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Biomedical subjects

C M Lockwood

Publications and source records attributed to C M Lockwood.

At least 91 records · Page 5Linked to original sources
PubMed1992

Association of IgM with IgG ANCA in patients presenting with pulmonary hemorrhage.

ANCA are markers for systemic vasculitis such as Wegener's granulomatosis (WG) and microscopic polyarteritis (MPA) and are usually of the IgG isotype. However, IgM ANCA may rarely occur in isolation, and in these circumstances, we have found that they are associated clinically with a syndrome of pulmonary hemorrhage and systemic vasculitis. How frequently IgM ANCA may occur in conjunction with IgG has not previously been investigated. We report here a study of 24 consecutive patients with IgG ANCA-positive systemic vasculitis (14 WG, 10 MPA) in whom we determined whether IgM ANCA occurred in association with IgG ANCA, and if so, whether this had clinical importance. Eight patients were found to have IgM ANCA as well as IgG ANCA, and of these, seven presented with severe pulmonary hemorrhage. None of the IgM ANCA-negative patients presented with pulmonary hemorrhage. Although the occurrence of pulmonary hemorrhage in ANCA positive vasculitis was closely correlated with the presence of IgM ANCA, the antigen specificity of these IgM autoantibodies was variable, since both myeloperoxidase (4 patients), PR3 (3 patients), and an unknown ANCA antigen (1 patient) were found to be targets. We conclude that knowledge of ANCA isotype may have important clinical and therapeutic implications for the management of patients with systemic vasculitis.

Adolescent↗
PubMed1992

Activation of normal neutrophils by anti-neutrophil cytoplasm antibodies.

Anti-neutrophil cytoplasm antibodies (ANCA) are markers of systemic vasculitis for which a pathogenetic role has been postulated. We have examined the effect of these autoantibodies on the function of normal human neutrophils in vitro. In the presence of ANCA positive sera luminol-amplified chemiluminescence was significantly increased compared to the values seen in the presence of normal or anti-double stranded DNA positive sera (P < 0.01). Five of six ANCA positive F(ab)2 preparations also produced significant neutrophil activation as demonstrated by the chemiluminescence response. This response was totally abrogated by the addition of neutrophil cytoplasm extract, containing the ANCA antigen. Addition of inhibitors to the chemiluminescence system demonstrated that the chemiluminescence response was inhibited by azide and salicylhydroxamic acid and reduced by histidine, suggesting that the chemiluminescence response was due to activation of myeloperoxidase, with generation of singlet oxygen. The chemotactic response to f-Met-Leu-Phe, a bacterial chemotactic peptide, was significantly augmented in the presence of ANCA. Chemotaxis to zymosan-activated serum and chemokinesis was not affected. Phagocytosis was also unaffected. We propose that neutrophil activation and modulation of neutrophil migration by ANCA may be of pathogenetic significance in systemic vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1991

Treatment of systemic vasculitis with pooled intravenous immunoglobulin.

The therapeutic effect of a course of high-dose, pooled, intravenous immunoglobulin (IVIg) on disease activity and circulating antineutrophil cytoplasm antibodies (ANCA) was investigated in 7 patients with systemic vasculitis. 5 had active disease despite conventional immunosuppression, and 2 had not received any treatment. All 7 had clinical improvement, which was sustained in 6 and transient in 1. The fall in ANCA concentrations to a mean of 51% of the pre-treatment values was maintained during follow-up. C-reactive protein concentration also dropped considerably. IVIg seemed to confer a useful therapeutic effect without adverse reaction.

Adult↗
PubMed1991

Immunoregulation of mercuric chloride-induced autoimmunity in Brown Norway rats: a role for CD8+ T cells revealed by in vivo depletion studies.

