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Biomedical subjects

D A Isenberg

Publications and source records attributed to D A Isenberg.

At least 217 records · Page 12Linked to original sources
PubMed1995

Antineutrophil cytoplasmic antibodies in systemic lupus erythematosus. Prevalence, specificities, and clinical significance.

OBJECTIVE: To examine the prevalence, subspecificities, and clinical associations of antineutrophil cytoplasmic antibodies (ANCA) in patients with systemic lupus erythematosus (SLE). METHODS: One hundred fifty-seven sera from 120 patients with SLE were examined for classic (c) and perinuclear (p) pattern ANCA by indirect immunofluorescence. Antibody subspecificities were determined by enzyme-linked immunosorbent assay (ELISA). Serologic results were correlated with clinical manifestations as categorized by the BILAG (British Isles Lupus Assessment Group) index. RESULTS: ANCA were found in 40 of the 157 sera (25%). Only a pANCA, not a cANCA, pattern of fluorescence was seen. By ELISA testing, 16 sera reacted to lactoferrin, 8 to elastase, and 4 to lysozyme. There was no reactivity to proteinase 3 (PR3) or myeloperoxidase (MPO). No correlation of pANCA, or any of the ANCA subspecificities, with organ system involvement, as categorized by the BILAG index, was found. Notably, there was no correlation of ANCA results with lupus vasculitis. CONCLUSION: The absence of cANCA, anti-PR3, and anti-MPO shows that with appropriate assay conditions, ANCA testing assists in the differentiation between SLE and the ANCA-associated vasculitides. The lack of a correlation between pANCA or any ANCA subspecificity and clinical manifestations suggests that ANCA do not identify particular clinical subsets among SLE patients, including those with lupus vasculitis.

Adult↗
PubMed1995

Tropical rheumatology. Immunological aspects.

The presence of auto-antibodies in infectious diseases continues to puzzle and provoke. It is hoped that sequencing studies in particular will yield further clues as to the role and mechanism of production of autoantibodies in infectious diseases. This, in turn, may also provide further insights into the role of auto-antibodies in auto-immune diseases. From a practical clinical viewpoint, the search for improved auto-antibody tests and new diagnostic markers with improved sensitivity and specificity must continue in the tropics. Until this is achieved, the results of auto-antibody tests in persons living in the tropics, persons from the tropics or patients with tropical infections, must be interpreted with caution.

Autoantibodies↗
PubMed1995

Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice.

We investigated the capacity of five human monoclonal IgG anti-DNA antibodies derived from lupus patients to produce glomerular immune deposits. The hybridomas secreting these antibodies were administered intraperitoneally to severe combined immunodeficiency (SCID) mice. Three of the five antibodies (B3, 35.21, 33.C9) were detected in the kidneys, but only one (33.C9) deposited exclusively in the glomeruli in the mesangium and capillary wall, whereas the other two antibodies bound to nuclei both in the kidney and in other organs. The antibodies were tested against a variety of autoantigens by ELISA, the only unique feature of 33.C9 was that it also bound strongly to histones. There were no particular amino acid motif that was related to immunoglobulin deposition in the kidney. All the mice that had immunoglobulin deposited in the kidney, either extracellularly or intranuclearly developed 2 to 3+ proteinuria, whereas the other mice had only trace amounts of proteinuria. This study demonstrates that some human monoclonal IgG anti-dsDNA antibodies are capable of binding to the glomerulus while others can penetrate cells and bind to nuclei in vivo. Although no abnormal pathology was observed, proteinuria was detected, perhaps representing an early phase of disease. These results indicate that the affinity for dsDNA is not the sole determining factor governing the biological properties of human anti-DNA antibodies in vivo.

Animals↗
PubMed1995

beta 1,4-Galactosyltransferase activity in B cells detected using a simple ELISA-based assay.

Lymphocytic beta 1,4-galactosyltransferase (beta 1,4-GalTase, EC 2.4.1.38) activity was measured in B cells using a neoglyco-protein, N-acetylglucosamine-phenylisothiocyanate-bovine serum albumin (GlcNAc-pITC-BSA), as an acceptor substrate in a novel enzyme-linked immunosorbent assay (ELISA)-based method. This assay proved to be much simpler to use than the lengthy and expensive radiochemical assays commonly used, and has the additional advantage that it specifically detects the enzyme mediating transfer via the Gal beta 1,4GlcNAc linkage. A F(ab')2 antibody against GalTase was able to specifically inhibit the reaction. Greater sensitivity for beta 1,4-GalTase activity was obtained using GlcNAc-pITC-BSA as an acceptor substrate rather than ovalbumin. Low levels of beta-galactosidase activity were detectable in lymphocyte cell lysates at acidic pH, although such activity was not detectable at the neutral pH used in the beta 1,4-GalTase activity assay. Using this assay with the GlcNAc-pITC-BSA acceptor, similar beta 1,4-GalTase activities were observed in CD19+ B cells from patients with rheumatoid arthritis (RA) to those seen in normal control individuals.

