Hypotheses on basic mechanisms arising from recent research: antinuclear antibodies.
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Animals↗
Biomedical subjects
R N Maini
Publications and source records attributed to R N Maini.
Antibodies to La, Jo-1, nRNP and Sm detected by multi-track immunoblotting using a novel filter holder: a comparative study with counterimmunoelectrophoresis and immunodiffusion using sera from patients with systemic lupus erythematosus and Sjögren's syndrome.
The use of Western blotting or immunoblotting to detect autoantibodies in the serum of patients with autoimmune connective tissue diseases was investigated. An apparatus suitable for simultaneously screening 16 sera on immunoblots was used to show that a complex pattern of antibody binding polypeptides was present in whole HeLa cells. A simpler and readily interpreted pattern of binding was achieved using affinity-purified rabbit thymus antigens. Seventy-seven patients with systemic lupus erythematosus, 44 with primary Sjögren's syndrome and 50 normals were screened for anti-Sm, anti-La, anti-nRNP and anti-Jo-1 by immunoblotting and the results compared with those obtained by counterimmunoelectrophoresis and immunodiffusion. It was shown that both IgG and IgM antibodies must be analysed on immunoblots to detect the maximum number of positive sera, and that the immunoblot detects many anti-La sera which do not form precipitins.
Antibody Specificity↗
Antibody class differences are detected in anti-nRNP and anti-Sm antibodies directed against distinct antigen subunits.
Antibodies to nRNP, Sm and La were detected and characterised by immunoblot analysis. A comparison was made between IgG and IgM autoantibodies in 77 patients with systemic lupus erythematosus (SLE) and 50 normal subjects. No antibodies were detected in the normal subjects. In all 3 antigen specificity groups, a heterogeneity of antibody class was observed between patients. Antibodies to the 2 nRNP-specific polypeptides (33 and 67 kD) were approximately equally frequent. Although IgG antibodies to the 67 kD polypeptide were detected in 88% of patients with antibodies to this polypeptide, IgG antibodies to the 33 kD polypeptide were only detected in 43% of patients with antibodies to this polypeptide. This suggested either that anti-33 kD antibody is produced by a B cell which cannot mature to an IgG-secretor, or that anti-33 kD antibody production succeeds an initial immune response producing anti-67 kD. Reactivity with the 29 kD, Sm-specific polypeptide appeared to be the most frequent in anti-Sm sera compared with the 16 kD polypeptide suggesting that this polypeptide may be the primary immunogenic component of Sm.
Antibodies, Antinuclear↗
Anti-C1q affinity isolated circulating immune complexes correlate with extra-articular rheumatoid disease.
Circulating immune complexes (CIC) were isolated from sera of 35 patients with rheumatoid arthritis (RA) by a two-step method using 2% polyethylene glycol precipitation and anti-C1q affinity chromatography. By this method CIC were exclusive to 19 patients with vasculitis, nodules, or Sjögren's syndrome. Levels of CIC did not correlate with the severity of synovitis but reflected the extent of extra-articular disease. Furthermore, in four patients with persistent severe synovitis observed over a period of 4 to 16 months, the levels of CIC paralleled changes in extra-articular disease. Despite such additional evidence, whether the relationship between CIC and tissue injury is causative or consequential remains unresolved.
Aged↗
Autoimmune disorders--analysis by study of T cells, implications and speculations.
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Antigen-Presenting Cells↗
Rheumatoid arthritis, juvenile arthritis, iridocyclitis and the Epstein-Barr virus.
In order to examine the relation of Epstein-Barry virus (EBV) infection to chronic arthritis in children antibodies to EB virus capsid antigen (EBVCA) and rheumatoid arthritis nuclear antigen (RANA) were analysed in sera from 133 patients classified as juvenile rheumatoid arthritis (JRA) or pauciarticular, polyarticular, or systemic juvenile chronic arthritis. Except for an increased frequency in the systemic subgroup, the prevalence of antibodies to EBVCA and titres of anti-RANA antibodies was similar in patients and controls. These data do not support an aetiological role for EBV in chronic arthritis in children, including JRA, and suggest that the mechanisms which may account for the higher titres of anti-RANA antibodies in adult RA do not occur in children.
Adolescent↗
HLA and rheumatoid arthritis: a combined analysis of 440 British patients.
