Immortalisation of human antibody producing cells.
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Antibodies, Monoclonal↗
Biomedical subjects
D A Isenberg
Publications and source records attributed to D A Isenberg.
Does mitogen-induced antibody production by normal blood cells mimic spontaneous production in lupus?
Blood cells from patients with systemic lupus erythematosus (SLE) showed a raised level of spontaneous IgG production that included antibodies to DNA and to common environmental antigens (influenza virus haemagglutinin, adenovirus hexon and mannan from Candida albicans). In contrast, no IgG antibody was produced against an antigen not normally encountered in the UK (egg antigen from Schistosoma mansoni) or a self-antigen not generally associated with SLE (thyroglobulin). IgM production was raised to a lesser extent and only antibodies to DNA were detected. When normal cells were stimulated with pokeweed mitogen or S. aureus organisms, the specificity pattern of IgG production was similar to that described above for SLE with the major exception of the absence of IgG anti-DNA. IgM antibodies to DNA and all the other antigens were detected, but the specificity of the IgM ELISA assays for the protein antigens needs further clarification. The activity of IgM anti-DNA relative to total IgM was far greater in the SLE system. These results provide further evidence that a response to self-antigen is required for production of pathogenic IgG autoantibodies in SLE.
Antibodies, Antinuclear↗
Lupus anticoagulant activity and anticardiolipin antibody titre in patients with systemic lupus erythematosus.
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Antibodies, Anticardiolipin↗
Asialylated IgG in the serum and synovial fluid of patients with rheumatoid arthritis.
A novel enzyme linked immunosorbent assay has been developed that detects an asialylation change in the IgG molecules from patients with rheumatoid arthritis (RA) by the binding of biotinylated RCA 1 (ricin) to capture IgG. Elevated levels of asialylated IgG were detected in paired serum and synovial fluids (SF) of patients with RA. When compared with healthy controls, particularly in the SF (p less than 0.05) correlations of the asialylation change were found in paired samples (p less than 0.01) and between asialylated IgG and rheumatoid factors (p less than 0.01), C-reactive protein (p less than 0.02) and the Lee and Ritchie indices p less than 0.02 and 0.05, respectively. We found the proportion of asialylated IgG was higher in DR4 positive patients, indicating a possible association of these individuals to a sialyl transferase abnormality.
Adolescent↗
Independent analysis of the 16/6 idiotype lupus model. A role for an environmental factor?
The recent description of a lupus-like disease in normal mice after injections of human mAb that bind DNA and carry the common Id 16/6 Id has excited much attention. In an effort to reproduce this model we have performed two experiments using eight human mAb three of which bear the 16/6 Id. Despite using an injection protocol very similar to that of the original authors and waiting for up to 1 yr we were unable to detect any autoantibodies or any evidence of renal disease. We suspect that our failure to reproduce the model may be due to differences in either or both the batches of CFA used, or in the animal house environments. It supports the view that a mosaic of effects is required to induce clinical expression of an autoimmune disease.
Animals↗
HLA class II restriction of autoantibody production in patients with systemic lupus erythematosus.
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Alleles↗
Quantitative clinical assessment of disease activity in systemic lupus erythematosus: progress report and research agenda.
No single test allows an adequate measure of disease activity in multisystem diseases such as systemic lupus erythematosus (SLE). In order to evaluate the spectrum of manifestations of disease activity in SLE, investigators have developed numerous ad hoc scales which have not been tested for their validity or reliability. Three instruments have been extensively studied: the British Isles Lupus Activity Group instrument (BILAG), the SLE Disease Activity Index (SLEDAI), and the Systemic Lupus Activity Measure (SLAM). All three have been demonstrated to have convergent and construct validity when compared to the clinician's judgement. The summation of the number of criteria of the American Rheumatism Association (ARA) SLE criteria has been shown to be an inadequate measure of disease activity. Standardized measures of disease activity for SLE should enhance our ability to compare results from different centers in finer distinctions than dead or alive.
Evaluation Studies as Topic↗
AIDS virus infection and autoimmunity: a perspective of the clinical, immunological, and molecular origins of the autoallergic pathologies associated with HIV disease.
The acquired immune deficiency syndrome (AIDS) is a viral-induced disorder of humans that is reaching pandemic proportions. The etiologic agent responsible for AIDS is recognized as a retrovirus termed the human immunodeficiency virus (HIV). This virus is both cytotropic and cytopathic for T lymphocytes in vitro, and patients with AIDS and HIV-related conditions invariably have serious T cell abnormalities, notably a reduced number of the helper/inducer (CD4+) subpopulation. There is now a substantial body of evidence to suggest that the AIDS virus triggers a diverse range of autoimmune phenomena. The purpose of this article is to summarize the clinical and immunopathological manifestations of autoimmunity in HIV infection and to provide a perspective of the possible origins and roles autoimmune reactions play in HIV disease progression.
Acquired Immunodeficiency Syndrome↗
Abnormalities in the glycosylation of IgG in spouses of patients with rheumatoid arthritis. A family study.