Adult↗
PubMed1995

Increased levels of beta 2 glycoprotein-I antigen and beta 2 glycoprotein-I binding antibodies are associated with a history of thromboembolic complications in patients with SLE and primary antiphospholipid syndrome.

beta 2 Glycoprotein-I (beta 2GPI), a plasma component with in vitro anticoagulant properties, has been identified as a cofactor for the binding of some antiphospholipid antibodies (aPAs). In order to determine whether beta 2GPI changes were associated with the thromboembolic complications of aPAs, we measured beta 2GPI antigen (beta 2GPI:Ag), beta 2GPI aPA cofactor activity (beta 2GPI:Cof) and antibodies to beta 2GPI (alpha beta 2GPI) in 44 systemic lupus erythematosus (SLE) patients, of whom 19 had evidence of aPAs (SLE-aPA+) and 17 patients with primary antiphospholipid syndrome (PaPS). beta 2GPI:Ag levels were significantly increased in SLE-aPA+ patients and PaPS patients compared with SLE-aPA- patients and normal healthy controls. The ratio of beta 2GPI:Cof/Ag was significantly reduced in SLE-aPA+ patients compared with SLE-aPA- patients, indicating functional modification of beta 2GPI in SLE-aPA+ patients. Eighty per cent of patients with anticardiolipin (aCL) IgG also had alpha beta 2GPI, and 13% patients with no detectable aCL IgG had alpha beta 2GPI. Increased beta 2GPI:Ag and alpha beta 2GPI were associated with a clinical history of thrombosis or recurrent fetal loss. The results of these investigations suggest that beta 2GPI may play a role in the pathogenic mechanism of thrombosis associated with aPAs.

Adult↗
PubMed1995

The occurrence, nature and distribution of flares in a cohort of patients with systemic lupus erythematosus: a rheumatological view.

This study examines the occurrence, nature and distribution of disease flares in systemic lupus erythematosus (SLE) according to organ involvement. One-hundred-and-fourteen patients were seen in the Lupus Clinic of the Bloomsbury Rheumatology Unit over a 3-yr period. At each visit a data sheet was completed to assess their disease activity in eight separate organs/systems according to the British Isles Lupus Assessment Group (BILAG) activity index. This information was entered into a computer and a score for each organ system was obtained. The record of each individual patient was examined to identify flares in the individual organs; 458 flares occurred in 107 patients. The majority of patients (69%) experienced more than one flare during the study period. Fifty-four per cent of patients had flares in more than one system simultaneously, but the majority (70%) of flares involved only one system. The most severe organ involvement (A score) was most commonly observed in the musculoskeletal system, whereas severe renal disease occurred only three times. These results indicate that although SLE is a multisystem disease, the flares that occur tend to be confined to one system at a time. Further, these results demonstrate that in our rheumatology practice the most common 'A' flare observed was severe polyarthritis (A score in musculoskeletal).

Adult↗
PubMed1995

Bcl-2 expression is unaltered in unfractionated peripheral blood mononuclear cells in patients with systemic lupus erythematosus.

It has been postulated that the high levels of autoantibodies observed in systemic lupus erythematosus (SLE) patients could result from abnormal longevity of polyclonally activated B-cells. This increased survival could be due to dysfunction of apoptosis, the normal regulatory process governing their life span. The protein product of the bcl-2 gene can enhance lymphoid cell survival by interfering with apoptosis. Moreover, transgenic mice overexpressing bcl-2 in their B-cells developed an autoimmune syndrome resembling SLE. To determine whether overexpression of bcl-2 occurs in SLE patients, bcl-2 protein was measured in peripheral blood mononuclear cells from 73 SLE patients, 20 healthy individuals and 47 patients with other autoimmune diseases. Only three lupus patients had raised levels of bcl-2 and there were no statistically significant differences in the mean bcl-2 levels measured in SLE patients compared to controls. Bcl-2 levels did not correlate with overall disease activity in SLE patients.

