Biomedical subjects

M R Daha

Publications and source records attributed to M R Daha.

At least 379 records · Page 21Linked to original sources

PubMed1987

Clearance of soluble aggregates of human immunoglobulin G in healthy volunteers and chimpanzees.

Using aggregates of IgG (AIgG) obtained by heat aggregation of a 16 g% human IgG solution, we sought a method for measuring the function of the mononuclear phagocyte system with a probe that bears more resemblance to soluble immune complexes than erythrocytes coated with anti-rhesus IgG (EIgG). It was found that intravenous administration of 10 micrograms AIgG/kg body weight did not cause any detectable side effects in chimpanzees. In nine healthy volunteers, a dose of 10 micrograms AIgG/kg body weight was used without any adverse reactions. AIgG is cleared from the human circulation with a t1/2 of 26 +/- 8 min (mean +/- SD). The site of clearance is predominantly the liver, as shown by an average liver spleen uptake ratio of 230:100. In whole blood obtained from the volunteers, it was found that erythrocytes bound significant amounts of AIgG, suggesting that CR1 on erythrocytes is involved in the clearance of complement activating immune complexes in humans. In five of the volunteers, clearance studies with EIgG had been done in a previous study. EIgG was cleared from the circulation with a t1/2 of 30 +/- 6.2 min (mean +/- SD). The predominant site of clearance of EIgG was the spleen. These data indicate that sensitized red blood cells are cleared from the circulation differently from soluble IgG aggregates.

Animals↗

PubMed1987

The pathophysiology of protein-overload proteinuria.

Alterations in glomerular function and structure were studied in protein-overload nephrosis in the rat induced by intraperitoneal administration of bovine serum albumin (BSA). Fractional clearance (C/GFR) studies using inulin and tracer proteins of different molecular size and charge revealed in proteinuric rats 1) unchanged glomerular filtration rate and renal plasma flow; 2) a 34-fold increase in C/GFR of rat serum albumin, reaching values similar to BSA; 3) a 2-fold increase in C/GFR for anionic horse radish peroxidase (HRP), but normal values for neutral and cationic HRP, and 4) an 11- and 3-fold increase for heterologous IgG and IgM, respectively. Glomerular epithelial cells showed degenerative changes, but the distribution of anionic sites in the glomerular basement membrane was found to be unaltered, as determined by polyethyleneimine binding studies. In summary, an elevation of serum albumin concentration resulted in an increased transcapillary albumin transport. This was found to lead to degenerative changes of glomerular epithelial cells with development of large pore defects, which were completely reversible.

Animals↗

PubMed1987

Diminished uptake and degradation of soluble aggregates of IgG by monocytes of patients with rheumatoid arthritis and vasculitis.

We investigated the capacity of monocytes to degrade soluble aggregates of IgG in vitro in the absence (Fc receptor [FcR] mediated) and presence of complement (FcR and C3 receptor mediated). Adherent monocytes from 33 patients with active rheumatoid arthritis (RA) and rheumatoid vasculitis, 32 patients with inactive RA alone, and 20 healthy controls were incubated with 125I-aggregated IgG (125I-AIgG) of restricted size with or without fresh serum. Normal monocytes degraded 9.8% of 125I-AIgG via FcR alone and the presence of complement enhanced degradation to 2.7%. Degradation of 125I-AIgG via FcR from patients without active RA suggested a depressed function of FcR. The maximal amount of 125I-AIgG which was bound by monocytes from patients with inactive and active RA, however, was increased compared to normals, suggesting a defect in intracellular processing in patients with RA. The degradation of 125I-AIgG in the presence of complement was also significantly depressed for both groups of patients. The monocytes from the patients also had decreased numbers of C3b receptors (CR1). Since CR1 are involved in the enhanced uptake of immune complexes bearing complement, the depressed capacity of monocytes from patients with RA to degrade 125I-AIgG in vitro may be caused both by a diminished uptake as well as a diminished capacity to degrade soluble AIgG.

Adult↗

PubMed1986

Spontaneous immunoglobulin synthesis by peripheral mononuclear cells in active rheumatoid arthritis.