Four hundred and forty unrelated British Caucasoid patients with rheumatoid arthritis (RA) have been HLA typed for class I and class II antigens. Analyses of HLA antigen associations were performed on the overall group and in patient subsets selected according to particular disease parameters or sex, or both. The results confirm previously reported positive associations of HLA-DR4, Dw4, and DRw53 and negative associations of HLA-DR2 and DR7 with RA. Patients subsets with severe erosions, seropositivity, and features of extra-articular disease showed a stronger association, also confirming earlier reports. The link between HLA and disease severity was emphasised by a significant trend of increased Dw4 frequency with increasing severity of radiological erosions. In addition, a positive association of RA with HLA-A2 was observed and a strong negative association with DR3. The frequency of HLA-B27 was significantly increased in patients with subluxation of the spine. Differences were observed between male and female patients in relation to the HLA association. In men an increase in the frequency of the haplotype HLA/Dw4/DR4/Bw62/Cw3/A2 was observed. This showed no relationship with parameters of disease severity other than extra-articular disease. In women only class II antigens (DRw53/Dw4/DR4) showed an increased frequency. This increase was strongly associated with disease severity. A significant decrease of this class II association was observed with increasing age of disease onset; this was not seen in men.
Adolescent↗
Multiple sclerosis: increased expression of interleukin-2 receptors on lymphocytes.
The percentage of interleukin-2-receptor-positive peripheral blood lymphocytes in MS patients was significantly higher in acute relapse than in remission or in controls. After stimulation by phytohemagglutinin, the expression of interleukin-2 receptor on peripheral blood lymphocytes of MS patients was within the range of healthy controls, implying no general impairment of receptor expression. These results confirm other evidence that there is a small population of activated T lymphocytes in acute relapse of MS.
Adult↗
Murine lupus monoclonal antibodies define five epitopes on two different Sm polypeptides.
Monoclonal anti-Sm (Smith) antibodies derived from the mouse strain MRL/lpr were isolated and characterized by binding to purified antigen, immunoprecipitating characteristic uridine-rich RNAs from Hela cell extracts, and by Western blot analysis using rabbit thymus extract. Five different Sm epitopes were demonstrated by epitope blockade and probing Western blots with the monoclonal antibodies. Human anti-Sm serum inhibited each monoclonal antibody from binding to antigen, indicating that both human and mouse antibodies bind to the same Sm epitopes. Human anti-Sm antibodies bound to 28,000 and 16,000 MW polypeptides, a small number also binding to a 14,000 MW polypeptide. The monoclonal antibodies also bound to the 28,000 and/or the 16,000 polypeptide, and provided evidence to suggest that these two Sm polypeptides bear some structural similarities, but are distinct molecules.
Animals↗
Histocompatibility antigens in adult obliterative bronchiolitis with or without rheumatoid arthritis.
We compared HLA antigens in 28 patients with obliterative bronchiolitis (16 with rheumatoid arthritis) with those in 150 normal controls, to determine their relationship to drug toxicity and to the pathogenesis of obliterative bronchiolitis (OB). There was a significantly increased prevalence of HLA-B40 in the whole group and in patients with OB and rheumatoid arthritis (RA). There was increased frequency of HLA-A2 and A28 within the whole group and in those with OB alone. HLA-A3 and B5 were completely absent in our patients. Of those antigens most frequently associated with RA, DR4 was significantly more prevalent in patients with OB, with or without RA, but DR1 occurred more frequently only in those with RA-associated OB. Increased prevalence of DR4 may indicate an association between the pathogenesis of both OB and RA and the HLA-DR locus. Although D-penicillamine has been implicated in the pathogenesis of OB our patients did not show an increase in those antigens associated with other gold/penicillamine toxicity (i.e. DR2/3), suggesting that they may constitute a distinct group.
Adult↗
Idiotypes on antibodies to the La (SS-B) antigen are restricted and associated with the antigen binding site.
Rabbit anti-idiotypic antibodies were prepared against affinity purified autoantibodies to the ribonucleoprotein La (SS-B) antigen from the sera of three unrelated patients. Each anti-idiotype recognized private idiotypes expressed only on the immunizing anti-La antibody. In each case they were conformationally dependent and related to the antigen binding site. This demonstration of immunodominant private idiotypes on human autoantibodies to ribonucleoproteins is in direct contrast to the cross-reactive idiotypes described on rheumatoid factors and autoantibodies to DNA. We discuss the possibility that anti-La antibodies, unlike anti-DNA, arise as a result of autoantigenic stimulation.
Adult↗
Administration of monoclonal anti-Sm antibody prolongs the survival and renal function of MRL-lpr/lpr mice.
The repeated administration of a monoclonal anti-Sm antibody (KSml) resulted in a significant prolongation of life in MRL-lpr/lpr lupus mice with a 50% mortality of 36 weeks compared with 18-24 weeks in the control groups. Control animals injected with APC11 (a myeloma protein of the same isotype) lived no longer than an untreated group. In addition the renal function as assessed by blood urea levels was less impaired in the KSml-injected mice than in the controls. All KSml-injected mice showed the presence of circulating anti-Sm antibodies which had a different Sm polypeptide binding specificity from that of the injected monoclonal antibody; the increased prevalence of these antibodies compared to the control mice (10-30%) suggested that the anti-Sm antibody response had been induced. The increased longevity in the KSml-treated animals was not associated with alterations in the anti-dsDNA antibody response. The data suggest that administration of anti-Sm antibodies modifies the course of murine lupus.
