[Systemic lupus erythematosus].
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Arthritis↗
Biomedical subjects
M G Malaise
Publications and source records attributed to M G Malaise.
[Immune and non-immune phagocytosis].
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Animals↗
Evidence for a role of accessible galactosyl or mannosyl residues of Fc domain in the in vivo clearance of IgG antibody-coated autologous erythrocytes in the rat.
The potential role of accessible galactosyl or mannosyl residues of IgG in the clearance of IgG-coated autologous red blood cells (IgG-RBCs) by the spleen and the liver was investigated in the rat using rabbit anti-rat RBC IgG antibody molecules differing from each other by their capacity to bind in vitro to peanut agglutinin (PNA) and concanavalin A (Con A), i.e., two lectins that specifically bind to beta-galactosyl and alpha-mannosyl residues of Fc domain, respectively. Those IgG molecules [IgG(PNA) or IgG(Con A)] were separated from the starting anti-RBC IgG antibody batch [IgG(total)] by affinity chromatography on lectin columns. Each IgG-RBC preparation was labeled with 99mTc, and was reinjected iv with autologous rat RBCs labeled with 111In to correct for 99mTc present in the blood contained in each organ. The mean specific spleen uptakes per gram of the three IgG-RBC preparations increased according to the level of RBC sensitization but were at least 10 times higher in each instance than the mean specific liver uptake per gram. Consistent with the clearance curves of IgG(PNA)-RBCs, the mean specific splenic uptake per gram of those RBCs was significantly increased as compared to the same parameters determined using either IgG(total)-RBCs or IgG(Con A)-RBCs. In contrast, the mean specific liver uptakes per gram of IgG(PNA)-RBCs, of IgG(Con A)RBCs, or of IgG(total)-RBCs were not significantly different under otherwise identical experimental conditions. The increase in the splenic removal of IgG(PNA)-RBCs was C3 independent. Furthermore, splenic macrophages isolated from rats were able to bind in vitro significantly more IgG(PNA)-RBCs than IgG(total)-RBCs or IgG(Con A)-RBCs. These data therefore support the concept that, in the rat, the kinetic of removal of IgG-RBCs from the bloodstream by the Fc receptors of splenic mononuclear phagocytes may vary according to the nature of accessible carbohydrates located in the Fc domain of IgG antibody molecules coating the erythrocytes.
Animals↗
The ability of normal human monocytes to phagocytose IgG-coated red blood cells is related to the number of accessible galactosyl and mannosyl residues in the Fc domain of the anti-red blood cell IgG antibody molecules.
The percentage of normal human monocytes (MCs) that are able to form rosettes with, and subsequently phagocytose, IgG-coated red blood cells (RBCs) has been determined in vitro using five batches of anti-RBC IgG antibodies. These antibodies differed from each other by their capacity to bind to lectins recognizing two of the oligosaccharide structures of the Fc domain, namely, peanut agglutinin (PNA) and concanavalin A (ConA) which specifically bind to beta-galactosyl and alpha-mannosyl residues, respectively. The threshold between high (H) and low (L) binding capacities (BC) was arbitrarily fixed at 15% of mean specific binding. For each level of RBC sensitization tested (1500-6000 Ab molecules/one RBC), the percentage of MCs binding at least three IgG-RBCs was similar whatever the IgG Ab preparations used. In contrast, the percentage of MCs capable of phagocytosing at least three IgG-RBCs coated with 3000, 4500 and 6000 IgG/cell, as well as the phagocytosis index (number of IgG-RBCs ingested/100 MCs) of IgG-RBCs coated with 1500, 3000, 4500 and 6000 IgG/cell, were significantly lower (P less than 0.01 at least) using IgG Ab molecules with either [(PNA-H)(ConA-H)] BC, [(PNA-L) (ConA-H)] BC or with [(PNA-L)(ConA-L)] BC than the corresponding values measured using RBCs coated with IgG Ab molecules exhibiting [(PNA-H)(ConA-L)] BC. The binding to MCs of 125I-labelled anti-RBC IgG Ab molecules exhibiting different binding profiles to PNA and to ConA was studied by Scatchard plot analysis. A single class of binding sites was observed in each case. MCs bound a mean of 23,000 IgG molecules with a mean association constant (Ka) for IgG binding of about 1.4 X 10(8) M-1. These data indicate that terminal (and/or accessible) galactosyl and mannosyl residues of IgG Ab molecules play a role in the ingestion of IgG-RBCs by human MCs, despite the fact IgG Ab binding to IgG(Fc) receptors is not significantly affected. Thus, when studying the phagocytosis of IgG-coated RBC by human MC monolayers, the assay should be performed not only using similar RBC/MC ratios and IgG coating values, but also with IgG antibodies having comparable mean PNA and ConA binding capacities.