Spontaneous production of immunoglobulins (Igs) by peripheral blood mononuclear cells (PBMC) in vitro was investigated to assess B cell activity in a group of 24 patients with rheumatoid arthritis (RA) with or without active joint disease and with or without rheumatoid vasculitis (RV) at the time of study. PBMC of patients with active arthritis (Ritchie index above 16) produced significantly more IgG and IgA than those of patients with inactive joint disease or those of 12 healthy controls. Enhanced production of IgG was found mainly among RA patients with concomitant RV, whereas markedly enhanced IgA production could also be found in patients without symptoms of RV. IgM production was only enhanced in two patients who had both active arthritis and RV. High production of IgG and IgA was probably due to increased numbers of Ig-secreting cells among freshly isolated PBMC, since the concentrations of Ig produced in vitro rose steadily, starting on day 0 and persisting throughout the entire culture period. Moreover, IgG and IgA concentrations measured after 7 days of culture showed significant correlations with the numbers of IgG- and IgA-containing plasma cells in PBMC on day 0. Comparison of the spontaneous production of Igs by PBMC with the levels of circulating immune complexes (CIC), showed that CIC levels were also significantly higher in active arthritis and in RV, but that there was no correlation between the CIC levels in individual patients and Ig production by their PBMC in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen-Antibody Complex↗

PubMed1986

Reestablishment of self tolerance by suppressor T-cells after active Heymann's nephritis.

Adoptive transfer experiments were performed to obtain evidence that the down-regulation of the autoimmune response in rats with active Heymann's nephritis (HN) is due to suppressor T cells. Late in the course of HN antigen-specific OX8+ suppressor T cells were found in the spleen, but never in the draining lymph nodes. These cells were shown to suppress the autoimmune response when transferred to naive recipients that were subsequently challenged. By mixing B cells or helper T cells from rats with HN with suppressor T cells from high-dose tolerant rats we showed that OX8+ suppressor T cells appeared to have a direct suppressive effect on autoreactive B cells. A profound suppressive effect on helper T cells appeared after 10 weeks. Possible mechanisms to account for the failure of Lewis rats to maintain self tolerance are discussed.

Animals↗

PubMed1986

Difference in clearance kinetics of particulate immune complexes and soluble aggregates of IgG in vivo.

In this study the similarities and differences in kinetics and site of clearance of particulate immune complexes and soluble aggregates of IgG (AIgG) were compared in rats. The rate of clearance of both antibody-coated erythrocytes (EA) and AIgG was dependent on the number of IgG molecules per EA or AIgG. Both probes were rapidly taken up by the liver. Whereas a minor part of the AIgG returned to the circulation as TCA-soluble breakdown products, a substantial part of the injected EA returned to the circulation as intact cells after 4 min. This rebound mechanism was shown to be complement (C)-dependent. Immediately after injection the injected EA bound C3 on their surface, whereafter the number of C3-bearing cells in the circulation rapidly decreased (T1/2 7.2 min). In C-depleted rats relatively more EA were taken up by the spleen than by the liver, in comparison with EA injected into normal rats (liver/spleen ratio in C-depleted rats 0.4 +/- 0.1; in normal rats 2.1 +/- 0.4). When C3 was bound and inactivated by preincubation of EA in vitro, a similar shift from liver to spleen (liver/spleen ratio 0.4 +/- 0.1) was observed. It is suggested that when the hepatic C receptors do not participate, the splenic Fc receptors become relatively more important in the clearance of EA from the circulation.

Animals↗

PubMed1986

Campylobacter jejuni bacteraemia as a cause of recurrent fever in a patient with hypogammaglobulinaemia.

In a hypogammaglobulinaemic patient with faecal cultures persistently positive for Campylobacter jejuni it was shown that C. jejuni bacteraemia was responsible for a long history of self-limiting attacks of fever. A focus of infection outside the gastro-intestinal tract was not found. Antimicrobial treatment failed to eradicate C. jejuni. Antibodies against C. jejuni were not detectable and there was also a defect in serum bactericidal activity. In contrast with normal serum, it was shown that, when patient's serum was used in tests, IgG and the components of complement C3 and C4 did not bind to C. jejuni.

Adult↗

PubMed1986

Complement split product C5a mediates the lipopolysaccharide-induced mobilization of CFU-s and haemopoietic progenitor cells, but not the mobilization induced by proteolytic enzymes.