Animals↗
Individual variation of anti-Sm autoantibodies in the MRL/MP-lpr/lpr mouse: age-related increase in diversity.
The prevalence and diversity of anti-Sm antibodies (which are a marker of human lupus) were investigated in MRL/MP-lpr/lpr mice. The low prevalence of anti-Sm reported by other workers was confirmed. Anti-Sm antibodies bound to either the 28 kD or both 28 and 16 kD polypeptides on immunoblots. Antibodies to the 16 kD polypeptide, detected on spectrotyping blots, were not detected on immunoblots probed with sera from three mice, suggesting that these antibodies were binding only to an additional conformational epitope. Isoelectric focusing of the sera showed that the anti-Sm antibodies were restricted in clonal diversity and in some cases resembled the pattern of a monoclonal antibody. A longitudinal increase in antibody titre was correlated in some mice with an increase in the diversity of clones expressing anti-Sm antibody. Anti-nRNP antibodies were also detected in the mouse serum but had a lower prevalence than anti-Sm antibodies.
Aging↗
The production of small IgG aggregates by glutaraldehyde cross-linking.
Reaction conditions have been determined for the production of soluble IgG polymers in the size range 10 S to 30 S by covalent cross-linking with glutaraldehyde. This size range is comparable with that of the immune complexes which are frequently found in the circulation of patients with certain autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. The yield of IgG aggregates in this size range is far greater than has been reported for cross-linking by other bifunctional reagents or for aggregation by heating. Glutaraldehyde cross-linked IgG polymers are stable and biologically reactive. They can also be labelled with fluorescein and freeze-dried with minimal loss of integrity or reactivity.
Aldehydes↗
Soluble IgG aggregates produced by heating remain stable on freeze-drying.
IgG aggregates produced by heating gamma globulin solutions were freeze-dried, kept at 4 degrees C and reconstituted up to 4 months later. By comparison with frozen (-20 degrees C) preparations, only minimal changes in biological reactivity and in physical integrity occurred during this period. These results demonstrate that freeze-dried preparations of heat-aggregated IgG are potentially useful as a reference reagent for the comparative evaluation and standardisation of immune complex assays.
Antigen-Antibody Complex↗
Monoclonal antibodies to the Sjögren's syndrome associated antigen SS-B (La).
The nuclear autoantigen SS-B (Sjögren's syndrome B antigen) was purified from rabbit thymus extract by immunoaffinity chromatography with human autoantibodies, and used to immunise BALB/c mice for production of monoclonal antibodies. Fusion of spleen cells from an immunised mouse with NS-1 myeloma cells resulted in the isolation of 3 clones secreting anti-SS-B antibody. Subclasses were shown to be IgG2b by immunodiffusion. Specificity of the monoclonal antibodies (MCA) was determined by ELISA and indirect immunofluorescence. By immunoblotting all 3 MCA identified a single 45 K immunoreactive polypeptide in rabbit thymus, identical with the major polypeptide recognised by human sera containing anti-SS-B. Affinity columns prepared from the 3 MCA all bound SS-B from rabbit thymus extract, without binding other nuclear antigens. Immunofluorescence studies on standard substrates showed that SS-B was located predominantly in the nucleoplasm but in cells transformed by EBV or phytohaemagglutinin more prominent nucleolar and cytoplasmic staining was seen.
Antibodies, Monoclonal↗
A rheumatoid arthritis B cell subset expresses a phenotype similar to that in chronic lymphocytic leukemia.
An abnormal subpopulation of B cells expressing the T1 antigen, which is normally restricted to T cells, was demonstrated in the peripheral blood of 16 patients with rheumatoid arthritis. This T1+ B cell population accounted for a mean of 19.6% (upper limit 48%) of the circulating B cells and did not correlate with clinical disease activity, rheumatoid factor, or drug treatment. The highest percentage of T1+ B cells found in the blood of 8 patients with connective tissue diseases, including systemic lupus erythematosus, was 5% of the B cells, and for normal controls, it was was 3% of the B cells. As previously reported, we confirmed that the T1+,Ig+ phenotype was a feature of leukemic cells in B-type chronic lymphocytic leukemia. The finding of increased numbers of T1+ B cells in patients with rheumatoid arthritis and those with B-type chronic lymphocytic leukemia raises the possibility that these cells play a role in a spectrum of diseases, including those involving autoimmunity and malignancy.
Antibodies, Monoclonal↗
Increased representation of a subpopulation of early B cells in the peripheral blood of patients with rheumatoid arthritis.
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Animals↗