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Biomedical subjects

D K Peters

Publications and source records attributed to D K Peters.

At least 37 records · Page 2Linked to original sources
PubMed1987

Monoclonal antibodies to restricted and cross-reactive idiotopes on monoclonal rheumatoid factors and their recognition of idiotope-positive cells.

Four human monoclonal rheumatoid factors (MRF) were used to raise a panel of mouse monoclonal antibodies (mAb) which were selected in a solid-phase radioimmunoassay for binding to MRF but not normal IgM. Three mAb, each raised against a different MRF, bound to the majority of MRF and also to most polyclonal RF. Four other mAb bound selectively to the MRF against which they were raised and to no other MRF, and rarely to any polyclonal RF. Competition studies using cold and radiolabeled mAb further indicated that these mAb recognize distinct and different epitopes on MRF. RF activity of MRF was inhibited by 3 of the 4 mAb binding to a single MRF and 2 of the 3 mAb binding to multiple RF. It was thus concluded that of this panel of mAb 3 recognized cross-reactive idiotopes and the remainder demonstrated highly restricted idiotopes on MRF. These mAb identified MRF idiotope-bearing cells in the peripheral blood of 3 of the MRF donors (and a further subject with type II essential cryoglobulinemia), with a frequency ranging from 0.3-10% of all mononuclear cells with the mAb to restricted idiotopes or 1.5-17% with mAb to cross-reactive idiotopes. These anti-idiotopic mAb should thus provide a highly specific means of identifying and monitoring MRF-producing cells in vivo.

Antibodies, Monoclonal↗
PubMed1987

A lysine-binding protein in SLE sera inhibits the binding of immune complexes to normal erythrocyte CR1 (complement receptor type 1).

The binding of 125I-labelled immune complexes (IC) to normal human erythrocyte CR1 (complement receptor type 1) by sera from patients with SLE was found to be significantly decreased compared to normal sera. In 13/29 patients, there was an inhibitor which decreased the binding of opsonized IC in normal sera to normal erythrocytes. It was found in each of the nine patients who had clinically active disease. The inhibitor was shown to be a globulin that was labile at 56 degrees C and bound to lysine; low concentrations of tranexamic acid and of lysine abolished the effects of the inhibitor which suggests that it possesses lysine-binding sites: these may block the CR1-binding site on IC opsonized with complement. This inhibitor may decrease the efficiency of IC carriage by erythrocyte CR1.

Antigen-Antibody Complex↗
PubMed1986

Effect of nephritic factor on C3 and on the terminal pathway of complement in vivo and in vitro.

Plasma samples from patients with nephritic factor (NeF) were examined for their C3 converting activity. C3, C3dg, C5 and the fluid phase terminal complement complex (TCC) were quantified. All patients had evidence of C3 activation with low plasma C3 and high C3dg. Some patients had normal C5 and normal TCC levels, and thus no evidence of terminal pathway activation in vivo; others, with slower C3 conversion in vitro, had low C5 levels with TCC either elevated or in the upper normal range, suggesting in vivo activation of the terminal pathway. These observations were confirmed by in vitro experiments using purified NeFs. It is concluded that considerable activation of C3 may occur in vivo without a simultaneous activation of the terminal pathway, and that NeF is heterogeneous with regard to its ability to activate complement.

Adult↗
PubMed1986

C3 nephritic factor (C3NeF): dissociation of cell-bound and fluid phase stabilization of alternative pathway C3 convertase.

Fluid phase C3 conversion by C3 nephritic factor (C3NeF) is usually easily detectable and forms the basis of the C3NeF screening test. We have described a group of patients with membranoproliferative glomerulonephritis or partial lipodystrophy and hypocomplementaemia who have an unusual C3NeF which stabilizes cell-bound C3 convertase of the alternative pathway (C3bBb) but causes such weak fluid phase C3 conversion that a C3NeF screening test is negative. These patients have low concentrations of C5 in serum.

Adolescent↗
PubMed1984

The influence of HLA-linked genes on the severity of anti-GBM antibody-mediated nephritis.