Mercuric chloride (HgCl2) induces the production of autoantibodies to glomerular basement membrane (GBM) in the Brown Norway (BN) rat. The autoimmune response is self-limiting and thereafter the animals are resistant to rechallenge with HgCl2. Resistance can be transferred to naive animals by spleen cells from HgCl2-treated rats. A similar state of resistance can be induced with a low dose of HgCl2, insufficient in itself to induce autoimmunity. We have examined the role of CD8+ T cells in the immunoregulation of this experimental model by depleting this subset in vivo. We have also used inhibition studies in a solid-phase radioimmunoassay in an attempt to demonstrate any effect of anti-idiotypic antibodies in the spontaneous resolution of the anti-GBM antibody response. The initial induction and spontaneous resolution of anti-GBM antibodies were unaffected by depletion of CD8+ T cells. However, CD8-depleted animals were no longer resistant to rechallenge with HgCl2. Cell transfer studies showed that spleen cells from CD8-depleted animals conferred less resistance to HgCl2 than those from animals which had received control antibody. CD8 depletion also reduced the resistance induced by pretreatment with low-dose HgCl2. Studies in which peak sera were pre-incubated with post-recovery sera before testing in a solid-phase anti-GBM radioimmunoassay did not support an important role for anti-idiotypic antibodies. We conclude that CD8+ T cells play an important role in the resistance to rechallenge with HgCl2 in the BN rat, although they are not required for the induction or spontaneous resolution of the initial autoimmune response. Demonstration of the reversal of a suppressive phenomenon in vivo using an anti-CD8 monoclonal antibody is unusual.

Analysis of Variance↗
PubMed1991

Plasmapheresis and subsequent pulse cyclophosphamide versus pulse cyclophosphamide alone in severe lupus: design of the LPSG trial. Lupus Plasmapheresis Study Group (LPSG).

A group of clinics are collaborating in the Lupus Plasmapheresis Study Group (LPSG) to investigate whether repeated plasmapheresis prior to pulse cyclophosphamide improves the therapeutical results in severe systemic lupus erythematosus (SLE). The underlying rationale is the hypothesis that plasmapheresis 1) eliminates pathogenic autoantibodies and immune complexes and 2) induces compensatory lymphocyte activation via feedback mechanisms between circulating antibodies and their respective clones ("antibody rebound"). It should be possible to utilize this enhanced activity for increased clonal deletion if pulse cyclophosphamide is applied shortly after plasmapheresis. Accordingly, in a randomized study, the LPSG will be comparing the repeated application of pulse cyclophosphamide alone with a treatment involving repeated plasmapheresis prior to the cyclophosphamide pulses in severe SLE. A third arm of the study will be gathering experience with a more intensified procedure. This overview summarizes the most important details of the planned study.

Combined Modality Therapy↗
PubMed1991

Antineutrophil cytoplasmic autoantibodies: the nephrologist's perspective.

Serologic tests for antineutrophil cytoplasmic autoantibodies (ANCA) provide diagnostic and prognostic information in patients with nephritis and systemic vasculitis. Four case histories are discussed that illustrate ANCA positivity in patients with renal impairment caused by interstitial, rather than glomerular, nephritis. Renal biopsy should continue to be used to diagnose the cause of renal impairment in ANCA-positive patients.

Adult↗
PubMed1991

Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies.

To determine whether plasma exchange was of additional benefit in patients treated with oral immunosuppressive drugs for focal necrotizing glomerulonephritis (without anti-GBM antibodies), we performed a randomized controlled trial with stratification for renal function on entry. Forty-eight cases were analyzed, 25 in the treatment group (plasma exchange, prednisolone, cyclophosphamide and azathioprine) and 23 in the control group (drug therapy only). There was no difference in outcome in patients presenting with serum creatinine less than 500 mumol/liter (N = 17), or greater than 500 mumol/liter but not on dialysis (N = 12), all but one of whom had improved by four weeks. However, patients who were initially dialysis-dependent (N = 19) were more likely to have recovered renal function (P = 0.041) if treated with plasma exchange as well as drugs (10 of 11) rather than with drugs alone (3 of 8). Long-term follow-up showed that improvement in renal function was generally maintained. The results of this trial confirm that focal necrotizing glomerulonephritis related to systemic vasculitis responds well to immunosuppressive drugs when treatment is started early, and suggest that plasma exchange is of additional benefit in dialysis-dependent cases.

