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Biomedical subjects

D S Pisetsky

Publications and source records attributed to D S Pisetsky.

At least 127 records · Page 7Linked to original sources
PubMed1991

Specificity of anti-DNA antibodies induced in normal mice by immunization with bacterial DNA.

To determine the specificity of anti-DNA antibodies induced in normal mice by immunization with bacterial DNA, sera from BALB/c mice immunized with single-stranded DNA from Escherichia coli (EC) were tested for binding to a panel of synthetic DNA and RNA homopolymers as well as duplexes. Results of these studies indicate that sera from EC DNA immunized mice preferentially bind certain DNA and RNA homopolymers as well as DNA duplexes. Furthermore, the specificity of the antibodies from immunized mice resembled those of sera from autoimmune MRL-lpr/lpr mice in terms of the synthetic antigens recognized, although some differences were noted in the magnitude of the response to individual duplexes. These results suggest that anti-DNA antibodies induced by bacterial DNA bind to DNA structures dependent on both the base and the sugar phosphate moieties of the nucleic acid antigen and may resemble some anti-DNA antibodies expressed in spontaneous autoimmune disease in these binding properties.

Animals↗
PubMed1991

Physiologic role for enhanced renal thromboxane production in murine lupus nephritis.

To investigate the physiologic significance of enhanced renal thromboxane production in murine lupus nephritis, we measured renal hemodynamics and eicosanoid production in MRL-lpr/lpr mice from 8 to 20 weeks of age. Over this age range, MRL-lpr/lpr mice develop an autoimmune disease with nephritis similar to human systemic lupus erythematosus (SLE). In these studies, glomerular filtration rate (GFR) and PAH clearance (CPAH) decreased progressively with age in MRL-lpr/lpr mice, but not in controls. This impairment of renal hemodynamics was associated with increased renal thromboxane production, as well as increased excretion of both thromboxane B2 (TxB2) and 2,3-dinor TxB2 in urine. There was an inverse correlation between renal thromboxane production in MRL-lpr/lpr mice and both GFR and CPAH. Furthermore, there were positive correlations between thromboxane production by the kidney and both the severity of renal histopathology and serum anti-DNA antibody levels measured in individual animals. Enhanced urinary excretion of TxB2 and the development of renal dysfunction also coincided temporally with the appearance of increased levels of interleukin 1 beta (IL-1 beta) mRNA in renal cortex. Acute administration of the specific thromboxane receptor antagonist GR32191 to MRL-lpr/lpr mice restored GFR to normal in early stages of the autoimmune disease. However, in animals with more advanced nephritis, the effect of acute thromboxane receptor blockade on renal hemodynamics was less marked. We conclude that thromboxane A2 is an important mediator of reversible renal hemodynamic impairment in murine lupus, especially in the early phase of disease.

Age Factors↗
PubMed1991

The specialized centers of research in rheumatoid arthritis. Recent progress and prospects for future advances.

Specialized Centers of Research (SCOR) in arthritis are interdisciplinary research programs to investigate disease pathogenesis as well as advance diagnosis and treatment. A recent meeting of investigators from the three SCOR programs in rheumatoid arthritis demonstrated progress in several important research areas. Because of the multiplier effects of SCOR programs, new investigators have been enlisted into arthritis research as issues related to this disease become a focus of investigation throughout universities and medical centers. Continued progress by the SCOR programs should provide new targets for therapeutic intervention as well as strategies for monitoring disease activity.

Academic Medical Centers↗
PubMed1991

Genetic control of inflammatory arthritis and glomerulonephritis in congenic lpr mice and their F1 hybrids.

