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L A Hebert

Publications and source records attributed to L A Hebert.

At least 55 records · Page 3Linked to original sources
PubMed1992

Stimulating erythropoiesis increases complement receptor expression on primate erythrocytes.

Erythrocyte complement receptors (CR) are unique to primates and play a role in the clearance of immune complexes from the circulation. Immune complex-mediated diseases (e.g., systemic lupus erythematosus, SLE) cause decreased erythrocyte CR levels, resulting in decreased capacity of the erythrocytes to bind immune complexes that form in the circulation. Thus, raising erythrocyte CR levels might benefit patients with immune complex-mediated diseases. Because young erythrocytes express more CR than old erythrocytes, increasing erythropoiesis should increase the average number of CR expressed per erythrocyte. The present study was undertaken to test that hypothesis. Erythropoiesis was stimulated in nine cynomolgus monkeys (CYN) by weekly phlebotomy (30% of blood volume was removed, erythrocytes were discarded, and leukocytes were returned to the animal) for 8 weeks. Sham phlebotomy (30% of blood removed, then all components returned to the animal) was carried out weekly in four additional CYN for a period of 4 to 8 weeks. Sham phlebotomy did not change any of the parameters measured. However, phlebotomy resulted in a progressive increase in the mean number of CR expressed per erythrocyte (CR/erythrocyte): 2780 +/- 700 to 4230 +/- 820, P less than 0.0005. The increase in erythrocyte CR was first detected at about 2 weeks after the start of phlebotomy and was sustained through the course of phlebotomy. The increase in CR/erythrocyte included an increase in the percentage of erythrocyte expressing CR in clusters (37.9 +/- 6.4 vs 50.8 +/- 8.7%, P less than 0.01) as demonstrated by a flow cytometry study of the binding of fluorescent beads coated with anti-CR1 antibody. No significant change in leukocyte or platelet counts were observed. We conclude that stimulating erythropoiesis causes an increase in CR/erythrocyte. The magnitude of the increase suggests that it could be biologically significant.

Animals↗
PubMed1992

Renal autotransplantation in the loin pain-hematuria syndrome: a cautionary note.

The current literature suggests that renal autotransplantation is nearly uniformly effective in controlling the severe and debilitating pain of the loin pain-hematuria syndrome (LPHS). However, we report two patients thought to have this syndrome in whom renal autotransplantation did not result in long-term control of pain. In case 1, autotransplantation resulted in immediate cessation of pain; however, the flank pain recurred 7 1/2 months later. The recurrent pain was also severe and debilitating, requiring narcotic medications for control. In case 2, autotransplantation of the left kidney resulted in chronic pain in the left pelvic area, the site of the autotransplanted kidney. In addition, the patient continued to experience chronic discomfort in the left flank and along the flank incision. One year after autotransplantation, the patient still requires multiple daily doses of narcotic medications for pain control. Our two patients represent the 13th and 14th reported patients subjected to renal autotransplantation for management of LPHS. They represent only the third and fourth reported patients with recurrence of pain after renal autotransplantation. Because studies with negative results are less likely to be reported in the literature than studies with positive results, it is possible that the literature overestimates the effectiveness of renal autotransplantation in the LPHS. To assess the true effectiveness of renal autotransplantation in LPHS, a survey of patients with LPHS who have undergone renal autotransplantation needs to be performed.

Adult↗
PubMed1992

Body at work.

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Cumulative Trauma Disorders↗
PubMed1991

Serum C3 levels are diagnostically more sensitive and specific for systemic lupus erythematosus activity than are serum C4 levels. The Lupus Nephritis Collaborative Study Group.

To determine whether serum C3 or C4 is more likely to be normal during systemic lupus erythematosus (SLE) remission and abnormal during SLE relapse we studied twelve SLE patients who presented with severe nephritis. The patients were followed long term (12 to 77 months) through multiple relapses (N = 41) and remissions (N = 13) defined by protocol. A total of 471 serum samples were obtained at defined intervals during these relapses and remissions and were analyzed for C3 and C4 levels by two different methods: nephelometry (N) and radial immunodiffusion (R). During SLE remission (defined by protocol and without reference to serum complement levels), C3 measured by N-assay (C3N) and by R-assay (C3R) tended to be normal (specificity of 93% and 71%, respectively). By contrast, C4 measured by N-assay (C4N) and by R-assay (C4R) showed no such tendency (specificity of 50% for both C4N and C4R). During SLE relapse (defined by protocol and without reference to serum complement levels), C3N and C3R were more likely to be abnormal (sensitivity 95% and 85%, respectively) compared with C4N and C4R (sensitivity 56% and 54%, respectively, P less than 0.001 compared with corresponding values for the C3 assay). Analysis by receiver-operator characteristic (ROC) curves demonstrated that the reduced diagnostic sensitivity of C4 versus C3 is not explained by use of an inappropriate lower limits of normal (LLN) for C4.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Diagnostic significance of hypocomplementemia.