Thirty-nine Caucasian patients with glomerulonephritis caused by autoantibodies to glomerular basement membrane (GBM) were studied. They were segregated into three groups depending on presentation: Group 1 (19 patients) were anuric or oliguric, group 2 (13 patients) had rapidly deteriorating renal function but were not oliguric, and group 3 (seven patients) had stable renal function. The incidence of HLA-DR2 was greatly increased; it was present in 34 of 38 patients in whom DR antigens were identified compared to 43 of 154 controls (Pc = 0.63 X 10(-8), relative risk 36, etiological fraction 0.86). The incidence of HLA-B7 was also increased; present in 23 of 39 patients and 43 of 193 controls (Pc = 0.26 X 10(-4), relative risk 5.0, etiological fraction 0.43). These data were analyzed for a third order association between HLA-DR2, HLA-B7, and anti-GBM disease. Such an association was probable for patients in group 1 (P = 0.27 X 10(-6), likely for those in group 2 (P = 0.024) but unlikely for patients in group 3 (P = 0.62) suggesting HLA-B7-associated genes influence severity. Clinical results from a subset of the patients referred directly on presentation showed that patients who inherited HLA-B7 together with DR2 had significantly higher plasma creatinines, a greater proportion of glomeruli surrounded by crescents and a worse prognosis. Despite this there was little difference in severity of their lung disease.

Adolescent↗
PubMed1984

C4-binding protein in sera of patients with systemic lupus erythematosus and mixed essential cryoglobulinemia.

C4-binding protein (C4BP) concentration was measured in sera of patients with systemic lupus erythematosus (SLE) (59) and mixed essential cryoglobulinemia (MEC) (6). The mean concentration of C4BP was not significantly different from the normal controls in both groups of patients; 1 patient with MEC and 11 patients with SLE had concentrations below the normal range. In addition there was no significant correlation between C4BP and C3, C4 or factor B concentrations in patients with SLE. These results suggest that C4BP is not consumed in these two diseases where strong activation of the classical pathway is known to occur in vivo. In addition, the significantly increased C4BP/C4 ratio, evident in both groups of patients, may provide a protective mechanism against C3 conversion by the classical pathway.

Carrier Proteins↗
PubMed1983

Complement, the immune-complex lattice, and the pathophysiology of complement-deficiency syndromes.

The role of the components of the complement classical pathway in maintaining antigen-antibody complexes in solution has implications for the understanding of the pathophysiology of complement-deficiency syndromes. It is proposed that this mechanism may normally keep immune complexes soluble for a sufficient time for their safe elimination by the mononuclear phagocyte system. When an early component of the classical pathway is deficient or depleted antigen-antibody complexes would be more likely to precipitate at or near their site of formation and lead to immunologically mediated inflammation. This hypothesis is supported by the predisposition to immune-complex diseases of patients with genetically determined deficiencies of components of the classical pathway.

Antigen-Antibody Complex↗
PubMed1983

Anti-glomerular basement membrane autoantibodies in the Brown Norway rat: detection by a solid-phase radioimmunoassay.

A solid-phase radioimmunoassay (RIA) is described for the detection of IgG autoantibodies to glomerular basement membrane (GBM) induced in the Brown Norway rat by mercuric chloride. The assay involves the adsorption of a collagenase digest of GBM to plastic microtitre plates and detection of bound antibody with affinity purified radiolabelled rabbit anti-rat IgG. Comparison with existing immunofluorescence methods for detection of anti-GBM antibody showed that the solid-phase RIA is highly sensitive, allowing detection of antibody in solutions with as low as 0.5 ng protein/ml. The assay is suitable for detection of anti-GBM antibody both in serum and in eluates from nephritic kidneys. The assay proved to be specific in competitive studies of inhibition brought by GBM, keyhole limpet antigen and ovalbumin. This solid-phase RIA is reproducible, robust and easy to perform.

Animals↗
PubMed1983

Prognosis after immunosuppression of patients with crescentic nephritis requiring dialysis.

48 patients with rapidly progressive glomerulonephritis were treated by a regimen of intensive plasma exchange, steroids, and cytotoxic drugs. All required dialysis before immunosuppressive treatment was started, and all had 50% or more of their glomeruli affected by crescent formation. Renal function was not recovered in any of the 21 patients with anti-glomerular basement membrane antibody disease. In contrast 63% of patients without these autoantibodies recovered renal function. Plasma creatinine remained stable over prolonged follow-up (6-60 months) in all but 1 of the 10 late survivors. There was no correlation between the extent of crescent formation and recovery of renal function in those patients without circulating anti-glomerular basement membrane antibodies.