MRL-lpr/lpr mice spontaneously develop a complex immunological disease characterized by glomerulonephritis, inflammatory erosive arthritis and the production of rheumatoid factors (RF) and anti-DNA antibodies. We have previously reported that, of congenic lpr strains, only MRL-lpr/lpr mice develop synovial pathology suggesting that both the lpr gene and another gene(s) in the MRL background are necessary for the development of arthritis. To define further the genetics of arthritis and its relationship to glomerulonephritis and autoantibody production, we studied disease expression in MRL-lpr/lpr and C57BL/6-lpr/lpr mice and their offspring (BM-lpr/lpr and MB-lpr/lpr). At 6 months of age these mice were killed and bled, and their kidneys and knee joints were removed for pathological studies. Fourteen of 28 MB-lpr/lpr mice displayed synovial hypertrophy, while eight of 28 had significant synovial inflammation. BM-lpr/lpr mice showed similar changes: nine of 22 and eight of 22 exhibited synovial hypertrophy and inflammation respectively. Joints from MRL-lpr/lpr mice revealed 13 of 17 with synovial hypertrophy and 12 of 17 with inflammation, while none of 14 B6-lpr/lpr mice had synovial changes. Renal pathology was minimal in the F1 mice with only mild hypercellularity in seven of 21 MB-lpr/lpr and five of 22 BM-lpr/lpr mice. All MRL-lpr/lpr mice, in contrast, had marked glomerular changes with 12 of 17 exhibiting glomerular crescents. Only one F1 mouse had both arthritis and renal abnormalities. IgM RF levels were elevated in all four experimental groups, but did not correlate with the presence or severity of arthritis. IgG RF levels were elevated in the MB-lpr/lpr and MRL-lpr/lpr mice, but did not correlate with the degree of arthritis. These results indicate that renal disease and arthritis develop independently in lpr mice, possibly on a genetic basis, and that the presence and titer of autoantibodies do not correlate with tissue injury.

Animals↗
PubMed1991

Systemic lupus erythematosus.

Systemic lupus erythematosus is a prototypic autoimmune disease characterized by antinuclear antibody production. In recent investigations, the contributions of various polymorphic immune response gene systems to disease pathogenesis have been analyzed. Unique cellular and molecular studies have also established the role of 'autoantigen drive' in autoantibody induction and its relationship to polyclonal B-cell activation.

Animals↗
PubMed1991

Enhanced renal leukotriene production in murine lupus: role of lipoxygenase metabolites.

To investigate the potential role of leukotrienes in murine lupus, we measured renal hemodynamics and renal leukotriene production in MRL-lpr/lpr mice at 12 and 20 weeks of age. Over this age range, these animals develop overt manifestations of autoimmune disease with nephritis similar to human SLE. In the current study, we demonstrated that glomerular filtration rate (GFR) and PAH clearance (CPAH) deteriorated with age in MRL-lpr/lpr mice, but not in MRL(-)+/+ controls. Impaired renal hemodynamic function in MRL-lpr/lpr mice was associated with enhanced ionophore-stimulated production of both leukotriene B4 (LTB4) and leukotriene C4 (LTC4) by preparations of renal cortex. There was a significant inverse correlation between GFR and in vitro production of both LTC4 and LTB4 in kidneys from MRL-lpr/lpr mice, but not in control animals. In addition, in vitro LTC4 production was correlated with the severity of renal histomorphologic abnormalities. Administration of the specific peptidoleukotriene receptor antagonist SKF104353 to 20 week old MRL-lpr/lpr mice significantly improved both GFR and CPAH, whereas this agent had no effect of renal hemodynamics in MRL(-)+/+ controls. These results suggest that renal production of LTC4 and LTB4 is increased in MRL-lpr/lpr mice with nephritis, and that enhanced production of peptidoleukotrienes causes reversible renal dysfunction. Increased leukotriene production within the kidney may therefore be important in the pathogenesis of lupus nephritis.

Animals↗
PubMed1991

Autoantibodies and their idiotypes.

Idiotypes are serologically defined markers in the variable region of an antibody molecule. In the study of autoimmunity, these markers have been valuable probes in defining patterns of autoantibody variable region gene utilization, mechanisms of immune dysregulation, and the operation of the network in the generation of abnormal responses. Recent advances in the molecular analysis of immunoglobulin genes have provided insights into the structural basis of autoantibody idiotypes and the manner in which sequence homologies between idiotype-bearing antibodies and autoantigens can lead to autoreactivity. Immune manipulation using these sequences could lead to novel models of disease as well as prospects for immunotherapy.

Antibodies, Anti-Idiotypic↗
PubMed1991

Soluble interleukin-2 receptor levels in patients with dermatitis herpetiformis.