Hypocomplementemia is an important marker for the presence of IC-mediated disease and can be used to assess disease activity. However, in interpreting the clinical significance of hypocomplementemia, the following must be kept in mind: 1) There are numerous non-immunologic conditions that also can cause hypocomplementemia. Furthermore, some of these conditions can cause a multisystem disease that, along with the hypocomplementemia, can closely resemble an IC-mediated systemic vasculitis. Furthermore, these nonimmunologic conditions that lower serum complement levels can complicate the course of patients with inactive IC-mediated disease, spuriously indicating that the disease is active. The most relevant of these differential diagnostic problems are listed in Table 2. 2) There are a few conditions (for example, pregnancy) that can raise serum complement levels, thereby possibly obscuring the presence of a disorder (such as, active SLE) that is lowering complement levels. 3) There are some conditions that might be expected to lower serum complement levels, because of their effect on protein metabolism, but do not. Nephrotic syndrome, and moderately poor nutrition are examples. All of these factors should be considered when interpreting results of serum complement levels in a given patient.

Complement System Proteins↗
PubMed1991

Measurement of SC5b-9 in urine in patients with the nephrotic syndrome.

In passive or active Heymann nephritis (HN) in the rat, the immune complexes that form in the glomerular subepithelial space result in complement activation and the urinary (U) excretion of S protein-membrane attack complex (SC5b-9, MAC). Because of the similarities between HN in rats and membranous nephropathy (MN) in humans, it has been suggested that measurement of SC5b-9 in urine (UMAC) could be useful in assessing the immunologic activity of MN in patients. The present study was undertaken in normal individuals and in patients with nephrotic syndrome to determine: 1) the conditions of urine collection and preservation needed for accurate measurement of UMAC for clinical purposes; and 2) whether UMAC levels are a sensitive and/or specific test for MN. In studies conducted on urine specimens from patients with increased UMAC levels, we found that UMAC in freshly voided urine was stable for at least three hours at 37 degrees C, with or without the addition of the enzyme inhibitors that were used to stabilize UMAC levels in the studies of HN in the rat. Urine pH, leukocytes and erythrocytes, over the ranges usually encountered, did not influence UMAC levels. However, freezing urine at -70 degrees C artifactually raised UMAC levels (1500 +/- 550 to 1800 +/- 580 SE ng/ml, P less than 0.001 by paired t-test). Normal urine contained low UMAC levels: 80 +/- 3 ng/mg urinary creatinine (UCr). By contrast, patients with glomerulopathies tended to have elevated UMAC levels: 18 of 38 patients had levels that ranged from 200 to 20,000 ng/mg UCr.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Experimental immune complex-mediated glomerulonephritis in the nonhuman primate.

This study was undertaken to develop a model of immune complex (IC)-mediated glomerulonephritis (GN) in the nonhuman primate that could be used in subsequent studies to examine critically the role of the erythrocyte complement receptor (E-CR) in the pathogenesis of IC-mediated disease. Cynomolgus monkeys were chosen for study because they constitutively express E-CR levels that are either less than, equal to, or greater than that seen in normal man. After immunization with bovine gamma globulin (BGG), the GN induction protocol was begun in 10 cynomolgus by initiating daily i.v. administration of BGG in amounts sufficient to achieve or exceed antigen/antibody equivalence (assessed by the quantitative precipitin assay) for precipitating antibody present in the plasma volume. We found that within eight weeks of daily BGG administration of all the cynomolgus developed IC-mediated GN, irrespective of the initial E-CR level of the animals. However, the high E-CR cynomolgus tended to receive the higher BGG doses because of higher initial antibody levels to BGG. When the total number of glomerular deposits (determined by morphometric studies) per total BGG dose for each animal was plotted against the initial CR/E of that animal, there was a tendency for the animals with higher CR/E levels to have a lower number of glomerular deposits/BGG dose (r = 0.62, P = 0.06). Also, the total number of glomerular deposits correlated with the severity of the GN. During the early weeks of the GN induction protocol, the IC that formed in vivo (assessed by infusion of 125I-BGG) bound in large amounts to the circulating erythrocytes of the cynomolgus with medium or high E-CR levels. However, when tested after the onset of heavy proteinuria, which occurred between weeks 5 and 8 of daily BGG administration, the IC that formed in the circulation bound only poorly to circulating erythrocytes. By this time the E-CR levels had declined to 43 +/- 9% of initial values (P less than 0.01). This study demonstrates that: 1) A workable model of IC-mediated GN has been developed in the nonhuman primate. 2) During the induction of GN, CR/E and the ability of the erythrocyte to bind IC in vivo are decreased significantly. This suggests that an intact E-CR system could play a role in the protection against IC-mediated disease. However, further study will be needed to test that hypothesis critically. The present model should be useful in such studies.