Adolescent↗
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

Experimental autoimmune glomerulonephritis induced by homologous and isologous glomerular basement membrane in Brown-Norway rats.

In order to study disease mechanisms and potential forms of therapy in glomerulonephritis, a model of experimental autoimmune glomerulonephritis (EAG) has been developed in the rat. We have examined the response of Brown-Norway (BN) rats to a single i.m. injection of collagenase-solubilised homologous (Sprague-Dawley, SD) or isologous (BN) glomerular basement membrane (GBM), with and without complete Freund's adjuvant (CFA). There was a dose-dependent circulating anti-GBM antibody response to all preparations of rat GBM. Animals given either antigen alone at a dose of 2 mg/kg developed circulating anti-GBM antibodies, which reached peak values by 6 weeks (63 +/- 5% following SD GBM; 53 +/- 8% following BN GBM), but did not develop glomerular deposits of IgG or nephritis. Animals given 2 mg/kg SD GBM in CFA developed greater concentrations of anti-GBM antibody by 6 weeks (122 +/- 20%) together with linear deposits of IgG on glomerular and tubular basement membranes (TBM), albuminuria (mean 7 mg/24 h), and variable focal segmental necrotising glomerulonephritis with mild interstitial nephritis. The same dose of BN GBM in CFA produced similar concentrations of circulating antibody (144 +/- 26%), with linear deposits of IgG on GBM but rarely TBM, little albuminuria, and variable mild focal glomerulonephritis. Other strains injected with SD GBM in CFA showed a variable circulating anti-GBM antibody response, which was similar to that of BN rats in PVG and DA rats but lower in LEW and WAG rats. Linear deposits of IgG on the GBM were detected in a proportion of PVG and DA rats, but not in LEW or WAG rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Anti-idiotypes against anti-neutrophil cytoplasmic antigen autoantibodies in normal human polyspecific IgG for therapeutic use and in the remission sera of patients with systemic vasculitis.

Anti-neutrophil cytoplasmic antigen (ANCA) activity was inhibited in 15 out of 21 sera from patients with acute systemic vasculitis following incubation with normal polyspecific IgG for therapeutic use (IVIg). ANCA antibodies reacted with IVIg through idiotypic-anti-idiotypic interactions, as shown in competitive binding assays using F(ab')2 fragments from IVIg and affinity chromatography of ANCA IgG on Sepharose-bound F(ab')2 fragments from IVIg. Co-incubation of sera from patients with acute systemic vasculitis with paired autologous remission stage sera also resulted in inhibition of ANCA activity in acute sera. Remission sera contain IgM and IgG capable of interacting with beta and or alpha idiotypes of ANCA IgG from acute sera. Anti-idiotypic IgM may account for the lack of expression of ANCA activity in whole serum from patients in remission from systemic vasculitis, which were found to contain high titres of ANCA IgG. These observations suggest that remission of systemic vasculitis is associated with the generation of anti-idiotypes against autoantibodies rather than the suppression of production of ANCA autoantibodies. IVIg may modulate the activity of systemic vasculitis in vivo.

Antibodies, Anti-Idiotypic↗
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

The effect of anti-neutrophil cytoplasm autoantibodies on the signal transduction in human neutrophils.

