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Biomedical subjects

C M Lockwood

Publications and source records attributed to C M Lockwood.

At least 145 records · Page 8Linked to original sources
PubMed1987

Restriction of human IgG subclass expression in the population of auto-antibodies to glomerular basement membrane.

To study the possible relationship between individual subclass expression and pathogenesis of antibody-mediated disease, we examined the immunoglobulin-G subclass of antiglomerular basement membrane (GBM) antibodies, in the sera of 20 patients with auto-antibody mediated nephritis, as well as in a limited number of kidney eluates, using a solid phase radioimmunoassay and monoclonal antibodies specific for human IgG subclasses. Only anti-GBM antibodies of the IgG1 and/or IgG4 subclass were detectable, both in the circulation and in renal eluates. Recurrence of circulating anti-GBM antibody during convalescence occurred in two patients out of 49 studied sequentially for more than 12 months. In both cases only antibodies of a single subclass were involved. The recurrence of IgG1 antibody (which can fix complement and bind macrophages) was associated with clinical manifestations of disease, whereas the reappearance of IgG4 antibody (which cannot engage amplifiers of the inflammatory response) did not appear to be harmful. Thus, in anti-GBM auto-antibody mediated nephritis, clear restriction in the subclass of IgG auto-antibody occurs, and this may be important in disease expression.

Autoantibodies↗
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

Clinical and immunological evolution of oligoanuric anti-GBM nephritis treated by haemodialysis.

Eight patients with oligoanuric anti-glomerular-basement-membrane (GBM), antibody-mediated glomerulonephritis without lung haemorrhage who were not treated with plasma exchange therapy were reviewed. All had severe crescentic nephritis and required dialysis. Circulating anti-GBM antibodies disappeared gradually and spontaneously in all patients. The autoantibodies became undetectable in five patients after an average of 11 months. No patient recovered renal function. Two patients have been successfully transplanted and anti-GBM nephritis has not recurred. One of these needed a pre-transplant course of plasma exchange and immunosuppression to reduce a slightly raised anti-GBM antibody titre. Of five patients who remain on dialysis, only two cannot be transplanted due to the persistence of circulating autoantibodies. One patient died from causes unrelated to renal disease. Oligoanuric patients with anti-GBM nephritis who need dialysis rarely benefit from aggressive therapy unless lung haemorrhage is present.

Acute Disease↗
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

Rapidly progressive nephritis in patients taking hydralazine.

Two patients with rapidly progressive glomerulonephritis associated with hydralazine are reported. The different types of hydralazine toxicity recognized are "lupus" syndrome, vasculitis and most recently proliferative nephritis with renal failure. These are reviewed with some discussion of possible mechanisms.

Female↗
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↗
PubMed1986

New advances in understanding the treatment of glomerulonephritis.

Glomerulonephritis is the commonest cause of renal failure, yet there is little understanding as to its etiology except that immunological mechanisms are thought to be important. This has considerably hampered efforts to develop appropriate treatment. Only in rapidly progressive nephritis (RPGN) has clear progress been made as a result a radical improvement in prognosis obtained. In some forms of RPGN aberrant immunological mechanisms have been identified and their components characterized. The best defined are those in which auto-immune responses are generated and lead directly or indirectly to renal injury. As yet, only humoral auto-immune responses are easy to characterize in man; technical difficulties surround attempts to identify cellular auto-immune reactants. However, both can be investigated in animal experimental models. This presentation will focus on the more recent studies of the auto-immune responses in human RPGN and the possible contribution that these (together with those derived from animal studies) make towards a better understanding of the treatment of glomerulonephritis.

Autoantibodies↗
PubMed1985

SBE presenting with type III cryoglobulinaemia.

A case of subacute bacterial endocarditis which presented with cryoglobulinaemia is reported. A secondary cause of cryoglobulinaemia was suggested following characterization, which revealed a Type III (mixed polyclonal) cryoprotein. Levels of cryoglobulin were high and remained so until the source of infection was eradicated, and the cause of the cryoglobulinaemia is briefly discussed.

Complement System Proteins↗
PubMed1985

Microscopic polyarteritis: presentation, pathology and prognosis.

We have described 34 patients with microscopic polyarteritis, all of whom had clinical evidence of a systemic small vessel vasculitis predominantly affecting the skin and musculoskeletal systems accompanied by a focal necrotising glomerulonephritis with renal impairment. Thirty three patients received immunosuppressive treatment, comprising prednisolone, azathioprine, cyclophosphamide and plasma exchange in various combinations. The five-year actuarial patient and kidney survival rates were 65 and 55 per cent respectively, suggesting that aggressive immunosuppressive therapy in these patients is beneficial.