Adult↗
Effects of mannose and mannose derivatives on the clearance of IgG antibody-coated erythrocytes in the rat.
The effects of D-mannose, mannose dimers, mannan, or lactotransferrin [a glycoprotein containing mannose alpha-(1,6) linkages] infusion on the clearance of IgG-coated, 99mTc-labelled, autologous red blood cells (IgG-RBC) by the spleen and liver were investigated in the rat. Untreated autologous rat RBC labelled with 111In were simultaneously injected to correct for 99mTc present in the blood contained in each organ. In normal rats, the mean specific spleen uptake (per g) of IgG-RBC was about 10 times higher than the mean specific liver uptake (per g). Consistent with the clearance curves of IgG-RBC, the mean specific splenic uptake of those RBC significantly decreased after D-mannose, mannose dimers, mannan, or lactotransferrin injections, compared with that measured in normal rats or in control rats receiving i.v. physiological saline, 5% or 15% glucose. In contrast, the mean specific liver uptake of IgG-RBC remained unchanged under otherwise identical experimental conditions. The splenic blockade induced by mannan and mannose derivatives was dose-dependent, C3-independent and spontaneously reversible within 42 hr. Splenic macrophages isolated from mannose- or mannan-treated animals expressed a decreased receptor activity for the Fc domain of IgG, whereas no consistent effect on the C3 receptors was noted. These data show a transient and specific impairment of the Fc(IgG)-receptor function of rat splenic macrophages after the i.v. injection of D-mannose or of mannose derivatives. They support the concept that simple sugar compounds can exhibit immunoregulatory activities in vivo, as has been already shown in vitro.
Animals↗
Evidence that the phagocytosis mediated by the peanut agglutinin-like activity of IgG(Fc) receptors of human monocytes is selectively modulated by estradiol and natural estrogens.
The percentage of human monocytes (MCs) that are able to form rosettes with, and to phagocytose, IgG-coated sheep red blood cells (IgG-SRBCs) has been first determined in vitro by a classical rosette assay in 12 postmenopausal (PM) women. Half of them never received any suppletive estrogen (E) therapy at the time of testing, whereas the other six were chronically treated with E. Three different preparations of the same anti-SRBC IgG antibody batch were coated to SRBCs: the first one was the starting antibody preparation [IgG(total] and the other two were purified by affinity chromatography either on Sepharose-concanavalin A (Con A) or on agarose-peanut agglutinin (PNA) columns specifically recognizing terminal, and/or accessible, alpha-mannosyl [IgG(Con A)] or beta-galactosyl [IgG(PNA)] residues of the Fc domain, respectively. The three IgG preparations exhibited similar hemagglutinating antibody titers (1/100). All experiments were conducted using a coating range of 5000 to 6000 IgG antibody molecules per SRBC. In PM women with E, the rosetting capacity of autologous MCs (percentage of MCs rosetting at least three IgG-SRBCs), their phagocytosing capacity (percentage of MCs ingesting at least three IgG-SRBCs), and the phagocytosis index (number of SRBCs ingested/100 MCs) were similar for each IgG-SRBC preparation considered. In contrast, in PM women without E, the capacity of MCs to phagocytose IgG(PNA)-SRBCs, as well as the phagocytosis index measured with those SRBCs, was strongly reduced (P less than 0.01 at least), when compared to the same parameters determined using IgG(total)-SRBCs and IgG(Con A)-SRBCs.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Defective in vitro gamma-interferon production in rheumatoid arthritis.
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Adult↗
The spontaneous ability of normal human IgG to inhibit the Fc receptors of normal human monocytes is related to their binding capacity to lectins.