To determine the role of T-cell activation in dermatitis herpetiformis (DH), soluble IL-2R levels were measured by enzyme-linked immunosorbent assay (ELISA) in the sera of 30 patients with DH. Levels of this shed receptor are considered to be a measure of in vivo T-lymphocyte activation, and are elevated in the sera of many patients with inflammatory and immune-mediated diseases. Fifteen of the thirty (50%) patients with DH had elevated levels of soluble IL-2R compared to one of 31 (3%) healthy HLA-B8 or HLA-DR3 control subjects (p less than 0.00001) and one of 10 (10%) healthy non-HLA-B8/-DR3 subjects (p less than 0.0018). In addition, the mean soluble IL-2R level in the patients with DH (744 +/- 381 U/ml) was also significantly higher than that seen in 31 healthy HLA B8 or HLA DR3 individuals (388 +/- 160 U/ml, p = 0.0001) and 10 healthy non-HLA-B8/DR3 individuals (397 +/- 201 U/ml, p = 0.002). Only two of the 30 patients with DH had active skin lesions at the time of serum sampling, one of whom had elevated levels of IL-2R. Measurement of soluble IL-2R levels in sequential serum samples, available in four patients with DH at times of active and inactive skin disease, demonstrated a temporal association between soluble IL-2R level elevations and active skin disease in two patients and no association in two patients. In one patient a marked elevation in soluble IL-2R levels occurred with the onset of gastrointestinal symptoms, which decreased by 14% with institution of a gluten-free diet. In order to determine if soluble IL-2R levels are related to the mucosal immune response, the IL-2R levels were compared to the level of IgA antibodies directed against the dietary antigen beta-lactoglobulin. Ten of eleven (91%) patients with circulating IgA anti-beta lactoglobulin antibodies were also found to have elevated levels of IL-2R. In contrast, in the patients with no detectable IgA anti-beta lactoglobulin antibodies, only four of 16 (25%) had elevated levels of IL-2R (p = 0.001). Because IL-2R levels are not related to activity of the skin disease in patients with DH but are associated with the presence of IgA antibodies against the dietary antigen beta-lactoglobulin, these results suggest that some of the T-cell activation commonly present in DH reflects an ongoing immune response in the gastrointestinal tract.

Antibodies↗
PubMed1991

The relationship between soluble interleukin 2 receptor levels and antidouble stranded DNA antibody levels in patients with systemic lupus erythematosus.

Levels of soluble interleukin 2 receptors (IL-2R) have been found to be elevated in the serum of patients with systemic lupus erythematosus (SLE) and are considered an indication of immune system activation in this disease. To assess the relationship between soluble IL-2R levels and other serological markers, we compared levels of soluble IL-2R and anti-double stranded DNA (anti-dsDNA) antibodies in SLE sera. In a cross sectional study of 34 patients with SLE, soluble IL-2R levels were elevated compared with healthy individuals (1126 U/ml vs 235 U/ml, p less than 0.0001), and a significant correlation between levels of soluble IL-2R and anti-dsDNA antibodies was present (r = 0.543, p = 0.0009). In a longitudinal study of 10 additional patients, the time courses of soluble IL-2R levels and anti-dsDNA antibody measurements were similar in 3 patients. In 7 patients, substantial differences in the levels of soluble IL-2R and anti-dsDNA antibodies over time were observed, including marked changes in anti-dsDNA antibody levels that were accompanied by only minor changes in soluble IL-2R levels, and soluble IL-2R measurements that were persistently elevated despite generally low anti-dsDNA antibody levels. Our results indicate that soluble IL-2R levels may not always parallel other serological markers of SLE, suggesting measurement of different facets of immune system activation by various assays.

Adult↗
PubMed1991

Serum immunoglobulin levels in systemic lupus erythematosus: the effects of age, sex, race and disease duration.

To determine whether factors other than disease activity influence immunoglobulin levels in patients with systemic lupus erythematosus (SLE), the effect of age, sex, race, and duration of disease on serum IgG and IgM levels in 170 patients with SLE were investigated. Serum IgM and IgG levels did not differ between men and women, while IgM levels were higher in whites. Serum IgG levels did not vary with age or duration of SLE. In contrast, serum IgM levels were negatively correlated with both age (r = -0.236; p = 0.002) and duration of SLE (r = 0.248; p = 0.001), and demonstrated a U-shaped age relationship, being higher in children and older patients. These patterns of immunoglobulin expression in patients with SLE contrast with those exhibited in populations of healthy individuals, suggesting that the immunoregulatory disturbances of SLE predominate over the normal mechanisms regulating levels of IgM and IgG.

Adult↗
PubMed1990

The fine specificity of anti-La antibodies induced in mice by immunization with recombinant human La autoantigen.

