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Biomedical subjects

M R Daha

Publications and source records attributed to M R Daha.

At least 325 records · Page 18Linked to original sources
PubMed1989

Correlates of plasma atrial natriuretic peptide levels in renal transplant recipients.

Plasma atrial natriuretic peptide (ANP) levels were measured with a radio-immunoassay in 56 patients, 3 weeks to 16 1/2 years after renal transplantation. At the time of the study their renal function was stable, with creatinine clearances ranging from 10 to 101 ml/min. Plasma ANP levels ranged from 1 to 941 pg/ml and were found to correlate positively with both age and systolic blood pressure. Moreover, a negative correlation was found between plasma ANP levels and creatinine clearance. We conclude that in renal transplant recipients neither renal denervation nor the use of immunosuppressive therapy abolishes the influence of age, systolic blood pressure and renal function on the plasma levels of ANP.

Adolescent↗
PubMed1989

Possible mechanisms of degradation of C1q in vivo and in vitro: role of macrophages.

Low levels of C1q may be found in sera of patients with diseases such as systemic lupus erythematosus, serum sickness and bacterial endocarditis. In vitro, C1q can be bound by immune complexes and induce activation of the proenzymes C1r and C1s, resulting in an activated C1 molecule. In the presence of C1-In in the reaction mixture C1r and C1s are dissociated rapidly from the immune complex-bound C1q. This C1q has the possibility to interact with free precursor C1r and C1s to form a new C1 molecule at the surface of the immune complex and induce a new cycle of activation. In vivo, however, such a possibility does not seem to play a major role, because low levels of C1q are found in various diseases which are thought to be mediated by immune complexes. Therefore we studied the clearance rate of C1q in rats in the presence and absence of soluble aggregates of IgG (AIgG). It was found that 125I-C1q is cleared from the circulation of rats with a halflife of 12.4 hrs and increasing concentrations of AIgG enhanced the clearance of 125I-C1q in vivo. Studies in which various organs were analyzed for 125I-C1q indicated that the liver is the main site of clearance and that the Kupffer cells seem to play a major role. These, and other in vitro studies, indicate that in vivo complement activation, may contribute to a higher degree of turnover of C1q in vivo and cause depletion of circulating C1q.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Immunopathogenetic aspects of IgA nephropathy.

IgA nephropathy is the most common primary glomerulonephritis worldwide, and is an important cause of end-stage renal failure. The pathogenesis of the disease has unfortunately remained unclear despite a considerable research effort in the past twenty years. Combining data from the recent literature with our own findings we propose a pathogenetic model in which a selective IgA1 hyperresponsiveness plays a key role. Everyday infections lead to abnormally high plasma IgA1 immune responses in patients, with the bone marrow as the main production site of this increased circulating IgA1. However, may questions still remain unanswered, such as: why are patients hyperresponsive with respect to plasma IgA1? Which antigens are involved? What causes the mesangial deposition of IgA1, and the subsequent tissue damage?

Animals↗
PubMed1989

Complement-mediated enhancement of IgA-induced H2O2 release by human polymorphonuclear leucocytes.

In a previous study we have demonstrated that heat-killed Staphylococcus aureus opsonized with either purified human serum IgA or secretory IgA (sIgA) can induce a respiratory burst (measured as H2O2 release) in human polymorphonuclear leucocytes (PMN; Gorter et al., 1987). In the present study we have investigated whether opsonization of IgA-coated staphylococci with complement has an additional effect on the H2O2 release of PMN. It was demonstrated that staphylococci coated with IgA (or sIgA) and subsequently opsonized with complement induced at least a two-fold increase in the specific H2O2 release compared with bacteria coated with IgA (or sIgA) alone (P less than 0.05 and P less than 0.02, respectively). The co-operative effect of IgA and complement was also observed in the presence of 10 mM ethyleneglycoltetraacetic acid containing 5 mM MgCl2 (MgEGTA), suggesting that activation of the alternative pathway of complement is sufficient to exert this effect. Using D-deficient serum as a source of complement we could demonstrate that activation of the alternative pathway is essential for the co-operative effect of complement and IgA. The increase in specific H2O2 release caused by complement was found to be dependent on the amount of IgA initially used to opsonize the bacteria. Finally the co-operative effect of IgA and complement was not restricted to one IgA subclass, because an additional opsonization of S. aureus coated with sIgA1 or sIgA2 with complement resulted in both cases in a statistically significant enhanced specific H2O2 release by PMN (P less than 0.05).

