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G Gaskin

Publications and source records attributed to G Gaskin.

32 records · Page 2Linked to original sources
PubMed1993

Renal transplantation following immunoadsorption in highly sensitized recipients.

Five highly sensitized patients, with panel reactivity greater than 80% for 1.75-5 years, were treated by extracorporeal staphylococcal protein-A immunoadsorption, prednisolone, and cyclophosphamide. The five patients underwent treatment of 18-40 (mean 31) liters of plasma, respectively in 4-7 (mean 5.6) sessions. This reduced the titer of cytotoxic antibodies to sensitizing antigens to < 1/8 in all cases and abolished reactivity to crossreacting antigens. Two patients required retreatment following resynthesis of cytotoxic antibodies. All five patients have been transplanted, and four of these now have stable serum creatinines of 168 mumol/L at 34 months, 208 mumol/L at 29 months, 96 mumol/L at 5 months, and 125 mumol/L at 3 months posttransplantation. One patient had primary graft dysfunction due to acute tubular necrosis; the kidney was removed after eight weeks and showed cortical necrosis without evidence of acute rejection.

Adult↗
PubMed1992

HLA class II specificities in vasculitis with antibodies to neutrophil cytoplasmic antigens.

HLA class II genes were examined in patients with small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA) using restriction fragment length polymorphism and allele specific oligonucleotide typing. Fifty-nine patients were studied, 34 with Wegener's granulomatosis and 25 with microscopic polyarteritis, and their results were compared with those from 1103 British Caucasoid controls. The frequency of HLA-DQw7 was significantly increased in patients with vasculitis (patients 53%; controls 27.8%, chi 2 17.8, Pc less than 0.0025, relative risk 2.9), and all the DQw7 bearing haplotypes commonly found in Caucasoid populations contributed to the increase. By contrast, the frequency of HLA-DR3 bearing haplotypes was decreased in the patients (patients 6.8%; controls 21.6%, chi 2 6.7, P less than 0.01). HLA specificities were similar in the groups of patients presenting with Wegener's granulomatosis and microscopic polyarteritis and with different types of ANCA assessed by indirect immunofluorescence. However, patients with the DQw7, DR4 haplotype were significantly more likely to have transiently positive tests for ANCA than patients with other DQw7 bearing haplotypes, whereas patients with DR2 bearing haplotypes were more likely to have persistently positive ANCA. These results show that HLA class II genes are associated with small vessel vasculitis and may influence the duration of the associated autoimmune response.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1992

Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells.

The ability of vasculitis-associated anti-neutrophil cytoplasm antibodies (ANCA) to activate neutrophils and mediate release of radiolabel from 111Indium-labeled cultured human umbilical vein endothelial cells (HUVEC) was determined as a measure of the potential cytotoxicity of ANCA-activated neutrophils against vascular endothelium. Priming of neutrophils with low doses of phorbol 12-myristate 13-acetate (PMA) (1 ng/ml) and ionomycin (0.1 mumol/1) was required, together with pretreatment of endothelial cells with BCNU (1,3-bis-[2-chloroethyl]-1-nitrosourea; 0.26 mmol/l). Under these conditions and using a 4-hour serum-free assay system, mouse monoclonal antibodies (MAb) to the target autoantigens proteinase-3 (Pr-3) and myeloperoxidase (MPO) mediated enhanced release of 111Indium from HUVEC compared with control MAb. Human IgG Fab2 C-ANCA (recognizing Pr-3) and P-ANCA (recognizing MPO) did likewise. Preactivation of HUVEC with TNF (50 U/ml, 4 hr) enhanced the release of 111Indium from HUVEC generated by neutrophils activated with anti-Pr-3 and anti-MPO MAb. These data support the suggestion that activation of neutrophils by ANCA within the vascular lumen may contribute to endothelial cell injury.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1992

A retrospective study of radiolabeled granulocyte kinetics in patients with systemic vasculitis.

Patients with systemic vasculitis, including Wegener's granulomatosis (WG) and microscopic polyarteritis (MP), may undergo white cell scanning for the investigation of infective complications and/or occult fever. In a retrospective study of 12 patients with systemic vasculitis (six each of WG and MP), all with renal disease, we observed increase diffuse lung radioactivity soon after the injection of 111In-labeled granulocytes or 99mTc-HMPAO-labeled leukocytes in all patients with WG and in three with MP. Lung activity was quantified by comparison with the liver or spleen. The lung:liver count rate ratio per pixel, 1-1.5 hr after injection, in patients with systemic vasculitis was 0.87 (s.d. 0.25), significantly higher (p less than 0.001) than the ratio 0.38 (0.13) in patient controls who had normal white cell scans. The majority of patients with systemic vasculitis had scintigraphic evidence of abnormal splenic function. Two had focal splenic defects, while 7 had increased labeled cell uptake. Nine of the patients with vasculitis showed cell migration into the gut, presumably as a result of vasculitis, and in 6 it was prominent. Focal nasal uptake was found in 5/7 patients with systemic vasculitis who had their heads imaged, and may be specific for WG. Although all patients had renal disease, there was scintigraphic evidence of diffuse parenchymal renal uptake of 111In-labeled granulocytes in only one (with MP). The presence of anti-neutrophil cytoplasmic antibodies did not correlate with any abnormality or with lung uptake. Systemic vasculitis is associated with abnormalities of granulocyte kinetics, particularly involving the lung and spleen.