The lectin-binding capacity of 96 normal human IgG, assessed by solid-phase radioimmunoassay, strikingly varied according to the lectin considered. Indeed, half of the IgG samples exhibited peanut agglutinin (PNA)- and pokeweed mitogen-specific binding capacities superior or equal to 4%, whereas less than 15% of IgG similarly bound to concanavalin A (Con A) and to phytohemagglutinin. The ability of those IgG to inhibit the Fc receptor (Fc-R) function of human monocytes, measured by a classical rosette assay, was inversely correlated to their binding ratios to PNA and Con A only. By affinity chromatography, three groups of IgG were separated: the IgG purified on agarose-PNA columns slightly reduced the Fc-R function (40-45% inhibition); the IgG purified on Sepharose-Con A columns exhibited the highest inhibitory properties (80-85% inhibition); the IgG that did not bind to PNA and Con A columns possessed intermediate inhibitory properties (65-70% inhibition). The different effect of IgG on Fc receptors was conserved when monocytes were first treated by trypsin and was unrelated to their specific binding to human monocytes, to their subclasses, and to their C1q- or protein A-binding capacities. Incubation of monocytes with D-galactose (10 mM) significantly improved their capacity to form IgG rosettes, whereas their incubation with D-mannose (10 mM) significantly reduced the Fc-R function. Scatchard plots of 125I-IgG1 myeloma protein binding to monocytes were linear under basal conditions, as well as after a prior incubation of the cells with D-galactose or D-mannose. Monocytes bound about 16,000 molecules of IgG1 per cell in each instance. In contrast, the mean association constant (Ka) for IgG1 binding was 2.59 +/- 0.50 X 10(8) M-1 under basal conditions, 4.4 +/- 0.75 X 10(8) M-1 after D-galactose incubation, and 1.35 +/- 0.50 X 10(8) M-1 after D-mannose incubation. These data suggest that the level of human monocyte Fc-R function blockade induced by human IgG depends mainly on the presence of "accessible" galactosyl or mannosyl residues in the Fc domain and that the modulation of the Fc-R function induced by these carbohydrates is due to a change in the affinity rather than in the number of single class of high-affinity binding sites.
Chromatography, Affinity↗
In vitro effects of thymopentin on the gamma-interferon production by peripheral blood mononuclear cells from normal subjects and from patients with rheumatoid arthritis.
The in vitro production of gamma-interferon (gamma-IFN) by peripheral blood mononuclear cells (MNC) was measured using a specific radioimmunoassay in 16 patients presenting with active rheumatoid arthritis (RA), in 14 patients with inactive disease, and in 36 control subjects (CS). Unstimulated cultures produced undetectable levels of gamma-IFN and did not incorporate tritiated thymidine. In response to phytohemagglutinin (PHA) 0.2 microgram/ml, MNC from active RA produced 9 times less, and under PHA 2.5 micrograms/ml, 4 times less gamma-IFN than did MNC from inactive RA or from CS. The uptake of tritiated thymidine was, however, similar in the 3 groups. In unstimulated cultures of the 3 groups, thymopentin (TP-5), at all concentrations tested, did not influence either the levels of gamma-IFN or the uptake of tritiated thymidine. In the presence of PHA 0.2 microgram/ml and TP-5, lambda-IFN levels were increased in CS, unchanged in inactive RA and reduced in active RA, whereas no changes were observed in the uptake of tritiated thymidine. Our results show that under our experimental conditions, TP-5 was able to increase the levels of gamma-IFN produced by normal MNC in vitro, but could not reverse the profound defect observed in active RA.
Adult↗
Thymopoietin and thymopentin enhance the levels of ACTH, beta-endorphin and beta-lipotropin from rat pituitary cells in vitro.
Thymopoietin and thymopentin are well characterized polypeptides influencing immunoregulation by several mechanisms. Proposed as a therapy in diseases with major immune abnormalities such as rheumatoid arthritis, thymopentin improved within 2 weeks some clinical parameters as pain and joint swelling. The hypothesis that this spectacular effect could be mediated through interactions with anti-inflammatory (ACTH) and pain relieving (beta-endorphin) hormones producing cells was tested on the rat isolated pituitary cell model. Thymopentin and thymopoietin can enhance in vitro the levels of ACTH, beta-endorphin and beta-lipotropin in a time- and dose-dependent fashion for physiological concentrations ranging from 10(-12) to 10(-8) mol/l. The action on pituitary cells was restricted to those molecules as no changes occurred in LH, FSH, GH, TSH and PRL levels, after otherwise identical experimental conditions.
Adrenocorticotropic Hormone↗
Methods of clinical and biological assessment of rheumatoid arthritis.