Intravenous (i.v.) injection of mice with lipopolysaccharide (LPS), and the proteolytic enzymes trypsin and proteinase, mobilizes pluripotent haemopoietic stem cells (CFU-s) as well as granulocyte-macrophage progenitor cells (GM-CFU) and the early progenitors of the erythroid lineage (E-BFU) from the haemopoietic tissues into the peripheral blood. We investigated the involvement of the complement (C) system in this process. It appeared that the early mobilization induced by LPS and other activators of the alternative complement pathway, such as Listeria monocytogenes (Lm) and zymosan, but not that induced by the proteolytic enzymes, was absent in C5-deficient mice. The mobilization by C activators in these mice could be restored by injection of C5-sufficient serum, suggesting a critical role for C5. The manner in which C5 was involved in the C activation-mediated stem cell mobilization was studied using a serum transfer system. C5-sufficient serum, activated in vitro by incubation with Lm and subsequently liberated from the bacteria, caused mobilization in both C5-sufficient and C5-deficient mice. C5-deficient serum was not able to do so. The resistance of the mobilizing principle to heat treatment (56 degrees C, 30 min) strongly suggests that it is identical with the C5 split product C5a, or an in vivo derivative of C5a. This conclusion was reinforced by the observation that a single injection of purified rat C5a into C5-deficient mice also induced mobilization of CFU-s.

Animals↗

PubMed1986

Enhanced binding and degradation of the C1q subcomponent of complement by thioglycollate-stimulated guinea pig peritoneal macrophages.

Expression of C1q receptors on the plasma membrane of thioglycollate-stimulated guinea pig peritoneal exudate macrophages increased 1.54 times as compared to unstimulated controls. A Scatchard plot of the binding of 125I-C1q to the cells revealed that the binding is a result of an increase in the number of receptors and not to an increased affinity of the receptors. Thioglycollate-activated macrophages were found to be 1.6 times more active than nonactivated macrophages in the binding of 125I-C1q at 4 degrees C. The enhanced binding of 125I-C1q by activated peritoneal macrophages was reflected in an increase in the amount of 125I-C1q degraded by these cells as compared to resident peritoneal macrophages. This suggests that stimulation of phagocytic cells leads to an increase in the expression of C1q receptors and to a concomitant increase in the uptake and degradation of C1q.

Animals↗

PubMed1986

Serum immune complexes containing IgA appear to predict erosive arthritis in a longitudinal study in rheumatoid arthritis.

Fifty seven patients with rheumatoid arthritis (RA) were studied longitudinally, and the presence of rheumatoid factor (RF) and various types of immune complexes (IC) was correlated with joint activity and the presence of extra-articular features (EAF). In a cross sectional study it was found that the levels of circulating IC and RF correlated significantly with joint disease activity and the presence of EAF. Longitudinally, levels of IC measured by the C1q binding activity and IC containing IgG and IgM correlated significantly with fluctuations in joint disease activity, whereas IC containing IgG and IgA correlated with the occurrence of EAF. RF and IC levels, however, did not predict the clinical course of the disease. IC containing C3 and C4 were found infrequently and were only present in patients with active rheumatoid vasculitis (RV). The continuous presence of these IC appeared to be linked to the recurrence of vasculitis, irrespective of treatment. Significantly more erosions of hands and feet were found after one year follow up in those RA patients who presented early (disease duration less than one year) who initially had a raised serum IgA IC level (r = 0.72; p less than 0.005).

Antigen-Antibody Complex↗

PubMed1986

Destructive and protective effects of antibody on transplants in humans: practical and theoretical considerations.

Clearly the pioneering studies on hyperacute rejection, which lead to the concept of antibody-mediated injury to transplants, still present challenges to the clinician today. It is obvious that tests for antibodies before and after transplantation must be further refined to more reliably distinguish among destructive, protective and innocuous antibodies. The current crossmatch tests detect antibodies to donor lymphocytes, but lymphocytes may not always represent adequately the antigenic composition of the tissue that will be transplanted. Moreover the distribution of antigens in transplanted tissues must be considered in relation to the functional anatomy of the organs in order to understand the ultimate effects of antibodies on specific transplants. Thus some antibodies that produce a positive crossmatch may be safely ignored because they exert either a beneficial or no effect on the organ that is to be transplanted, while other antibodies that remain undetected by crossmatches on lymphocytes may damage some types of transplants. Moreover, the balance between protective and destructive antibodies is not dynamic; with time potentially dangerous antibody responses may be inhibited by a variety of autoregulatory mechanisms, some of which may be mediated by antibodies. Regulatory as well as cytotoxic antibody production may be actively stimulated by pretransplant blood transfusions. These antibody-mediated immune responses probably are magnified in the clinical setting by our current therapeutic immunosuppressive drugs which have more impact on cell-mediated immunity than on antibody-mediated mechanisms. New immunosuppressive interventions devised to inhibit undesired antibody-mediated immune responses might be of benefit to those patients who fail to respond to current rejection therapy as well as to patients who have pre-existing antibodies and are waiting for transplants.

