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Biomedical subjects

R N Maini

Publications and source records attributed to R N Maini.

At least 199 records · Page 11Linked to original sources
PubMed1990

SLE nephritis: an ultrastructural immunogold study to evaluate the relationship between immune complexes and the basement membrane components type IV collagen, fibronectin and heparan sulphate proteoglycans.

The nature of immune complexes and their relationship to the normal glomerular basement membrane (GBM) components type IV collagen, fibronectin, and heparan sulphate proteoglycans (HSPG) have been examined in the glomeruli of 7 cases of systemic lupus erythematosus (SLE) glomerulonephritis using an ultrastructural immunogold technique. In paraformaldehyde-fixed, Lowicryl resin-embedded tissue, the electron-dense deposits contained IgG, IgM, IgA, and C3 whether they were subepithelial, intramembranous, subendothelial, or mesangial and there was no particular relationship between the class of immunoglobulin and site of immune complex localization within the glomerulus. The normal GBM components type IV collagen, fibronectin, and HSPG were found within all the glomeruli, but did not have the same distribution. Type IV collagen and fibronectin were found predominantly on the inner aspect of the GBM and diffusely throughout the more central regions of the mesangial matrix. By contrast the HSPG was seen mainly on the outer aspect of the GBM and at the periphery of the mesangial matrix. In none of the cases were GBM antigens localized within the electron-dense deposits, results which suggest that autoantibodies to these GBM components may not play a role in the development of the glomerulonephritis.

Adult↗
PubMed1989

The detection by immunofluorescence of distinct cell populations producing interleukin-1 alpha and interleukin-1 beta in activated human peripheral blood.

An immunofluorescent staining method using specific monoclonal antibodies was used to detect IL-1 alpha and IL-1 beta in individual cells in stimulated human peripheral blood. No staining was seen in unstimulated cells but intense, maximal staining of approximately 5% of the cells was seen 20-24 h after activation with PHA/PMA. The large irregularly shaped stained cells were surrounded by smaller unstained cells with lymphocyte-like morphology. By 44 h post activation a few cells only showed weak staining. The staining pattern was different for the two molecules studied, with a granular pattern for IL-1 alpha staining and diffuse cytoplasmic staining for IL-1 beta. Staining post-activation could be abolished by preincubation of the monoclonal antibody with the appropriate recombinant IL-1, but not by pre-incubation with the other IL-1 type. When both anti-IL-1 alpha and anti-IL-1 beta were used together two populations of cells were identified; one had the granular staining as seen with anti-IL-1 alpha alone and the other had the diffuse staining pattern as seen with anti-IL-1 beta. The percentage of cells showing bright staining with anti-IL-1 alpha and anti-IL-1 beta together was approximately equal to the sum of the percentage of cells staining for IL-1 alpha or IL-1 beta alone. This study demonstrates a method for the detection of individual IL-1 alpha- and IL-1 beta- producing cells and suggests that in activated human peripheral blood IL-1 alpha and IL-1 beta are produced by separate populations of cells.

Antibodies, Monoclonal↗
PubMed1989

Increased expression of HLA-DQ antigens by interstitial cells and endothelium in the synovial membrane of rheumatoid arthritis patients compared with reactive arthritis patients.

We investigated cellular phenotypes and expression of class II major histocompatibility complex antigens on endothelium and cellular infiltrates in synovium from patients with rheumatoid arthritis (RA) or reactive arthritis, using an indirect immunoperoxidase technique. The RA specimens showed synovial lining layer hypertrophy and several focal accumulations of lymphocytes, both of which were absent in the reactive arthritis synovium. The percentage of cells expressing monocyte/macrophage markers was significantly higher in RA specimens. The percentages of cells expressing B and T cell markers were similar in both diseases. There was no significant difference in the expression of HLA-DR or DP by endothelium in the 2 diseases, but a marked increase in expression of HLA-DQ by endothelium was observed in the RA synovium versus that from patients with reactive arthritis. This overexpression of HLA-DQ was also seen in the interstitial cells of RA patients compared with reactive arthritis patients. In the reactive arthritis synovium, a significant population of cells (30%) was noted to be HLA-DR positive, and negative for macrophage and lymphocyte markers. Some of these cells had a dendritic morphology. The coexpression of HLA-DQ and HLA-DR may play an important role in antigen presentation and disease chronicity in RA.