Animals↗
PubMed1990

Evaluation of the mechanisms responsible for the reduction in erythrocyte complement receptors when immune complexes form in vivo in primates.

Patients with immune complex-(IC) mediated diseases frequently have low levels of CR1 on E. The present study was undertaken to determine the role of circulating IC in causing low E-CR1 levels. E-CR1 were enumerated by measuring the binding of anti-CR1 mAb (E11) and rabbit anti-CR1 antibodies (RbaCR1) to E. In addition, the distribution of CR1 among E was assessed by flow cytometry of E stained with E11 and RbaCR1 and by evaluating the binding of E11-coated fluorescent beads (E11-beads) to E. E11-beads bind to clusters of CR1 on E. Five cynomolgus monkeys (CYN) were preimmunized to bovine gamma-globulin (BGG). E-CR1 changes in these animals were assessed: 1) acutely, during the first 60 min after an infusion of BGG and 2) chronically, during daily administration of BGG infusions over 2 wk. Acutely, there was a decrease in the number of E-CR1 as measured by E11 binding to E (E11/CR1). This decrease was not attributable to occupancy of CR1 by IC because the decrease in E11/CR1 number persisted after the IC had been cleared from E. By comparing the E11/CR1 levels in arterial blood to hepatic vein blood (n = 5), or in pulmonary artery blood (n = 1), we determined that the acute decrease in E11/CR1 number did not occur whereas E circulated through liver, spleen, or lung. The decrease in E11/CR1 number required the binding of IC to E because it did not occur after BGG was infused into nonimmunized CYN (n = 2) or into a preimmunized complement-depleted CYN. The decrease in E11/CR1 number was not due to loss of CR1 from E because E11/CR1 number recovered 24 h after infusion of BGG and in addition, enumeration of E-CR1 with RbaCR1 and E11-beads did not reflect a decrease in E-CR1 number. After several daily BGG infusions there was a persistent decrease in E-CR1 levels and that decrease appeared to be mainly the result of loss of CR1 from E because the decrease was confirmed with all methods of E-CR1 measurement and because E-CR1 levels recovered only slowly after BGG infusions were discontinued. Both in vitro and in vivo IC bound preferentially to subpopulations of E, identified by their ability to bind multiple E11-beads and by their high intensity staining with the anti-CR1 antibodies E11 and RbaCR1.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Immune complexes bind preferentially to specific subpopulations of human erythrocytes.

Primate erythrocytes have complement receptors (CR1) that, both in vivo and in vitro, bind immune complexes (IC) opsonized with C3b. The present study was undertaken to determine whether the ability of human erythrocytes to bind IC is a characteristic shared by all erythrocytes. Binding of IC to erythrocytes probably involves the interaction of several C3b molecules with several CR1 clustered in small areas of the erythrocyte surface. To identify IC binding CR1 clusters, we first assessed the binding to erythrocytes of fluorescein-labeled polystyrene beads coated with monoclonal anti-CR1 antibodies (anti-CR1-beads) and second, performed IC. The binding of these ligands to erythrocytes was evaluated by immunofluorescence microscopy and flow cytometry. We found that only a fraction of erythrocytes from normal individuals bound anti-CR1-beads specifically and the percentage of erythrocytes able to bind beads increased with increasing numbers of CR1 per erythrocyte. However, the number of anti-CR1-beads bound per erythrocyte varied among cells from the same individual. We demonstrated further that the erythrocyte binding sites for anti-CR1-beads are also binding sites for opsonized IC. This was shown by demonstrating that anti-CR1-beads inhibited the binding of opsonized IC to erythrocytes and opsonized IC inhibited the binding of anti-CR1-beads to erythrocytes. Incubation of erythrocytes with opsonized IC, followed by FITC-labeled secondary antibodies, confirmed that indeed only a fraction of erythrocytes is capable of binding opsonized IC and that the binding sites for IC occupy small regions on the erythrocyte membrane. By contrast, we demonstrated that greater than 90% of erythrocytes express CR1. In conclusion, only some erythrocytes have the capacity to bind IC. Differences in the ability of erythrocytes to bind IC are probably related to differences in the clustering of CR1 in the erythrocyte membrane. Anti-CR1-beads identify erythrocyte binding sites for IC. These beads should prove useful to assess the changes that occur in the erythrocyte CR1 after exposure to IC in vivo.

Antibodies, Monoclonal↗
PubMed1990

On the natural tendency to progressive loss of remaining kidney function in patients with impaired renal function.