ABO Blood-Group System↗

PubMed1986

Comparison of immune complexes and complement components in arterial and venous blood of patients with rheumatoid arthritis.

Immune complexes (IC) are frequently found in the venous blood and synovial fluid of patients with rheumatoid arthritis (RA). Although IC are claimed to have a pathogenetic role in RA, there is generally poor correlation between different IC tests and between individual tests and clinical features. We have therefore sought differences in the levels of IC detected by the Clq binding assay (ClqBA) and the indirect polymorphonuclear phagocytosis test (IPPT) in the arterial and venous blood of 16 patients with RA and 6 disease control subjects to determine which IC are pathogenetically important. Complement components, IgA, IgG, and rheumatoid factor were also measured. Eight of 10 patients with clinically active RA had higher ClqBA results in arterial blood while IgA IC in the IPPT and most complement components were higher in venous blood. No such differences were seen in patients with inactive RA or controls. These results suggest that IC other than those containing IgA are not formed in limb tissues including the synovium and may explain the variable results previously seen in patients with RA.

Adult↗

PubMed1985

Activation of factor B of the complement system by kallikrein and its light chain.

The cleavage of factor B, a protein of the alternative pathway of complement, by kallikrein was studied. Like factor D, kallikrein can cleave B to generate the alternative pathway C3 convertase C3bBb. When this convertase was formed on erythrocytes previously coated with C3b, lysis was observed indicating that a functionally active C3 convertase was formed. B was also cleaved by kallikrein in the presence of fluid phase C3b, and this resulted in B fragments comparable in size to those generated in the presence of D. The capacity of kallikrein to cleave B is localised in the light chain of the kallikrein molecule, which is the same chain of kallikrein that is responsible for its other enzymatic activities. Since on a molar basis D is much more active then kallikrein in cleaving B, a physiological role for B activation by kallikrein is only likely under certain conditions, and still has to be established.

Binding Sites↗

PubMed1985

The value of complement and immune complex determinations in monitoring disease activity in patients with systemic lupus erythematosus.

Serial serum samples from 33 patients with systemic lupus erythematosus were tested for CH50, C3, C4, and circulating immune complexes. Circulating immune complexes were determined by 5 different assays. Disease activity was determined by a scoring system we devised. On an interpatient analysis, overall disease activity correlated significantly with levels of CH50, C3, and a positive result on C1q binding assay. However, with the exception of depressed C3 levels, the sensitivity, specificity, and predictive values of all the serologic tests were low. An intrapatient analysis revealed a patient-specific activity parameter in 11 of the 33 patients. We conclude that these serologic tests are not reliable in assessing disease activity in patients with systemic lupus erythematosus, although a small subgroup of patients will exhibit a patient-specific activity parameter.

Adolescent↗

PubMed1985

Effects of soluble aggregates of IgG on the binding, uptake and degradation of the C1q subcomponent of complement by adherent guinea pig peritoneal macrophages.

Earlier studies have indicated that C1q, the first subcomponent of complement component C1, is bound to lymphocytes via specific C1q receptor sites. We have recently shown that adherent guinea pig peritoneal exudate macrophages express specific receptors for C1q (Veerhuis, R. et al., Immunology 1985. 54: 801). The present studies were performed to determine whether binding of 125I-labeled human C1q (125I-C1qhu) to adherent guinea pig peritoneal exudate macrophages would also result in ingestion and subsequent degradation of 125I-C1qhu. The binding of 125I-C1qhu to adherent peritoneal macrophages at 4 degrees C is inhibited fully not only by C1qhu and guinea pig C1q (C1qgp) but also by pepsin fragments of C1qhu. The amount of trichloroacetic acid nonprecipitable radioactivity that appeared in the supernatant was used as a measure for the degradation of 125I-C1qhu. 125I-C1qhu is degraded initially into fragments of 25 kDa, after which it is degraded further into small molecular weight peptides. Ingestion of 125I-C1q by the macrophages occurs before the 125I-C1q is degraded. In the presence of limited amounts of soluble aggregates of guinea pig IgG2 (AIgG), a known activator of C1, part of the C1q is bound to the AIgG and all of the AIgG in turn is bound to the cellular Fc receptors leading to an enhanced binding of 125I-C1q to the cells, a binding that was maximal at near equimolar concentrations of 125I-C1qhu and 131I-AIgG. In the presence of a 30-fold excess of AIgG, however, only a small percentage of the AIgG binds to cellular Fc receptors and the interaction of C1q with its receptor is decreased due to competitive inhibition. The results presented in this report thus suggest that free C1q may be eliminated by specific interaction with C1q receptors present on circulating and tissue phagocytoses and, in addition, that in the presence of immune complexes modulation of elimination of C1q may be encountered.