Adult↗
PubMed1995

The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CDP571) in rheumatoid arthritis.

Pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF alpha) have been implicated in the pathogenesis of rheumatoid arthritis (RA), and have therefore become therapeutic targets. An engineered human antibody, CDP571, that neutralizes human TNF alpha was administered intravenously in single doses of 0.1, 1.0 or 10 mg/kg to patients with active RA (n = 24). The effects of the antibody were compared in a double-blind fashion with those of placebo (n = 12). In an open continuation phase patients were given either 1.0 or 10 mg/kg. We found that CDP571 was well tolerated and caused reductions in markers of disease activity such as erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP): this was confirmed by a reduction in the disease activity score (DAS). There was a reduction in the number of tender joints, maximal in degree and duration after 10 mg/kg. Patients also documented a reduction of pain and relief of arthritis symptoms. The effects of 10 mg/kg CDP571 on ESR, CRP, tender joints, pain and symptom relief compared to placebo were statistically significant at weeks 1 or 2. The continuation phase, although open, confirmed both the safety and the beneficial effects of CDP571 in active RA. In conclusion CDP571, an engineered human anti-TNF alpha antibody, is well tolerated and, after a single dose of 10 mg/kg, provides improvements in symptoms, signs and serological markers of disease activity in patients with active RA.

Adolescent↗
PubMed1995

Thyroid autoimmunity in systemic lupus erythematosus: the clinical significance of a fluctuating course.

A number of studies have demonstrated an association between thyroid autoimmune disease and systemic lupus erythematosus (SLE), but there is little information on the course of thyroid autoimmunity over time in SLE patients. We reviewed the thyroid serology of 150 SLE patients tested at or soon after diagnosis of SLE, and examined the follow-up data on those found to have positive thyroid serology. Thirty-one (21%) were thyroid autoantibody positive. Follow-up data were available on 20 of these patients, over an average of 7.9 yr. Twelve of the 20 patients (60%) were persistently thyroid autoantibody positive, but eight (40%) were thyroid autoantibody negative on at least one occasion during follow-up. All five cases of clinical thyroid disease that were diagnosed, and two out of three cases of subclinical elevation of thyroid-stimulating hormone (TSH), occurred in the group with persistently positive thyroid serology. We also retested the thyroid serology of 46 of the 119 patients who originally tested thyroid autoantibody negative, with an average of 6.2 yr between the two tests, and found that four (9%) now had positive thyroid serology. One had an elevated TSH. We conclude that thyroid serology follows a fluctuating course in a subgroup of SLE patients who are found to have positive thyroid serology on a single occasion. Although the number in this subgroup of our series was small, and the trend did not reach statistical significance, our findings suggested that this subgroup of patients is unlikely to develop clinical or subclinical thyroid disease.

Antigen-Antibody Reactions↗
PubMed1995

Adult- and childhood-onset systemic lupus erythematosus: a comparison of onset, clinical features, serology, and outcome.

This study examines the differences which may distinguish systemic lupus erythematosus (SLE) presenting in adult life or childhood. A common database was established, with analysis of clinical, serological and outcome features of a cohort of patients with SLE, with disease diagnosed before the age of 16 (n = 39) or after the age of 16 (n = 165). Disease onset was generally more severe in the childhood-onset patients. Cardiopulmonary disease was more common in the older-onset group, but major haematological manifestations were more frequent in the childhood-onset group. Serologically, anti-DNA, anti-Sm and anti-RNP antibodies and a low C3 were all found more frequently in the younger patients. Twice as many adult-onset cases had died at the time of the last follow-up (10 vs 5%), but this group had been followed for a longer period (average 7.5 yr, S.D. 3.9 for adults vs average 4.8 yr, S.D. 3.2 for children). However, the younger patients were twice as likely (82 vs 40%) to require high-dose prednisone, although the requirement for immunosuppressive agents was similar in the two groups. Clinicians should anticipate that children with SLE have a more severe disease onset than adults in general.