Complement C3↗
PubMed1989

Immunoelectron microscopic visualization of the transcytosis of low density lipoproteins in perfused rat arteries.

A postembedding labeling technique was employed to visualize human native low density lipoproteins (LDL) during transcytosis in rat arterial endothelium. For this purpose human LDL was perfused through rat vasculature before fixation and processing for immunoelectron microscopy. The LDL particles were located on sections by anti-human apolipoprotein B-100 (LDL) antibodies and secondary antibodies or protein-A conjugated to 10-nm colloidal gold. LDL molecules were seen in plasmalemmal vesicles as well as in the subendothelial space. No colloidal gold was found in the intercellular junctions. Perfusion with reductively methylated LDL, which cannot bind to the LDL receptor, gave a similar labeling pattern, indicating that transcytosis of LDL via plasmalemmal vesicles is most likely receptor independent. Furthermore, the passage of LDL through intact vascular endothelium is a vesicular transport rather than an intercellular diffusion process.

Animals↗
PubMed1989

Pathogenesis of naturally acquired bovine respiratory syncytial virus infection in calves: evidence for the involvement of complement and mast cell mediators.

Indicators of immune-mediated disease were studied in calves with severe natural bovine respiratory syncytial virus infection. Although antigen and antibody were detected concurrently in most calves, immune complexes were not detected by use of immunofluorescence, ELISA, and binding of the 1q component of complement. Complement component C3, however, was observed by immunofluorescence in the cranioventral, virus-infected portion of the lungs of 19 of 25 calves. Reductions in the amount of histamine and in the numbers of mast cells and mast cell granules in the virus-positive cranioventral and virus-negative caudodorsal portions of the lungs, indicated activation of mast cells and liberation of their granule contents. On the basis of these and previous findings, a model for the pathogenesis of bovine respiratory syncytial virus-induced disease was proposed.

Animals↗
PubMed1989

Elimination of soluble 123I-labelled aggregates of human immunoglobulin G in humans; the effect of splenectomy.

To study the role of the spleen in the elimination of immune complexes we examined mononuclear phagocyte system function in eight healthy controls and eight splenectomized patients, with soluble 123I-labelled aggregates of human immunoglobulin G (AIgG). No differences were found between the two groups in elimination and degradation of AIgG. The loss of splenic function was compensated for by increased uptake of AIgG by the liver. With the dose of 123I-AIgG used in this study (10 micrograms/kg body weight), significant generation of C3a was observed. No correlation was found between erythrocyte CR1 number and the fraction of aggregates that bound to erythrocytes.

Adult↗
PubMed1989

Induction of antibody-dependent cellular cytotoxicity against endothelial cells by renal transplantation.