Adolescent↗
PubMed1985

Clinical application of a radio-immunoassay for auto-antibodies to glomerular basement membrane.

We describe a sensitive radio-immunoassay for auto-antibodies to glomerular basement membrane (GBM). The assay discriminates patients with glomerulonephritis associated with circulating auto-antibodies to glomerular basement membrane from those with other forms of nephritis. Monitoring of antibody levels in sequential serial serum samples enables drug therapy to be tailored precisely to control the aberrant immune response, a situation unique in the management of glomerulonephritis.

Autoantibodies↗
PubMed1984

Regulation of autoantibody responses to glomerular basement membrane in man and experimental animals.

Autoantibodies reacting with the glomerular basement membrane (GBM) are a rare cause of severe nephritis in man. Their development is HLA-DR-associated and their pathogenicity has been demonstrated by transfer experiments. Their production is spontaneously self-limiting over a period of years but irreversible renal failure usually occurs within weeks or months in the untreated patient. A regimen of intensive plasma exchange together with cytotoxic drugs and steroids induces a rapid and permanent arrest of antibody synthesis; this is associated with recovery of renal function, provided that target organ injury is not irreversible when treatment is initiated. To understand the homeostatic mechanisms engaged by the therapeutic regimen we have studied an experimental model of autoimmune nephritis in the Brown Norway rat, where autoantibody-mediated injury to the GBM is induced by mercuric chloride. Suppressor cells and humoral factors (putatively anti-idiotypic antibodies) were found to regulate autoantibody production, and cyclophosphamide can prevent its reinduction. To identify the autoantigenic component in human GBM we have produced a mouse monoclonal antibody which recognizes the same components as are recognized by autoantibodies from all 35 patients tested. This monoclonal antibody can be used to study the autoregulatory components from human blood which we have found to be important in the animal model.

Animals↗
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

Autoregulation of autoantibody synthesis in mercuric chloride nephritis in the Brown Norway rat. II. Presence of antigen-augmentable plaque-forming cells in the spleen is associated with humoral factors behaving as auto-anti-idiotypic antibodies.

Plaque-forming cell (PFC) assays were used to investigate in vitro the immunoregulatory mechanism operating in the self-limiting anti-glomerular basement membrane (GBM) autoantibody response of Brown Norway (BN) rats given HgCl2. The peak splenic PFC response occurred at day 9; thereafter the response fell sharply and was rarely detected after day 12. In specificity studies, incorporation of soluble GBM in the PFC assays of animals at day 9 had two distinct effects. In some animals the PFC response was inhibited in a dose-dependent fashion; however, in others an augmented number of PFC was observed. Furthermore, addition of GBM to the PFC mixture from certain animals studied at day 12 (or after) revealed large numbers of GBM-specific PFC when originally no GBM-specific PFC had been observed in the standard PFC assay. Sera from such animals, with and without antigen-augmentable PFC, were incorporated in the PFC mixture containing cells taken from day 9 animals. Sera from animals with revealed plaques could inhibit the GBM-specific PFC response of day 9 animals, whereas sera from animals without revealed plaques could not. Thus sera, from BN rats whose own antibody levels were falling, could inhibit the GBM-specific plaque-forming capability of cells from animals at an earlier stage of the autoimmune response and showed the potential importance of humoral factors, putatively antiidiotypic antibodies, in effecting autoregulation of autoantibody formation in this model.

Animals↗
PubMed1984

Objective monitoring of activity in Wegener's granulomatosis by measurement of serum C-reactive protein concentration.

Serial measurements of the serum concentration of C-reactive protein were made in 38 patients with Wegener's granulomatosis during a period of 6 years. The concentration was always elevated when the disease was active, even in patients receiving immunosuppressive treatment, and fell rapidly in association with clinical remission induced by immunosuppression. During periods of complete remission, in the absence of any intercurrent condition, the value remained within the normal range. The correlation between C-reactive protein level and disease activity was much closer than that between erythrocyte sedimentation rate and disease activity. These results indicate that serial measurement of the serum C-reactive protein fills the urgent need for an objective index of the activity of Wegener's granulomatosis and its response to therapy.

Adolescent↗
PubMed1984

Recurrence of circulating anti-glomerular basement membrane antibody three years after immunosuppressive treatment and plasma exchange.

A patient with auto-antibody mediated Goodpasture's syndrome was successfully treated with cytotoxic drugs, steroids and plasma exchange. After an absence of three years, circulating anti-glomerular basement membrane antibodies reappeared, and linear IgG staining of the glomeruli was shown by immunofluorescent studies. Renal function did not change and there was no evidence of pulmonary hemorrhage. Antibody levels then fell spontaneously over the succeeding 18 months.

Adult↗
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↗