Because of increasing evidence suggesting that anti-La autoantibodies are induced in humans by an Ag-specific mechanism, we investigated the antibody response of animals immunized with the human La Ag and studied its relationship to the anti-La response of autoimmune patients. Anti-La antibodies were raised in 6- to 8-wk-old male MRL(-)+/+, C57BL/6J, BALB/c, and A/J mice by immunizing with authentic human La protein obtained by recombinant expression in Escherichia coli. As we have shown previously for human autoantibodies, induced mouse anti-La antibodies reacted with recombinant fusion proteins containing nonoverlapping sequences from different portions of the La molecule. The epitope specificity of antibodies to the middle region of the La Ag was further evaluated using six synthetic La peptides predicted to be antigenic based on their hydrophilic properties. Although the induced mouse anti-La antibodies bound to five of the six synthetic La peptides, human anti-La autoantibodies failed to recognize any of the peptide homologs. These results suggest that mice respond to immunization with human La protein differently than humans who develop autoimmunity to this self Ag.

Amino Acid Sequence↗
PubMed1990

Correlation between erythrocyte CR1 reduction and other blood proteinase markers in patients with malignant and inflammatory disorders.

Erythrocyte CR1, a C3b/C4b-binding complement-regulatory protein, is sensitive to proteolysis in vitro. To test the hypothesis that in vivo erythrocyte CR1 reduction results from intravascular proteinase activities, we used enzyme-linked immunosorbent assays to measure gamma-crosslinked fibrin degradation products (D-dimers) as indicators of coagulation/fibrinolytic activity, and complexes of neutrophil elastase with alpha 1 proteinase inhibitor (E/A) as indicators of neutrophil enzyme release in malignant and inflammatory disorders. Erythrocyte CR1, measured by monoclonal anti-CR1 antibody binding, was inversely related to disease activity and blood proteinase markers. Levels of erythrocyte CR1 were significantly lower for patients with active versus remittent squamous and small cell lung cancers, Hodgkin's and diffuse large cell lymphomas, and acute myelogenous leukemias. In patients with active thoracic cancers, elevated D-dimer levels correlated with reduction of CR1. In patients with rheumatoid arthritis, CR1 reduction was correlated with elevated levels of elastase complexes. Our findings substantiate the relationship of acquired CR1 reduction to the activity of certain diseases and provide circumstantial support for the hypothesis that erythrocyte CR1 is lost to proteolysis in vivo. Although heritable differences in CR1 expression reduce the interpretability of single measurements of erythrocyte CR1 levels, disease-associated CR1 reduction may be a useful indicator of disorders with chronically increased blood proteinase activity.

Adult↗
PubMed1990

Cellular requirements for anti-DNA production induced in mice by immunization with bacterial DNA.

To further define DNA immunization as a model for anti-DNA production, we investigated the cellular requirements for this response in mice immunized with single-stranded DNA from E. coli. The anti-DNA responses of genetically immune-deficient mice and congenic controls were measured by ELISA after immunization with E. coli DNA as complexes with methylated bovine serum albumin in complete Freund's adjuvant. T cell-deficient BALB/c-nu/nu mice failed to produce IgG anti-DNA by this protocol despite high backgrounds of IgM anti-DNA. In contrast, CBA/N mice expressing the xid defect displayed IgG anti-DNA responses comparable to those of CBA/J mice despite a reduced IgM response; the specificity of CBA/N and CBA/J anti-DNA antibodies was similar as determined by binding to synthetic DNA and RNA antigens. These results suggest that the anti-DNA response stimulated by DNA immunization is dependent on T cells but not the B cell population affected by xid. The intact IgG response of immunized xid mice differs from that of lupus mice bearing xid where this gene defect leads to significant reduction of spontaneous anti-DNA production.

Animals↗
PubMed1990

Serum interleukin-2 receptor responses to immunization.

Serum interleukin-2 receptor (sIL-2R) levels have been used to assess immune activation in inflammatory and infectious illnesses, although the cellular origin of these receptors and the dynamics of their production are not well defined. To investigate the relationship between sIL-2R levels and the degree of immune activation in antigen-specific responses, sIL-2R were measured in healthy individuals after both primary and secondary immunization with keyhole limpet hemocyanin (KLH). Despite induction of strong antibody responses, KLH immunization did not result in consistent elevations of sIL-2R levels, with only one of six subjects developing a substantial (twofold) increase in sIL-2R levels. The absence of sIL-2R elevation after a discrete antigenic stimulus suggests that inflammatory illnesses in which elevated sIL-2R levels have been noted involve more extensive stimulation of immune cells, either in number or in degree, than that present after simple immunization in healthy individuals.