Adult↗
PubMed1989

Mechanism of immune complex-mediated damage: induction of interleukin 1 by immune complexes and synergy with interferon-gamma and tumor necrosis factor-alpha.

The ability of immune complexes derived from patients with type II mixed essential cryoglobulinemia to trigger the production of interleukin 1 (IL 1) was investigated. Immune complexes containing either IgM/IgG or IgA/IgG aggregates were shown to induce IL 1 production in human peripheral blood monocyte-enriched populations. Interferon-gamma alone did not induce detectable IL 1, but increased the IL 1 production induced by the immune complexes. Tumor necrosis factor-alpha, which is a potent inducer of IL 1, also enhanced IL 1 production following stimulation with suboptimal doses of the immune complex. The findings suggest that immune complexes may induce inflammation partly due to their capacity to induce the synthesis of IL 1.

Antigen-Antibody Complex↗
PubMed1989

Cytokine production in culture by cells isolated from the synovial membrane.

Cytokine expression was investigated in synovial cell cultures isolated from diseased joints of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Tumour necrosis factor alpha (TNF alpha) was produced spontaneously at high levels by both RA and OA synovial cells. There was no correlation between cell composition and level of TNF alpha produced. In contrast, lymphotoxin (LT) and Interferon gamma (IFN gamma) (greater than 50 pg/ml) were not found. This was further investigated in the RA cultures at both the mRNA and protein level. The results indicated that high levels of mRNA were produced spontaneously by these cells, but the relevant protein was undetectable. The presence of inhibitors and/or shed receptor is unlikely to account for undetectable LT as most of the recombinant LT added to the cultures could be recovered. In addition, in some cases this resulted in an increase in IL-1 production indicating that LT is biologically active in this system. It is not clear at this stage why the protein for these mediators (produced by activated T cells) are not found in the rheumatoid cultures, although it may be due to a post-transcriptional mechanism. This possibility is currently being investigated in addition to the development of more sensitive assays for these cytokines.

Arthritis, Rheumatoid↗
PubMed1989

'Fetal-type' B and T lymphocytes in rheumatoid arthritis and primary Sjögren's syndrome.

B lymphocytes expressing CD5 (CD5+B cells) and T lymphocytes using the gamma and delta chains to form their antigen receptor (gamma delta +T cells) are major populations in developing fetuses, but become relatively minor in normal adults. However, both subsets are expanded in the peripheral blood of more than 50% of patients with rheumatoid arthritis and primary Sjögren's syndrome. We have examined the surface phenotype of these subsets using flow cytometry and have studied the frequency of IgM-producing lines after EBV-transformation of sorted CD5+B and CD5-B cells isolated from neonatal umbilical vein and RA peripheral blood. The intensity of CD5 expression on B cells was at least 10 times 'duller' than on T cells, CD5 'dull' cells were CD3 negative, and T cells bearing the gamma delta antigen receptor did not express either CD4 or CD8 on their surface. In vitro stimulation by Staphylococcus aureus Cowan I or transformation by Epstein-Barr virus of CD5+B cells resulted in loss of CD5 antigen from the surface of B cells. EBV-transformation of sorted CD5+B and CD5-B lymphocytes from neonatal blood gave rise to IgM-secretion in 100% of the Ig-secreting lines. CD5+B fraction isolated from RA blood also generated 100% IgM-secreting lines, whereas 29% of the Ig-secreting lines obtained from RA CD5-B fraction did not secrete IgM. The function of these 'fetal-type' T and B lymphocytes is unknown, however their expansion in rheumatoid arthritis and primary Sjögren's Syndrome suggests that they may play a role in autoimmune diseases.