Inflammation has long been recognised as notoriously difficult to measure both in clinical practice and in the laboratory. Of all the cardinal features of inflammation, pain relief is really what the patients want, and among disabled persons, rheumatic patients are the only ones who must cope with chronic pain. The rheumatologist, however, is also interested in other parameters that are thought to reflect improvement of the inflammatory process. The methods used to clinically assess rheumatoid arthritis (RA) should share the following four parameters: validity, sensitivity, reliability and simplicity. Unfortunately, at present, no single ideal method is capable of accurately reflecting disease activity in RA. The measurement of pain relief by the visual analogue scale, the determination of the Ritchie index and the duration of morning stiffness, plus patient assessment of global response should be enough to detect clinical activity of the drug in RA. If we are working with slow-acting drugs or so-called disease modifying antirheumatic drugs (DMARDs), it should be appropriate to include X-ray analysis and laboratory tests in the evaluation. A reduction in the number of fresh erosions and/or the healing of present erosions can give reliable information on the capacity of the drug to really modify the course of the disease. At present, measurement of the erythrocyte sedimentation rate and of acute phase serum proteins seems to offer the best available assessment during early weeks of therapy. The other biological tests are of limited value in reflecting or predicting a beneficial clinical response to DMARDs.(ABSTRACT TRUNCATED AT 250 WORDS)
Arthritis, Rheumatoid↗
Increased concanavalin A-binding capacity of immunoglobulin G purified from sera of patients with rheumatoid arthritis.
A solid phase radioimmunoassay was set up for direct measurement of the binding capacity of human IgG to three lectins recognizing different carbohydrates of the Fc domain, i.e. peanut agglutinin (PNA), Concanavalin A (Con A) and pokeweed mitogen (PWM) which mainly bind to beta-galactose, alpha-mannose and dimers of N-acetyl-beta-glucosamine respectively. The mean specific binding of the 96 normal IgG tested to PNA and to PWM was statistically higher (P less than 0.001) than that to Con A, whereas no significant differences were observed between the mean specific bindings to PNA and to PWM. A statistically significant linear negative correlation could be established only between the relative bindings (expressed in percentage of the total binding to the three lectins) to PNA and to PWM (r = -0.65, P less than 0.001). The mean specific binding of IgG purified from 34 patients suffering from rheumatoid arthritis (RA) to PNA and to Con A was statistically higher (P less than 0.001) than that reached with PWM, whereas no significant differences were noted between their mean binding capacities to PNA and to Con A. When compared to normal IgG, only four out of 34 RA IgG exhibited a significantly higher binding capacity to PNA, whereas all but one RA IgG possessed a significantly higher binding capacity to Con A. Accordingly, the mean specific binding of RA IgG to Con A was significantly higher than that of normal IgG (P less than 0.001). Besides (and contrary to normal IgG), a statistically significant negative linear correlation was noted between the relative bindings of RA IgG to PNA and to Con A (r = -0.89, P less than 0.001). All the five RA IgG tested exhibited an abnormal circular dichroism. Our data suggest that, by altered steric conformation and glycosylation, mannosyl-residues of RA IgG become prominent or terminal or both, and are therefore able to react more effectively with Con A than normal IgG do.
Adult↗
In vitro studies on the Fc-receptor function of mononuclear phagocytes in rheumatoid arthritis: relation between the Fc-receptor blockade and the concanavalin A-binding capacity of autologous immunoglobulin G.
The Fc-receptor (Fc-R) function of monocytes isolated from 19 control subjects and from 30 patients presenting with a rheumatoid arthritis (RA) was assessed in vitro by a classical rosette assay using IgG-coated sheep red blood cells. In RA patients, the percentage of monocytes forming rosettes was significantly lower than in controls (34.4 +/- 20.4 versus 67.4 +/- 4.5%; P less than 0.001). The blockade observed was reversed by a prior trypsin treatment of RA monocytes, the percentage of recovery being correlated with the IgG plasma levels. Besides, IgG purified from the serum of four RA patients bound a mean of 7.3, 5.2, 1.6, and 1.6 times more than normal IgG did onto concanavalin A (Con A), peanut agglutinin (PNA), phytohemagglutinin (PHA), and pokeweed mitogen (PWM), respectively. Although similar amounts of 125I-labeled normal and RA IgG were bound to normal monocytes, RA IgG inhibited more efficiently than normal IgG the Fc-R function of normal monocytes, for all concentrations tested (10 to 100 micrograms/100 microliters). A prior treatment of RA IgG by alpha-mannosidase, but not by beta-galactosidase, significantly reduced their inhibitory properties. The incubation of monocytes with D-mannose or mannan reduced their capacity to form rosettes. The percentage of monocytes forming rosettes in the presence of both mannan and normal IgG was significantly lower than that measured in the presence of normal IgG only. On the contrary, the rosetting capacity of monocytes in the presence of both RA IgG and mannan was the same as that calculated in the presence of RA IgG only. The inhibitory effect of RA IgG was not related to their abnormal circular dichroism. Our data suggest that the greater ability of RA IgG to block the Fc-R function of monocytes probably depends on the presence of a greater number of accessible mannosyl residues on the glycosidic side chains located in the Fc domain of the molecules.