Adult↗
PubMed1990

Heavy and light chain utilization in autoantibodies of elderly patients with systemic lupus erythematosus.

To determine whether age-related changes in immune function affect patterns of autoantibody production, we have examined the isotype and light chain utilization in autoantibodies of elderly patients with systemic lupus erythematosus (SLE). Enzyme-linked immunosorbent assays (ELISA) were used to determine the frequencies of IgG and IgM antibodies to single-stranded DNA (ssDNA), Sm, and the 70K protein component of RNP in the sera of 53 patients with SLE older than age 60. The IgG subclass distributions and kappa/lambda ratios for each of these autoantibodies were also determined and compared to measurements performed on the sera of 53 young adult patients with SLE. The frequencies of autoantibodies of each specificity, except IgM anti-ss DNA antibodies, were higher among the young adult patients, although the magnitudes of the responses were similar in both age groups. IgG anti-Sm antibodies were composed of both IgG1 and IgG2 subclasses, while IgG anti-70K RNP and IgG anti-ssDNA were predominantly of the IgG1 subclass. There were no differences in the IgG subclass distributions of any of the three autoantibodies between the elderly and young adult patient sera. The kappa/lambda ratios for each of the three autoantibodies were similar to that present in total serum immunoglobulins, and kappa/lambda ratios of autoantibodies, standardized to the kappa/lambda ratios of serum, were not different between elderly and young adult groups. Few patient sera of either age group (9 elderly, 7 young adult) demonstrated even midly skewed light chain ratios in their autoantibody responses. Thus, despite developing in an immunological environment that may have altered the clonality and isotype distribution of their responses, the autoantibodies produced by elderly patients with SLE were qualitatively similar to autoantibodies of younger patients.

Adolescent↗
PubMed1990

Expression of autoantibodies to recombinant (U1) RNP-associated 70K antigen in systemic lupus erythematosus.

To determine the specificity of antibodies to the (U1) ribonucleoprotein antigen in systemic lupus erythematosus (SLE), patient sera were tested for binding to a recombinant human 70K antigen. By solid-phase immunoassay, we detected anti-70K reactivity in sera from 31 of 96 patients with systemic lupus erythematosus (SLE), demonstrating that anti-70K antibodies may occur in patients with SLE as well as other clinical diagnoses. In sequential sera from 2 of these patients, we found that anti-70K binding varied dramatically over the course of disease. The changes in anti-70K antibody levels did not correlate with clinical events nor evolving antibody reactivity with the Sm-specific antigens.

Autoantibodies↗
PubMed1990

Expression of IgM and IgG autoantibodies in pediatric and adult systemic lupus erythematosus.

To compare patterns of autoantibody responses in pediatric and adult patients with systemic lupus erythematosus (SLE). IgG and IgM antibodies to single-stranded DNA (ssDNA), Sm, and the 70-kDa protein component of the RNP antigen (70-kDa RNP) were measured in 29 pediatric and 36 adult patients by enzyme-linked immunosorbent assays. Antibodies of either isotype to ssDNA, Sm, and 70-kDa RNP were present in 64, 58, and 79% of pediatric patients, respectively, comparable to prevalences of these autoantibodies in the adult SLE patients. Pediatric SLE patients were more likely than adult patients to have IgM anti-Sm antibodies (41.4% vs 13.9%, P = 0.02) and tended to more commonly express IgM anti-70-kDa RNP and IgM anti-ssDNA antibodies. The prominence of IgM autoantibody responses among pediatric SLE patients was shown by multiple logistic regression analysis to be related to total IgM concentrations and not related to age or duration of disease. Sequential serum samples available from several pediatric patients revealed the maintenance of similar patterns of isotype responses over time in approximately one-half of patients. In those patients whose responses changed over time, the variations in isotype expression were consistent with maturation of antibody responses of each specificity. While these results demonstrate similarities in autoimmune reactivities between pediatric and adult SLE patients, the serologic study of pediatric patients may provide an opportunity to more readily investigate the evolution of autoantibody responses.

Adolescent↗