Antibodies that induce antibody-dependent cellular cytotoxicity (ADCC) of human umbilical-vein endothelial cells (EC) were detected using serum of a renal transplant patient who had experienced a severe vascular rejection episode after receiving an HLA-identical kidney graft from a living-related donor. This reactivity was absent in sera obtained before transplantation. The antibody nature of the reactivity present in the post-transplantation sera was proven by gelfiltration studies, protein A absorption, pepsin-digestion experiments, and incubation with subclass specific monoclonal antibodies; predominantly IgG1 antibodies were found to bind to EC and induce ADCC. The specificity of the antibodies could be shown in panel studies using EC lines of various donors. In order to investigate the clinical relevance and incidence of anti-EC ADCC, we examined whether anti-EC reactivity could be observed in 9 additional renal transplant patients. Sera of 2 of these patients were found positive in the ADCC assay, whereas 20 normal serum donors were negative. ADCC against EC in these patients was not caused by classic antiendothelial-monocyte (EM) antibodies. Using various experimental systems (adherent cell depletion, monoclonal antibody blocking, cold target cell inhibition) it was shown that the natural killer/killer (NK/K) cells present within the peripheral blood mononuclear cell population were responsible for EC lysis. These findings demonstrate that IgG1 antibodies directed against polymorphic non-HLA, non-EM antigens on EC can be induced by renal allotransplantation. Via Fc-receptor interaction with NK/K cells, these antibodies can be responsible for ADCC against EC.

Antibodies, Monoclonal↗
PubMed1989

Anti-endothelial cell antibodies in patients with rheumatoid arthritis complicated by vasculitis.

IgG antibodies reactive with human umbilical vein endothelial cells were found in 19 out of 28 patients with rheumatoid vasculitis (RV), in four out of 24 patients with rheumatoid arthritis (RA), in seven out of 10 patients with systemic lupus erythematosus (SLE), but not in healthy donors. In four patients with RV who were followed longitudinally, regression of vasculitic episodes coincided with decreasing titres of anti-endothelial antibodies (AEA). Binding activity to endothelial cells was observed in intact IgG and F(ab')2 fragments of IgG. AEA activity was unrelated to antibodies against nuclear, blood group or major histocompatibility complex antigens and did not involve immune complexes. AEA activity was not specific for endothelial cells since the AEA-positive sera and the IgG fractions prepared from these sera also reacted with fibroblasts. Adsorption of positive sera and corresponding IgG fractions with endothelial cells decreased the IgG binding reactivity on both fibroblasts and endothelial cells. These findings show that RV patients have IgG-AEA, and suggest that these antibodies may play a role in the pathogenesis of the disease.

Antibody Specificity↗
PubMed1988

The complement subcomponent C1q mediates binding of immune complexes and aggregates to endothelial cells in vitro.

The present studies were initiated to investigate whether soluble immune complexes, upon interaction with complement, can bind to endothelial cells. Human umbilical vein endothelial cells (HUVE) were incubated with purified human 125I-labeled C1q at 4 degrees C in RPMI-0.5% bovine serum albumin and assayed for binding. Optimal binding of 125I-labeled C1q to HUVE was reached within 2 h, and saturation of binding was found at concentrations of 5 micrograms/well input. The binding of 125I-labeled C1q was inhibitable with unlabeled C1q and by the collagenous region of pepsin-cleaved C1q. No inhibition was observed with the globular heads of C1q, suggesting that C1q binds to HUVE via the collagenous region of C1q. When HUVE were first reacted with various concentrations of C1q, washed and subsequently incubated with 125I-labeled aggregated human IgM (AIgM), binding of 125I-labeled AIgM to HUVE occurred depending on the dose of C1q. Only those aggregates of IgM which react with C1q in a solid-phase C1q binding assay were able to bind to HUVE presensitized with C1q. In addition it was shown that C1q mediated binding of aggregated IgG to HUVE. Furthermore, immune complexes (IC), that were prepared with bovine thyroglobulin (BTg) and rabbit anti-BTg, bound to C1q-preincubated HUVE. These studies suggest that localization of IC on endothelium can be enhanced following interaction of the IC with complement.

Antigen-Antibody Complex↗
PubMed1988

Activation of rat complement by soluble and insoluble rat IgA immune complexes.