Adult↗
Elevated antigalactosyl antibody titers reflect renal injury after gold or D-penicillamine in rheumatoid arthritis.
Titers of circulating antigalactosyl antibodies (a-Gal Ab) were assessed by passive hemagglutination using rabbit red blood cells in 40 normal subjects, in 14 patients with immunodeficient states, in 47 patients with active rheumatoid arthritis (RA), and in 15 patients with an Henoch-Schönlein disease (HS). Titers of controls ranged from 1:16 to 1:64. All immunodeficient patients exhibited very low titers (1:1). On the contrary, the existence of an enhanced humoral immune response status, as observed in RA, was not reflected by a parallel increase of a-Gal Ab titers. However, in this disease, a strong relationship existed between titers exceeding control values (greater than 1:64) and the prior occurrence of renal injury under gold or D-penicillamine therapy. Lastly, the discovery of elevated titers (greater than 1:64) in HS only when renal involvement occurred further suggests that such antibodies reflect a renal injury.
Acquired Immunodeficiency Syndrome↗
Treatment of active rheumatoid arthritis with slow intravenous injections of thymopentin. A double-blind placebo-controlled randomised study.
41 patients with active rheumatoid arthritis entered a placebo-controlled double-blind randomised study in which 21 received slow intravenous injections (given in fractions over 10 min) of thymopentin (TP-5) 50 mg 3 times a week for 3 consecutive weeks and 20 received placebo in the same way. After 3 weeks of treatment the TP-5 group showed improvement (p less than 0.05 or p less than 0.01) in all but one of the clinical variables tested. There was improvement in the number of joints painful at rest, the number of joints painful on motion, scores for tenderness on pressure and swollen joints, severity of pain on awakening and morning stiffness, and right-hand grip strength; left-hand grip strength remained unchanged. In the placebo group, only morning stiffness improved significantly. The intergroup comparisons showed that thymopentin was significantly better than placebo in reducing tenderness, joint swelling, severity of pain on awakening, and disease activity. 4 weeks after the end of the TP-5 therapy, the improvement was still present although there was a trend towards relapses. No significant modifications occurred in any of the laboratory variables tested and only minor side-effects were experienced by either group.
Adult↗
The Fc-receptor function of human mononuclear phagocyte system: physiological role, alteration in immune diseases and modulation.
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Arthritis, Rheumatoid↗
In vivo studies on the mononuclear phagocyte system Fc receptor function in rheumatoid arthritis. Correlations with clinical and immunological variables.
The mononuclear phagocyte system Fc receptor function was assessed in 13 control subjects and 17 patients with rheumatoid arthritis (RA) by intravenous injection of IgG coated (IgG-RBC) or of heat-damaged (HD-RBC) 99mTc-labeled autologous erythrocytes. Although the clearance half-times of control and RA erythrocytes were not significantly different, the spleen to liver uptake ratios per surface area (S/Ls), determined by quantitative scintigraphic analysis, were significantly lower in RA patients than in controls. The S/Ls were significantly correlated with the Steinbrocker stages (r = 0.92; p less than 0.01), the disease duration (r = 0.73; p less than 0.01) and the total immunoglobulin levels (r = 0.73; p less than 0.01). The Clq binding activity of the sera was inversely correlated with the spleen (r = 0.90; p less than 0.01) and liver uptakes (r = 0.73; p less than 0.02). Our results therefore show an alteration of the Fc receptor function of splenic and hepatic mononuclear phagocytes in RA patients.
Adult↗