Forty-seven members of eight families with a rheumatoid proband were analysed for abnormal glycosylation of IgG. The results (%G(o) which is the percentage of oligosaccharide chains lacking galactose) were corrected for age and expressed as SD units about the mean for the normal population. Seven of 8 probands, 3/8 spouses, 3/5 RA relatives and 4/26 non-RA relatives had %G(o) values greater than 1SD above the age corrected mean for the normal control population (P less than 0.001, less than 0.01, less than 0.005 and greater than 0.5 respectively). A further 13 spouse pairs were studied. Ten of 13 probands and 8/13 spouses had %G(o) values greater than 1SD above the mean (P less than 0.001 and less than 0.001 respectively). Thus in total, a strikingly high number of unaffected spouses had high %G(o) values (11/21). IgM, IgA and IgG rheumatoid factors were studied. While RA patients' sera showed a correlation between IgM and IgA rheumatoid factors and %G(o), (IgM, r = 0.41 0.05 greater than P greater than 0.02, IgA, r = 0.36, P = 0.05), no correlation between IgG RF and %G(o) was noted in the RA patients. No correlation was found between any of the RF classes and %G(o) in spouses and non-RA relatives.
Arthritis, Rheumatoid↗
Does plasma exchange have any role in the treatment of systemic lupus erythematosus?
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Humans↗
The fibrinolytic response to venous occlusion and the natural anticoagulants in patients with antiphospholipid antibodies both with and without systemic lupus erythematosus.
Patients with systemic lupus erythematosus (SLE) have an increased risk of thrombosis and this is increased in the presence of antiphospholipid antibodies (APA). These APA are also associated with thrombosis in patients who do not have SLE. We compared haemostatic parameters in SLE patients with and without APA, and also compared patients who had APA but not SLE with healthy normal controls. No relationships between the natural anticoagulants, antithrombin III, heparin cofactor II, protein C and protein S, and the presence of APA were found. In the patients with SLE both tissue plasminogen activator antigen and plasminogen activator inhibitor (PAI) were increased, but these changes were not due to APA which had no effect on fibrinolysis in these patients. In the patients with APA who did not have SLE the fibrinolytic response to venous occlusion was reduced due to raised levels of PAI; similar changes have, however, been reported in some patients with idiopathic thrombosis.
Adolescent↗
Detection of human and murine common idiotypes of DNA antibodies in tissues and sera of patients with autoimmune diseases.
The expression in tissue and serum of a panel of murine and human common DNA antibody idiotypes (Ids) (BEG 2, PR 4, F-423, I-402, II-28, IV-228, V-88) has been investigated. The murine V-88 Id was detected in eight out of 10 and the human BEG 2 Id in five out of 10 labial biopsies from patients with Sjögren's syndrome. The murine F-423, I-402 and IV-228 Ids were identified in one out of 10 biopsies. In each case the pattern of staining was similar with staining of the acinar basement membrane and a cell population. Using double-labelling immunohistochemistry this cell population were identified as plasma cells. No staining was seen in four normal labial biopsies. The V-88 Id was detected on the epithelial aspect of the thickened basement membrane in three out of nine renal biopsies from patients with systemic lupus erythematosus (SLE). None of the other Ids (BEG 2, PR4, IV-228, F-423 or I-402) could be detected in renal tissue. None of the Ids were found in skin biopsies from SLE patients. Id V-88 may, like the 16/6 Id to which it is phenotypically related, play a role in the pathogenesis of renal lesions in SLE. The BEG 2 Id could be detected in the serum of patients with rheumatoid arthritis (RA) and active untreated tuberculosis. Ids II-28, V-88 and I-402 were elevated in serum from patients with Sjögren's syndrome and II-28 Id in serum from patients with myositis and RA. None of the Ids were elevated in serum from patients with SLE. Apart from the BEG 2 Id, none of the Ids were elevated in serum from patients with tuberculosis or Gram-negative infections. The presence of murine Ids in human tissue and serum suggests that they are cross-species idiotypes and have been conserved through evolution.
Animals↗
Analysis of antibodies to RNA in patients with systemic lupus erythematosus and other autoimmune rheumatic diseases.
The frequency and clinical associations of anti-RNA antibodies measured by ELISA were assessed in 138 patients with systemic lupus erythematosus (SLE). Of the sera from these patients 9.4% had anti-RNA antibodies but no distinguishing features, clinical, serological or immunogenetic, between those with or without these antibodies could be identified. However, investigations of patients with other autoimmune rheumatic diseases did not reveal any anti-RNA positivity, which indicates a marked disease specificity for anti-RNA antibodies in SLE. The initial anti-RNA antibody screen used a soluble yeast extract as test antigen. The positive sera were further tested against a range of RNAs from 10 different types of rat tissue. In essence few differences were observed, suggesting that the anti-RNA response is directed against common, highly conserved epitopes.
Antibody Specificity↗
Relation between antinuclear antibodies and the autoimmune rheumatic diseases and disease type and activity in systemic lupus erythematosus using a variety of cultured cell lines.