The effect of anti-neutrophil cytoplasm autoantibodies (ANCA) on neutrophil activation was studied by pre-incubating neutrophils with IgG and F(ab')2 prepared from ANCA patients with Wegener's granulomatosis or microscopic polyarteritis. We measured the generation of inositol triphosphate (IP3) (a product of hydrolysis of membrane phospholipid which acts as a second intracellular messenger), and the translocation of protein kinase C (PKC) upon stimulation by a chemotactic peptide, fMet-Leu-Phe (fMLP). ANCA+ F(ab')2 did not induce a significant increase in IP3 generation. Nonetheless, ANCA+ F(ab')2 and ANCA+ IgG pretreatment of human neutrophils reduced the production of inositol phosphates upon subsequent fMLP stimulation compared with experiments performed when cells were pretreated with F(ab')2 and IgG prepared from ANCA- healthy subjects. A significantly reduced generation of IP3 and inositol biphosphate (IP2) was observed. ANCA+ F(ab')2 pretreatment of neutrophils inhibited fMLP-stimulated IP3 generation in a dose-dependent manner. The membrane-bound PKC activity upon stimulation by FMLP and PMA was reduced in neutrophils pretreated with ANCA+ F(ab')2 and IgG. These results indicate that ANCA affect in vitro signal transduction (IP3 generation, and translocation of PKC) in human neutrophils. Apparently, further activation of signal transduction by chemotactic peptide is significantly blunted in cells pre-incubated with ANCA+ F(ab')2 but not with F(ab')2 from healthy controls.

Arteritis↗
PubMed1991

Inability to detect circulating anti-idiotypic antibodies in human anti-GBM antibody-mediated disease using a splenic PFC assay.

Anti-idiotypic antibodies are antibodies that are directed against the variable region of the corresponding antibody molecule and have been postulated to have a regulatory role in the immune response. Circulating anti-idiotypic antibodies have been reported in several antibody-mediated autoimmune diseases. We have established the following detection system for anti-idiotypic antibodies in human anti-glomerular basement membrane (GBM) disease. Spleen cells harvested from BALB/c mice immunised with human GBM were incubated with GBM-coated sheep red blood cells in the presence of guinea pig complement. Each spleen cell that produced anti-GBM antibodies resulted in a surrounding plaque where antibodies lysed the GBM-coated RBC. The number of plaques could be inhibited by the addition of heterologous anti-idiotypic antibodies to the plaquing mixture. Anti-idiotypic antibodies were then sought in both acute and convalescent phase sera from patients with anti-GBM disease and in laboratory staff who repeatedly handled GBM and sera containing anti-GBM antibodies. Anti-GBM antibodies were removed from all material before testing and affinity-purified preparations contained concentrations of IgG corresponding to the range that resulted in inhibition when affinity-purified rabbit anti-idiotypic antibody was examined. No anti-idiotypic antibodies could be demonstrated in any of the sera or IgG preparations examined. We conclude that if circulating anti-idiotypic antibodies are present in patients with anti-GBM disease, they must be infrequent, or at concentrations below the limits of detection of this assay (less than 1 mcg/mL). The observations of anti-idiotypic antibodies in other antibody-mediated diseases need to be confirmed.

Animals↗
PubMed1991

IgG subclass distribution and relative functional affinity of anti-myeloperoxidase antibodies in systemic vasculitis at presentation and during follow-up.

Circulating IgG autoantibodies to myeloperoxidase (MPO) are associated with renal vasculitis and have been implicated in its pathogenesis. However, raised levels of these autoantibodies may persist during clinical remission. We tested whether this paradox could be explained by immunoglobulin subclass switching during disease evolution, since different subclasses have different immunological and biochemical properties. Sera with anti-myeloperoxidase (anti-MPO) activity from 33 patients with active disease and 20 anti-MPO positive follow-up sera were studied by an ELISA using a panel of anti-human IgG subclass monoclonal reagents previously calibrated on human myeloma proteins. Anti-MPO subclass distribution in initial sera was: IgG1, 31 (94%); IgG2, 10 (30%); IgG3, 24 (73%); and IgG4, 22 (67%). IgG3 anti-MPO decreased during follow-up (P less than 0.02), with no change in IgG1 and IgG4. Relative functional affinity of anti-MPO antibodies in purified IgG subclasses was studied by the diethylamine method. IgG3 fractions consistently had a greater affinity for MPO than the other subclasses. Sequential studies in four patients demonstrated an affinity maturation for IgG1 and IgG4 anti-MPO as IgG3 anti-MPO disappeared. We conclude that dynamic changes of subclass distribution and affinity may explain discrepancies between anti-MPO antibody titre and disease expression.

Antibody Affinity↗