Adolescent↗
PubMed1983

Effects of cyclophosphamide on autoantibody synthesis in the Brown Norway rat.

The effects of cyclophosphamide on autoantibody synthesis were studied in an experimental model of glomerulonephritis due to autoantibodies to the glomerular basement membrane (GBM). Brown Norway rats develop anti-GBM antibodies, as part of a polyclonal response, when repeatedly injected with mercuric chloride (HgCl2). Anti-GBM antibody levels peak between days 11 and 14 and thereafter rapidly fall; convalescent animals show a time-dependent resistance to rechallenge with HgCl2 which remains significant for up to 3 months. The administration of cyclophosphamide, as a single intramuscular injection at day 0, has three distinct dose-dependent effects on anti-GBM antibody production. Firstly, lower doses (2.5 mg/kg) increase antibody levels at the time of peak response; secondly, higher doses (greater than or equal to 20 mg/kg) prevent antibody synthesis following HgCl2; and thirdly, the higher doses also reduce the response to rechallenge with HgCl2 3-4 months later. These effects of cyclophosphamide also apply to the polyclonal response to HgCl2, as judged by measurement of total IgG concentrations. Further investigation of the mechanisms of action of cyclophosphamide in this model should provide information relevant to the treatment of human autoimmune disease.

Animals↗
PubMed1983

Immune adherence and staphylococcus protein A binding of soluble immune complexes produced by complement activation.

Complement has been shown to affect the solubility of antigen-antibody complexes by two mechanisms: in the first, classical pathway dependent, complement inhibits the formation of the immune precipitate; in the second, alternative pathway dependent, complement reacts with a formed precipitate to bring about its solubilization. The biological properties of complement reacted immune complexes (IC) has been assessed by studying their binding to staphylococcus protein A (SPA) and to human erythrocytes. BSA-anti-BSA complement reacted IC bound to human erythrocytes and to SPA. Complexes generated by solubilization of immune precipitates showed greater immune adherence than complexes held in solution by complement, despite their similar size. Complexes held in solution in a factor D depleted human serum bound more efficiently to erythrocytes than complexes formed in normal serum. These experiments demonstrate that complement reacted IC cannot be regarded as biologically inert and that factors affecting complement function may have important effects on the properties of antigen-antibody complexes.

Antigen-Antibody Complex↗
PubMed1983

Factors affecting severity of injury during nephrotoxic nephritis in rabbits.

All 22 rabbits injected with sheep globulin containing high titres of antibodies to rabbit glomerular basement membrane (GBM)--nephrotoxic globulin (NTG)--developed antibodies to sheep IgG. Despite this only 15 rabbits developed obvious autologous phase injury. Eleven days after injection of NTG titres of autologous antibody to sheep IgG were similar in rabbits with and without definite autologous phase injury but were detected earlier and rose significantly more rapidly in those with autologous phase injury. In experiments on heterologous phase injury after intravenous injection of NTG, binding of defined amounts of nephrotoxic antibodies (NTAb) to the GBM after bolus injection caused significantly more injury, assessed by proteinuria, than binding of similar amounts of NTAb after infusion of NTG over 3 h (P less than 0.02 Student's paired t-test). In in vitro experiments, aliquots of homogenized rabbit kidney taken 2 days after injection of NTG bound appreciable amounts of rabbit anti-sheep Ig whereas homogenates of kidneys taken 20 days after NTG showed no such binding. These results show that the rate of deposition of NTAb in kidney influences the severity of injury in heterologous and autologous phases of NTN and that antigenic sites or heterologous IgG fixed to the GBM become saturated during the autologous phase of injury.

Animals↗
PubMed1983

Production of a monoclonal antibody to autoantigenic components of human glomerular basement membrane.

We describe a mouse monoclonal antibody which reacts on immunoblotting with those components of collagenase digested human glomerular basement membrane (GBM) that are also recognized by autoantibodies in sera from patients with anti-GBM nephritis. Competition between the monoclonal antibody and anti-GBM autoantibodies was demonstrated in a solid phase radioimmunoassay, suggesting that both are directed against the same autoantigen.