The ability of rat monoclonal IgA, specific for 2,4-dinitrophenyl (DNA), to activate the complement (C) system of the rat was investigated using aggregated IgA or IgA immune complexes (IC). IgA was coated onto a solid phase, and tested for its capacity to bind C3 upon incubation at 37 degrees C in normal rat serum (NRS) in the presence of Mg-EGTA. Binding of C3 was observed dependent on the dose of dimeric (d-), polymeric (p-) and secretory IgA tested. In contrast, little C3 fixation was observed in this system with monomeric (m-) rat IgA or with mouse m- and d-IgA (MOPC315). Soluble and insoluble rat IgA IC were prepared using dinitrophenylated rat serum albumin (DNP8RSA) as antigen (Ag), and assessed for C activation. It was shown that insoluble IC (immune precipitates; IP) containing m-, d- or pIgA of rat origin activate the alternative pathway of rat C, as demonstrated by their capacity to induce C consumption in NRS in the presence of Mg-EGTA. When p- and m-IgA IP were compared for their capacity to activate C, it was found that p-IgA activated C four times as efficiently as m-IgA IP (at 2 mg/ml). Soluble rat IgA IC were prepared in an excess of DNP8RSA, fractionated by gel filtration on Sepharose 6B, and analyzed for C activation and antibody (Ab)/Ag ratio. In contrast to m-IgA IP, soluble m-IgA did not activate C. On the other hand soluble d-IgA IC activated C dependent on their concentration and size: at a concentration of 0.1 mg/ml high-molecular weight d-IgA IC with a high Ab/Ag ratio were four times as efficient as low-molecular weight IC with a low Ab/Ag ratio, and twice as efficient as IP prepared at equivalence. To demonstrate the induction by IgA of the assembly of the terminal membrane attack complex, trinitrophenyl (TNP)-conjugated rat red blood cells (TNP-RRBC) coated with d- or p-IgA were shown to be lysed in NRS in the presence of Mg-EGTA. No lysis of m-IgA-coated TNP-RRBC was observed. The results in this study demonstrate that both soluble and insoluble rat IgA IC activate the alternative pathway of homologous rat C. Alternative pathway activation by soluble rate IgA IC is dependent on the size of the IC. The degree of polymerization of the IgA Ab itself also influences C activation.

Animals↗
PubMed1988

Circulating IgA immune complexes and skin IgA deposits in liver disease. Relation to liver histopathology.

Alcoholic liver disease (ALD) is characterized by elevated serum IgA concentrations, the presence of circulating immune complexes containing IgA, and IgA deposits along sinusoids in the liver. When combined with the presupposed IgA-clearance function of the liver, a causal association between IgA abnormalities and the liver disease in ALD can be suggested. This prompted us to study the presence and concentration of circulating IgA-containing immune complexes (IgA-CIC) in 41 patients with ALD and 41 patients with other nonalcoholic liver diseases having comparable serum IgA levels. We searched for relationships among IgA-CIC and history of alcohol abuse, liver histopathology, and IgA deposits in the liver. Using an anti-IgA inhibition binding assay, 56% of the patients exhibited IgA-CIC in polyethylene glycol precipitate of serum and 38% showed IgA-CIC in whole serum. The prevalence and concentration of IgA-CIC was lowest in cases with nonspecific changes or steatosis in the liver biopsy and highest in cases with hepatitis or cirrhosis (P less than 0.01). The occurrence of IgA-CIC was not related to a history of alcohol abuse or to the presence of IgA deposits along hepatic sinusoids (which occurred in 78% of ALD and 20% of non-ALD cases). A skin biopsy was available from 34 patients (19 with ALD and 15 with non-ALD). In 68% of these biopsies, IgA deposits were observed in superficial blood capillaries.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen-Antibody Complex↗
PubMed1988

Effects of the rate of acetylcholine receptor synthesis on the severity of experimental autoimmune myasthenia gravis.