Antinuclear activity was assessed in serum samples from a series of 40 patients with differing clinical subsets (including renal and neurological disease) of systemic lupus erythematosus (SLE) against a transformed keratinocyte line (SvK14)* and normal human keratinocytes. Paired serum samples were studied during disease activity and inactivity, and the effects of ultraviolet radiation on the availability of nuclear antigens in the cell substrates were assessed. Serum samples from 20 healthy controls and 40 disease controls, comprising 10 patients each with rheumatoid arthritis, Sjögren's syndrome, scleroderma, and myositis, were also studied. The keratinocytes all provided sensitive substrates for the detection of antinuclear antibodies (ANAs), and in normal keratinocytes treated with ultraviolet radiation nuclear antigens were exposed on the cell surface. There was no correlation between ANAs and disease activity or patterns so, apart from assisting diagnosis, the detection of ANAs is of little relevance to predicting disease activity.
Antibodies↗
Influence of C4 null alleles on C4 activation in systemic lupus erythematosus.
Deficiencies of early components of the classical complement pathway are known to be associated with systemic lupus erythematosus (SLE). C4 null alleles, C4A Q0 and C4B Q0, are prime candidates for the major histocompatibility complex associated factor which determines susceptibility to SLE. There is poor correlation, however, between the presence of low concentrations of C4 and possession of C4 null alleles, and thus the basis of the association between C4A Q0, C4B Q0 and SLE remains obscure. The possibility that activation of C4 may be related to the possession of C4 null alleles was examined. C4 phenotypes were investigated, and C4 concentration and activation were estimated in patients with SLE. C4 activation was determined by measuring the concentration of C4d--a split product of C4. Twenty five of 35 patients had C4 phenotypes which include null alleles. No association between low C4 concentrations and C4 null alleles was found, but a significant association between low C4d concentrations and C4 phenotypes including null alleles, particularly those with C4A Q0, was noted. No correlation between concentrations of C4 and C4d was found. These results show an influence of C4 null alleles on the activation of the C4 molecule, which is independent of the concentration of C4. The possession of silent genes coding for C4 null alleles might predispose to SLE by conditioning poor C4 activation, a critical event for the clearance of immune complexes mediated by the classical complement pathway.
Alleles↗
Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus.
A prospective, double blind, cross over study assessing the effects of a low fat, high marine oil diet in 27 patients with active systemic lupus erythematosus has been performed. The patients were given 20 g daily of MaxEPA (eicosapentaenoic acid) or 20 g of olive oil (placebo) in matching capsules added to a standardised isoenergetic low fat diet. When individual outcome measures of the 17 patients who completed the full 34 week study were considered 14 who were receiving MaxEPA achieved useful or ideal status, whereas 13 receiving placebo were rated as worse or no change. The difference between the two types of capsule was statistically significant. No major side effects were noted, and it is suggested that dietary modification with additional marine oil may be a useful way of modifying disease activity in systemic lupus erythematosus.
Adult↗
Measurement of haematological indices of chronic rheumatic disease with two newer generation automated systems, the H1 and H6000 (Technicon).
Two automated counters, the H1 (Technicon) and the H6000 (Technicon), which count 10,000 cells per sample, were compared and used to examine the clinical relevance of the additional haematological information now provided to the rheumatologist in three groups of patients--38 with rheumatoid arthritis (RA), 41 with ankylosing spondylitis (AS), and 35 with systemic lupus erythematosus (SLE). The two machines agreed in their estimations of the main indices (haemoglobin, red blood cell count, and white blood cell count), but estimations of platelet count and volume were significantly lower on the H6000 machine, as were mean cell haemoglobin and monocyte count, whereas packed cell volume and red cell distribution width were higher. As expected, both machines identified pancytopenia among the group with SLE, while low haemoglobin and high platelet count were found particularly among patients with RA and AS respectively. Additional information available from these counters showed marked variability in red cell size in SLE, and also of haemoglobin content, which is only measured on the newer H1 machine. Flags for microcythaemia, anisochromasis, and white cell noise (usually due to nucleated red cells) were all more common in SLE. Interpretation of results was complicated by the inevitable difference in age and sex distribution among the disease groups, and identification of active disease was also limited by the effect of drugs. In conclusion, the increasingly widespread use of automated counters as part of the routine haematological service may provide the rheumatologist with useful information, but, as always, care should be taken in the interpretation of indices in patients receiving non-steroidal or second line agents, and also in extrapolating results from one machine to another when they are updated or when patients are monitored at more than one centre.
Adolescent↗
Reduction in IgG galactose in juvenile and adult onset rheumatoid arthritis measured by a lectin binding method and its relation to rheumatoid factor.
Glycosylation changes in patients with juvenile chronic and adult onset rheumatoid arthritis have been studied using a novel binding method. Both these major types of arthritis showed decreased galactosylation of serum IgG, which confirms earlier studies using a different, more complex chemical method. No significant correlation between serum IgG, IgM, and IgA rheumatoid factors and age corrected G(o) (percentage of oligosaccharide chains lacking galactose) was found. The possibility that the less glycosylated IgG is preferentially confined to circulating IgM/IgG immune complexes cannot be excluded, however.
Adolescent↗