Patients who lose more than 50% of their functioning renal mass are at risk to develop progressive deterioration of their remaining kidney function, even though the process that caused the original loss of kidney function may no longer be present. The glomerular capillary hyperperfusion, hypertension, and hyperfiltration that occur in the surviving nephrons may play an important role in the natural tendency for renal function to deteriorate. Nevertheless, recent studies suggest that these glomerular hemodynamic events may not be the final common pathway for the natural deterioration of renal function, as was once thought. With regard to the general management of patients with impaired renal function, recent evidence suggests that controlling systemic blood pressure, reducing dietary protein and phosphorus intake, and controlling hyperlipidemia may be effective in slowing the loss of renal function.

Hormones↗
PubMed1990

Immune complex erythrocyte complement receptor interactions in vivo during induction of glomerulonephritis in nonhuman primates.

Multiple lines of evidence indicate that the erythrocyte complement receptor (E-CR) system, which is unique to the primate, may play an important role in the clearing of immune complexes (ICs) from the circulation. However, all previous investigations of IC/E-CR interactions in vivo have involved the study of small amounts of preformed or passively formed ICs interacting with E-CR that were numerically in vast excess. The present study was undertaken to assess IC/E-CR interactions under conditions in which large amounts of ICs were formed in the circulation, amounts that when sustained for several weeks by daily intravenous administration of antigen resulted in the development of active glomerulonephritis. Twelve cynomolgus monkeys with E-CR levels ranging from 25 to 5000 mean CRs per erythrocyte (CR/E) were actively immunized to BGG, and 6 to 12 weeks later they were studied first at low levels of IC formation in vivo (L-Protocol experiments, mean 125I-labeled BGG dose of 0.04 mg/kg given over 1 minute, a marked antibody excess state) and then at high levels of IC formation in vivo (H-Protocol experiments, mean 125I-labeled BGG dose 4.9 mg/kg given over 10 minutes, a state approximating antigen-antibody equivalence). Cynomolgus monkeys with fewer than 100 CR/E showed no evidence of binding of ICs to erythrocytes with either low-dose or high-dose 125I-labeled BGG. However, cynomolgus monkeys with greater than 450 CR/E showed significant binding of ICs to erythrocytes: mean peak binding of 125I-labeled BGG to erythrocytes was 22.1% +/- 1.1% in the L-Protocol experiments and 33.4% +/- 8.0% in the H-Protocol experiments. During H-Protocol experiments, mean CR/E, measured by using a monoclonal anti-human CR1 antibody, decreased acutely (mean decrease 36.2% +/- 14.1%, p less than 0.05), with recovery of E-CR levels within the next 24 to 72 hours. The acute decrease in E-CR levels could not be accounted for by occupancy of E-CR by ICs or by change in hematocrit. In summary, the present study demonstrates that during the development of glomerulonephritis, IC/E-CR interactions occur and the E-CR system is altered by these interactions. The present observations are consistent with the hypothesis that the E-CR system may play a role in the pathogenesis of IC-mediated disease in the primate.

Animals↗
PubMed1989

Human erythrocytes inhibit complement-mediated solubilization of immune complexes.

Incubation of precipitable immune complexes (IC) with fresh human serum or guinea pig serum resulted in solubilization of IC. When packed human E were added to human serum or guinea pig serum, binding of IC to the E occurred and IC solubilization was significantly inhibited. By contrast, SRBC did not bind IC nor inhibit IC solubilization. Because IC binding to human E is mediated by CR type 1 (CR1) we evaluated whether CR1 was responsible for the inhibition of IC solubilization. Human E were treated with trypsin or anti-CR1 mAb. Both treatments abrogated IC binding to human E but did not affect the ability of the human E to inhibit IC solubilization. Human E inhibited C activation by IC. Thus, incubation of IC in human serum caused significant activation of C3 and C5, but not C4. However, when IC were incubated in whole blood or with isolated human E and serum, C3 activation by IC was inhibited significantly. In addition, we demonstrated that the C3b generated during C activation by IC deposited on both IC and human E. Thus, human E may compete for nascent C3 generated during C activation by IC. In conclusion, human E inhibit both complement-mediated solubilization of IC and C activation by IC.

Antigen-Antibody Complex↗
PubMed1988

Disposition of IgA-containing circulating immune complexes.

Two fundamentally different mechanisms may account for the glomerular immune deposits in IgA nephropathy (IgAN): (1) deposition of circulating immune complexes and (2) the in situ formation of immune complexes. In this review the experimental evidence for and against an important role of circulating IgA-containing immune complexes in the pathogenesis of IgAN is summarized. Several physical characteristics, including size, lattice composition, and electrical charge, may influence the deposition of immune complexes in the renal mesangium. Furthermore, the likelihood of deposition of circulating IgA-containing immune complexes in vulnerable locations (such as the kidney) may be increased because of their impaired removal from the circulation by macrophages of the liver and spleen and the erythrocyte-immune complex clearing mechanism. However, the relative contributions of these factors to the pathogenesis of IgAN remain speculative.

Animals↗