The effect of target organ manipulation by means of denervation and treatment with anabolic steroids on the severity of disease in EAMG was assessed in inbred rats. Unilateral limb denervation, a procedure known to increase the AChR content of muscle, 'protected' the denervated leg against antibody-mediated AChr loss in acute EAMG induced by passive transfer of mAb 35 directed against the main immunogenic region. Also in chronic EAMG, brought about by immunizing rats with AChR in complete Freund's adjuvant, the AChR loss of the denervated leg was about one fourth (13.5 vs. 53%) of the control leg. In both acute and chronic EAMG the amount of AChR complexed with antibody was lower in the denervated leg. This lower AChR occupancy with antibody in the denervated leg occurred also in conditions of marked antibody excess and was therefore due to enhanced AChR synthesis. Next the effect of treatment with a weakly virilizing anabolic steroid nandrolone in chronic and acute EAMG was examined in order to examine whether a hypothesized enhanced synthesis of AChR would protect animals from disease. In the absence of an immunosuppressive effect, in terms of concentration of antibodies to AChR, nandrolone treatment protected the rats from severe disease in the chronic EAMG model as shown by the fact that of the 9 rats 6 showed mild (1+) disease and 3 no disease at all; conversely 6 out of 9 control rats showed severe (3+) disease. Rats treated with nandrolone showed a 48 +/- 1.7% loss of AChR compared to a loss of 58 +/- 3.6% in the control rats, suggesting enhanced AChR synthesis. When nandrolone-pretreated rats were given acute EAMG by passive transfer of mAb 35 a paradoxical effect was seen. In contrast to the controls all of the rats pretreated with nandrolone showed severe signs of EAMG; this was associated with a higher loss of AChR and increased consumption of complement C4 as suggested by decreased concentrations of C4 in the serum. Results show increased AChR synthesis to protect against chronic EAMG both in terms of clinical disease (nandrolone) as well as AChR loss (nandrolone, denervation). In addition it was shown that nandrolone increases serum C4 consumption which in the complement-dependent acute EAMG model causes enhancement of the severity of clinical disease and increased AChR loss.

Acute Disease↗
PubMed1988

Mitogenic stimulation of malignant B cells CLL: diminished in-vitro stimulation with anti-CR1 antibodies.

Peripheral B lymphocytes of five CLL patients were tested in a radioimmunoassay to determine the density of the C3b receptor (CR1) and the cells were assayed for their ability to mature into IgM secreting cells after in-vitro culture with a combination of Pokeweed Mitogen (PWM) and antibodies directed against CR1. Despite the presence of normal amounts of CR1 on the leukemic B cells, crosslinking of these receptors by anti-CR1 antibodies stimulated only a fraction of the leukemic cell population to differentiate into IgM secreting cells. These results add to the partial functional impairment of CLL-B cells.

Antibodies↗
PubMed1988

Activation of complement by human serum IgA, secretory IgA and IgA1 fragments.

UNLABELLED: Activation of the complement (C) system by human IgA was studied. Both subclasses of IgA, IgA1 and IgA2, and secretory IgA were shown to activate C, as determined by deposition of C3 on glutaraldehyde-activated microwells coated with IgA. The activation of the C system occurred in the presence of MgEGTA and not in D-deficient serum. In addition to C3, deposition of properdin (P) but not of C4 was detected. These results indicate that C activation, as determined by measuring deposition of C3 and P, occurred by the alternative pathway (AP). The data further show that the major part of the hinge region, which is deleted in IgA2 as compared with IgA1 and which forms the major structural difference between the two subclasses, is not involved in C activation. Reduction and alkylation destroyed the ability of IgA to activate C, as has also been demonstrated for IgG. In order to define the C activating region of the IgA molecule, several fragments of IgA1 were tested. The four-chain molecules F(ab')2 and F(abc)2 were shown to activate the AP. No activation was observed with the two-chain fragments Fab and Fc. The Fc fragment of IgA also did not activate the CP, as does the Fc fragment of IgG. This indicates that activation of the AP of C by IgA is dependent on the presence of the F(ab')2 fragment. IN CONCLUSION: human IgA does activate C by the AP. This activation requires an intact F(ab')2 fragment.

Complement Activation↗