Animals↗

PubMed1985

The autoimmune response in active Heymann's nephritis in Lewis rats is regulated by T-lymphocyte subsets.

In this study the cellular events which are responsible for the induction and suppression of active Heymann's nephritis (HN) in Lewis rats were investigated. Using an enzyme-linked short-term culture assay specific autoantibody production in vitro by lymphoid cells directed against the nephritogenic renal tubular epithelial glycoprotein (RTE-Gp) was measured. By this method it was shown that only the lymph nodes that drain the site of immunization contained autoreactive B cells. Pretreatment with cyclosporine A (Cy-A) or with multiple injections of high doses of antigen in Freund's incomplete adjuvant markedly inhibited the development of disease to a subsequent nephritogenic challenge. In challenged high-dose-tolerant (HDT) rats the autoimmune response was only 5-10% of immunized nontolerant rats. This tolerance could not be transferred by lymphoid cells from Cy-A-treated rats, but could be transferred by lymphoid cells derived from the thymus or spleen of HDT rats. Thus a suppressor cell of thymic origin may be responsible for HDT. Transfer of affinity column-fractionated splenic T cells from HDT rats demonstrated that OX8- helper and OX8+ suppressor T cells are involved in the induction and suppression, respectively, of the autoimmune response in this experimental nephropathy.

Animals↗

PubMed1985

In vivo modulation of rat complement activities by infusion of anti-H antibodies.

Regulation of the activity of the alternative pathway of complement occurs by the plasma proteins I and H. H is able not only to prevent formation of the amplification convertase C3bBb but also to cause the decay-dissociation of Bb from C3bBb. The present studies have investigated the role of H in vivo. Affinity-purified goat (Fab')2-anti H was infused intravenously in rats, and its effect on C4, C3 and CH50 activities was assessed. In addition, H, C3, C4 and B were quantitated by immunochemical methods. H depletion was dependent on the dose of anti-H, and maximal consumption in vivo occurred between 5 and 15 min. A maximum of 51% and 77% hemolytic C3-consumption was seen after 15 min with 3.8 and 8.4 mg anti-H, respectively. The injection of 6.3 mg affinity-purified goat IgG anti-rat H caused 96.8 +/- 0.7% and 85.0 +/- 1.4% consumption of CH50 and C3 hemolytic activity, respectively. Using this dose of IgG anti-rat H, it was found that the clearance in rats of rat erythrocytes sensitized with 8000 molecules of guinea pig IgG2 per E was impaired as compared to the clearance of these intermediates in control rats injected with a comparable dose of normal goat IgG. The results indicate that H functions as a potent regulator of C in vivo and that infusion of anti-H can be used as a method to achieve depletion of circulating complement components.

Animals↗

PubMed1985

Possible involvement of terminal complement complex in active Heymann nephritis.

We investigated whether the appearance of various complement components in renal deposits of immune complexes correlated with the development of proteinuria in rats with active Heymann nephritis. Sequential kidney biopsy specimens and serum samples were obtained from Lewis rats immunized with Fx1A in complete Freund's adjuvant. Circulating antibodies against purified auto-antigen renal tubular epithelial glycoprotein, as measured by ELISA, were found in the circulation together with a diffuse granular deposition of IgG1, IgG2a, and IgG2b in the glomeruli within 2 weeks after immunization. Biopsy specimens taken 4 weeks after immunization showed diffuse deposition of C4 and C3, which indicated that activation of complement by the classical pathway had occurred. The detection of the C5b-9 complex of complement in glomerular deposits coincided with the development of abnormal proteinuria indicating that the glomerular damage in this autoimmune disease may be caused by complement-mediated lesions in the glomerular capillary walls.

Animals↗