Granulocytes↗
PubMed1991

Anti-neutrophil cytoplasmic antibodies and disease activity during long-term follow-up of 70 patients with systemic vasculitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) have been identified as a diagnostic marker in primary systemic vasculitis, and immunofluorescence assays identify two patterns of binding: cytoplasmic (C-ANCA and perinuclear (P-ANCA). We have examined retrospectively the use of such assays in long-term monitoring of disease activity, in order to determine the relationship between presence of ANCA and relapse, and to assess their suitability as a guide to therapy. Seventy patients were studied over a period of 50 months, using clinical and laboratory criteria for the diagnosis of relapse and the internationally standardised immunofluorescence assay for detection of ANCA. In 19 patients C- or P-ANCA were detectable throughout the study period; six of these (with C-ANCA) relapsed. In 18 patients ANCA were undetectable during long-term follow-up; none of these patients relapsed. In 33 patients C- or P-ANCA were intermittently present; nine of these relapsed and all had C-ANCA detectable at the time of relapse. In six of the nine cases, relapse was accompanied or closely preceded by reappearance of C-ANCA. We conclude that continuing presence and reappearance of ANCA may identify patients who are at risk of relapse and who are most likely to benefit from long-term immunosuppressive therapy.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1991

Vascular damage in Wegener's granulomatosis and microscopic polyarteritis: presence of anti-endothelial cell antibodies and their relation to anti-neutrophil cytoplasm antibodies.

To define mechanisms of vascular injury in Wegener's granulomatosis and microscopic polyarteritis, anti-endothelial cell antibodies (AECA) were sought in serum from 168 patients, all of whom had anti-neutrophil cytoplasm antibodies (ANCA) detectable by indirect immunofluorescence. Using an ELISA with human umbilical vein endothelial cells (HUVEC), IgG AECA were demonstrated in 59% and IgM AECA in 68% of patients. Pretreatment of HUVEC with tumour necrosis factor (TNF), IL-1 or interferon-gamma (IFN-gamma) led to increased binding. Adsorption of AECA/ANCA-containing serum with HUVEC or neutrophils demonstrated that AECA and ANCA recognized different targets. von Willebrand factor (vWf) antigen levels in the patient samples were markedly elevated, with a mean of 3.10 +/- 1.89 U/ml (control population mean 1.04 +/- 0.36 U/ml), suggesting widespread endothelial cell damage. Studies using an 111In-labelled HUVEC release assay with 29 AECA-containing sera did not demonstrate complement-mediated cytotoxicity, even following activation of HUVEC with TNF. Four out of 16 AECA-containing sera tested showed antibody-dependent cellular cytotoxicity with unfractionated peripheral blood mononuclear cells. These data suggest that patients with Wegener's granulomatosis or microscopic polyarteritis can develop AECA to constitutively expressed but cytokine modulated determinants on HUVEC. These antibodies do not appear to support complement-mediated cytotoxicity, but a proportion can support antibody-dependent cellular cytotoxicity, suggesting that they may contribute to vascular injury.

Arterioles↗
PubMed1991

Immune markers in vasculitis.

Systemic vasculitides are a group of autoimmune diseases associated with intense leucocytic vascular infiltrates and the presence in the serum of autoantibodies to neutrophil enzymes. This article discusses the significance of these and other immune markers for the diagnosis and monitoring of patients with vasculitis, as well as their possible pathogenic consequences.

Autoantibodies↗
PubMed1990

Towards a more rapid diagnosis of rapidly progressive glomerulonephritis.

An attempt was made to provide simple practical guidelines to alert general practitioners to the diagnosis of rapidly progressive glomerulonephritis and lead to early referral to hospital. The duration of illness before referral to this hospital and its effect on outcome in patients with crescentic nephritis were assessed retrospectively from the case notes of 24 patients referred over two years. Four patients had Goodpasture's syndrome, 11 Wegener's granulomatosis, seven microscopic polyarteritis, and two idiopathic progressive glomerulonephritis. The duration of symptoms before referral to the local hospital was similar in the four groups of patients and varied from one week to 28 months (mean 10 months). The duration of stay in the local hospital was two, nine, 11, and 180 days in the patients with Goodpasture's syndrome and a mean of four days (range one to eight) in those with Wegener's granulomatosis and 10 days (one to 18 days) in those with microscopic polyarteritis. In the local hospital the diagnosis was based on the results of renal biopsy and detection of antibodies to glomerular basement membrane in two patients with Goodpasture's syndrome and on the results of renal biopsy in seven of the other patients aided by the detection of antibodies to the cytoplasm of neutrophils (ANCA) in 10. Three of the 24 patients died and four required maintenance haemodialysis. Patients who present to their general practitioners with persistent non-specific symptoms should have a urine dipstick test and then blood tests and emergency referral to hospital if necessary. Hospital physicians should be aware of the speed and accuracy with which current assays can confirm a diagnosis of rapidly progressive glomerulonephritis.

Adult↗
PubMedDate not supplied

Anti-neutrophil cytoplasm antibodies can recognize vascular endothelial cell-bound anti-neutrophil cytoplasm antibody-associated autoantigens.

Anti-neutrophil cytoplasm antibodies (ANCA) are strongly associated with the development of systemic vasculitis. Myeloperoxidase and proteinase-3 have been identified as targets for P-ANCA and C-ANCA, respectively. Both enzymes are released from neutrophil azurophil granules following neutrophil activation and both are highly cationic. Purified myeloperoxidase is demonstrated to bind non-convalently to endothelial cell membranes, to retain its enzymic function following binding, and to retain its antigenicity for P-ANCA. Endothelial cell-bound myeloperoxidase enhances complement-dependent cytotoxicity of some P-ANCA sere that also contain anti-endothelial cell antibodies. Studies using purified proteinase-3 show that it also can bind to endothelial cells and be recognized by C-ANCA. The interactions of myeloperoxidase and proteinase-3 with endothelial cells and ANCA may thus contribute to the development of vascular injury in patients with systemic vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