Adolescent↗
PubMed1995

Elevated levels of beta 2 glycoprotein-I (beta 2 GPI) in antiphospholipid antibody syndrome are due to increased amounts of beta 2 GPI in association with other plasma constituents.

beta 2 glycoprotein-I (beta 2 GPI) is a 50 kDa plasma protein which associates with a number of anionic plasma constituents and has been identified as a cofactor for the binding of some antiphospholipid antibodies (aPAs). beta 2 GPI antigen levels are increased in some patients with aPAs. In order to examine the distribution of beta 2 GPI in these patients, we developed a method for measurement of free beta 2 GPI. Forty-three patients with SLE, of whom 18 had laboratory evidence of aPAs, and 22 normal healthy subjects were studied. Plasma was filtered by centrifugation at 650 x g through a 100 kDa filter in order to allow separation of free and complexed beta 2 GPI, and beta 2 GPI levels were measured in the starting plasma and filtrate by a standardized ELISA. Total beta 2 GPI levels of the SLE aPA positive patients (253.3 mg/l) were significantly increased compared with the SLE aPA negative patients and normal controls (188.0, P < 0.001 and 194.9 mg/l, P < 0.01, respectively), but there were no significant differences between free beta 2 GPI levels of these groups (20.8, 24.0 and 20.5 mg/l, respectively). These results suggest that levels of complexed beta 2 GPI are increased in patients with aPAs, perhaps as a result of immune complex formation, or altered binding to other plasma constituents.

Adult↗
PubMed1995

The use of an anti-beta 2-glycoprotein-I assay for discrimination between anticardiolipin antibodies associated with infection and increased risk of thrombosis.

Antiphospholipid antibodies (aPAs), occurring in association with infection, are not generally associated with an increased risk of thrombosis. Anticardiolipin antibodies (aCL) from patients with infection, unlike those from patients with SLE, do not have the beta 2GPI cofactor requirements. Antibodies to beta 2GPI (alpha beta 2GPI) are more closely associated with a previous history of thrombosis than aCL in patients with SLE. In the present study we have investigated the reactivity of the alpha beta 2GPI assay for aPAs associated with infection. Serum from 114 patients with infections including syphilis (n = 11), tuberculosis (n = 63) and Klebsiella (n = 42) were assayed for alpha beta 2GPI and aCL antibodies. The incidence of aCL in serum of patients with tuberculosis. Klebsiella infection and syphilis was 6.0%, 5.0% and 64.0%, respectively, but all patients were negative for alpha beta 2GPI. These results indicate that the alpha beta 2GPI assay is negative in patients with transiently positive aCL assays associated with infection.

Adult↗
PubMed1995

Phospholipid binding specificities and idiotype expression of hybridoma derived monoclonal autoantibodies from splenic cells of patients with systemic lupus erythematosus.

OBJECTIVE: To analyse the phospholipid binding specificity, functional characteristics and idiotype expression of human hybridoma derived monoclonal autoantibodies (MAb) derived from the spleens of two patients with active systemic lupus erythematosus (SLE). METHODS: The IgM MAbs binding to phospholipids were generated from spleen cells of two patients (RSP and RT) with active SLE and their specificity of binding to neutral phospholipids (phosphatidyl ethanolamine, phosphatidyl choline, platelet activating factor, sphingomyelin) and negatively charged phospholipids (phosphatidyl glycerol, phosphatidyl serine, phosphatidic acid, phosphatidyl inositol and cardiolipin (CL)) analysed. Binding specificity of cross reactive antibodies (those binding to CL and DNA) was confirmed by fluid phase inhibition assays. Lupus anticoagulant activity and beta 2-glycoprotein-1 (beta 2 GP-1) requirement for the antigen binding of these MAbs were detected using the modified dilute Russell's viper venom test and modified anti-CL enzyme linked immunosorbent assay (ELISA), respectively. Expression of idiotypes (Id) Id RT-84 and Id H3 was analysed using rabbit polyclonal and murine monoclonal anti-idiotype reagents, respectively. RESULTS: Twelve clones from the patient RSP and eight clones from patient RT were reactive with phospholipids. Marked differences in phospholipid binding of these MAbs were noted, varying from truly polyreactive (RT-72 bound to most phospholipids tested) to monospecific (RT-84 bound only to CL). Furthermore, MAbs RT-84, RT-129, and RSP-57 had lupus anticoagulant activity and required beta 2 GP-1 for CL binding. It was found that 75% of phospholipid binding antibodies from RT clones expressed RT-84 Id, but none from RSP clones did so, and that Id H3 was expressed only by the RT-83 antibody. CONCLUSION: These results show that human anti-phospholipid MAbs are heterogeneous with respect to phospholipid binding, functional characteristics, and Id expression.

Adolescent↗