suppressor cells.

Mercuric chloride injections in the Brown Norway rat induce the transient formation of anti-glomerular basement membrane (GBM) autoantibodies. Transfer of spleen cells from convalescent animals, after circulating anti-GBM autoantibodies are no longer detectable, inhibits reinduction of the disease by HgCl2 in naive recipients. This inhibition is significantly less when the T suppressor cell population is depleted by the monoclonal antibody, MRC OX8 , before transfer. Our studies suggest a role for T suppressor cells in autoregulation in this animal model of autoimmune nephritis and may form a basis for the design of specific therapy for anti-GBM disease in man.

Animals↗
PubMed1984

Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome.

Drawing on our experience of 16 cases and a review of the English literature, we propose that CSS is under-diagnosed because of exclusive emphasis upon pathologic recognition of the disorder. The classical histological picture comprises a necrotizing vasculitis, eosinophilic tissue infiltration and extravascular granulomas, but it is only found in a minority of cases, and is not pathognomonic of the condition (69, 108). On the other hand, the clinical pattern of the disorder is most distinctive, and CSS can be readily identified on clinical grounds. Typically, it begins with allergic rhinitis, which is often complicated by nasal polyposis and sinusitis. Asthma and peripheral blood eosinophilia are essential features, often accompanied by pulmonary infiltrates. The systemic vasculitis of CSS resembles that of PAN, but severe renal disease is uncommon (the typical renal lesion is a focal segmental glomerulonephritis), and cardiac involvement accounts for 50% of deaths. Diagnostic difficulties arise from the close relationship of CSS to other granulomatous, vasculitic and eosinophilic disorders. CSS is usefully regarded as a point of overlap between these three disease spectrums (Fig. 5). Individual components of each spectrum can occur in the course of CSS; hence cases may be reported as PAN developing as a complication of Löffler syndrome or eosinophilic gastroenteritis (37, 57, 66). The hypereosinophilia of CSS tends to be less severe and more steroid-responsive than in HES, and evidence of eosinophil degranulation was not found in the patients we studied. Complement abnormalities are not a prominent feature of the disorder, and circulating immune complexes were detected in only two cases; both contained IgM. This may be of pathogenetic significance as IgM deposition was a dominant feature in four of the five cases with positive renal immunofluorescence. IgE levels were elevated in all patients studied during the vasculitic phase, and skin-prick tests were positive in 8 of 10 patients tested. CSS responds well to treatment with steroids, although some patients benefit from the addition of immunosuppressive agents. The vasculitic illness is usually of limited duration, but relapses can occur, and should be detected and treated early. Major problems in the post-vasculitic phase stem from hypertension and persisting peripheral nerve damage. Allergic upper and lower respiratory tract disease is an important cause of morbidity in the pre- and post-vasculitic periods.

Adult↗
PubMed1984

Severe intestinal involvement in Wegener's granulomatosis.

A case of Wegener's granulomatosis is described, in which the presentation was blood stained mucus diarrhoea. Severe ileal, caecal, and rectal involvement improved rapidly after treatment with cyclophosphamide, azathioprine, and prednisolone. Although intestinal disease is an uncommon feature of Wegener's granulomatosis, both in our own experience (four of 45 cases) and in the literature, this diagnosis should be considered in view of the response to appropriate therapy.

Adult↗