Animals↗
PubMed1983

Plasma exchange and immunosuppressive drugs in the treatment of glomerulonephritis due to antibodies to the glomerular basement membrane.

Glomerulonephritis due to autoantibodies to the glomerular basement membrane (GBM) usually results in the rapid development of renal failure in untreated patients. We report our experience of the use of plasma exchange and immunosuppressive drugs in the management of this condition. Treatment consisted of daily 4 litre plasma exchanges for plasma protein fraction, together with prednisolone 60 mg daily (reducing to 20 mg daily by 4 weeks), cyclophosphamide 3 mg/kg daily and azathioprine 1 mg/kg daily. It was found that plasma exchange was generally required for 2 weeks, and cytotoxic drugs for 8 weeks. Forty four patients, aged 4 to 72 years, were treated. Anti-GBM antibody production was rapidly controlled, and in 21 of 34 patients antibody was undetectable within 8 weeks. Of 22 oliguric patients, none recovered renal function, 16 remained dialysis-dependent and 6 died; of 5 patients whose initial plasma creatinine was greater than 600 mumol/l, one improved and 4 proceeded to dialysis; and of 17 patients whose creatinine was less than 600 mumol/l, 15 recovered renal function, one became dialysis-dependent and one died. Long term follow-up of those who improved revealed that 2/16 subsequently deteriorated. Our results represent a great improvement in the prognosis of anti-GBM disease, and demonstrate that the majority of patients will recover renal function if treated before irreversible glomerular damage has occurred.

Adolescent↗
PubMed1983

Wegener's granulomatosis: observations on 18 patients with severe renal disease.

Eighteen patients with Wegener's granulomatosis with renal involvement have been studied. Their course before treatment has indicated how the disease may progress and has provided a framework for diagnosis based on clinical and radiological features combined with available histology. The need for such diagnostic criteria is emphasised by the fact that a firm histopathological diagnosis could only be made in nine patients. A strong association between Wegener's granulomatosis and previous suppurative or tuberculous respiratory infection has been noted as well as between intercurrent infection and relapse. Evidence that immune complexes play a pathogenetic role has come from the association between active disease and circulating immune complexes. The observation of a reversible abnormality of splenic clearance of altered red cells suggests that immune complex handling by the spleen is defective. Treatment of these patients has shown a surprising degree of reversibility in many manifestations, especially renal failure. Remissions occurring spontaneously or induced by steroids alone are temporary and steroids, if used alone, may adversely affect outcome. While confirming the central role of cyclophosphamide in the induction of remission, this study has indicated that its combination with steroids and/or plasma exchange may be valuable in initial control of fulminating disease. The fact that seven patients died during induction (as well as a further four in the succeeding five years) reflects the advanced disease at presentation and the infective problems associated with immunosuppressive therapy. This highlights the need for earlier diagnosis.

Adrenal Cortex Hormones↗
PubMed1983

Metabolism of IgG in type II mixed essential cryoglobulinaemia--autologous cryoprecipitated and normal homologous IgG are incorporated into complexes and metabolized in vivo at similar rates.

The metabolism of autologous cryoprecipitated and normal homologous IgG was studied in four patients with type II mixed essential cryoglobulinaemia. 131I-autologous IgG purified from each patient's cryoglobulin (Cryo-IgG), and 125I-pooled normal homologous IgG (N-IgG) were studied simultaneously to compare the extent of their incorporation into complexes with IgM in vitro and in vivo, and their turnover in vivo. A proportion of each preparation of IgG was incorporated into macromolecular complexes in vitro and in vivo in all patients, the Cryo-IgG only slightly more so than N-IgG. Results of the turnover studies were heterogeneous, but the common finding was the absence of any significant difference in the metabolism of Cryo-IgG and N-IgG. In two patients the fractional catabolic rates (FCR) of Cryo-IgG and N-IgG were increased and in one they were normal. The fourth patient was also hypogammaglobulinaemic (IgG 0.52 mg/ml) and it was shown that in vivo virtually all his IgG was combined with IgM; despite this the FCR of both types of IgG was reduced. These results suggest (1) that the IgG component of the cryoglobulins in these patients is unlikely to differ significantly from normal IgG and (2) that, contrary to expectation, complexed IgG is not necessarily rapidly eliminated from the circulation.

Aged↗