Antigens, Differentiation↗
PubMed1989

The response to Epstein-Barr virus infection in Sjögren's syndrome.

To assess the response to Epstein-Barr virus (EBV) infection in patients with primary Sjögren's syndrome (SS), the frequency of detection of EBV DNA was studied in salivary gland biopsies and the antibody and idiotypic response to the virus was compared with healthy controls and infectious mononucleosis (IM). Viral DNA, detected by in-situ hybridization, was found in biopsies from two out of 12 patients with SS and six out of 10 controls. IgG, IgA and IgM antibodies to the virus, measured by ELISA using synthetic peptides (early antigen and EBNA-1) and a cloned fusion protein (EBNA-1), were normal in sera from 20 patients with SS, whereas infectious mononucleosis patients showed an increase in IgM antibodies to EBNA-1 and IgG antibodies to early antigen. One similarity between infectious mononucleosis and Sjögren's syndrome was a significant increase in the germline heavy chain idiotype G6 in both diseases, suggesting activation of similar B-cell subsets. It is possible that this is due to EBV, though the low frequency of EBV DNA in biopsies and the normal levels of EBV antibodies in SS does not lend any evidence that the virus itself is the causative agent.

Antibodies, Viral↗
PubMed1989

Autoantibody synthesis in salivary glands of Sjögren's syndrome patients.

We investigated the possibility that autoantibodies are locally synthesized and secreted within salivary glands of patients with Sjögren's syndrome by measuring specific autoantibody as a proportion of the total immunoglobulin present both in serum and saliva. Of 25 patients studied, 21 showed salivary enrichment of IgA anti-La, in three cases IgA anti-La being detected in saliva when IgG anti-La was negative (by ELISA) in serum. Twenty-four showed enrichment of salivary rheumatoid factors and IgA and/or IgM carrying the 17-109 idiotype, a marker of kappa IIIb light chains. These data suggest that autoantibodies, especially of the IgA class, are synthesized primarily in salivary gland and that they can be detected in saliva before they become apparent in the peripheral circulation. The subsequent deposition of these antibodies within salivary glands may be a contributory factor to the pathogenesis of Sjögren's syndrome.

Antibodies↗
PubMed1989

Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis.

Rheumatoid arthritis is an autoimmune disease characterized by T-cell infiltration of the synovium of joints. Analysis of the phenotype and antigen specificity of the infiltrating cells may thus provide insight into the pathogenesis of rheumatoid arthritis. T cells were cloned with interleukin 2, a procedure that selects for in vivo-activated cells. All clones had the CD4 CDW29 phenotype. Their antigen specificity was tested by using a panel of candidate joint autoantigens. Four of 17 reacted against autologous blood mononuclear cells. Two clones proliferated in response to collagen type II. After 21 months, another set of clones was derived from synovial tissue of the same joint. One of eight clones tested showed a strong proliferative response against collagen type II. The uncloned synovial T cells of a third operation from another joint also responded to collagen type II. The persistence of collagen type II-specific T cells in active rheumatoid joints over a period of 3 years suggests that collagen type II could be one of the autoantigens involved in perpetuating the inflammatory process in rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed1989

High rate of HLA class II mRNA synthesis in rheumatoid arthritis joints and its persistence in culture: down-regulation by recombinant interleukin 2.

The expression of HLA class II mRNA was investigated in the joints of patients with active rheumatoid arthritis (RA) in order to evaluate patterns of synthesis. Northern hybridization analysis showed that HLA class II gene transcripts in RA joints were of the correct sizes, and subsequent analyses were performed by slot blotting. All active RA samples expressed high levels of HLA-DR, DP, and DQ mRNA with DP and DQ less than DR. Synovial fluid or membrane cells, chiefly a mixture of T cells and macrophages, were placed in culture, in the absence of any stimulation. The levels of mRNA remained at a high level in vitro. The half of HLA-DR mRNA in joint cells was very brief (approximately 30 min), indicating that prolonged synthesis was due to restimulation of the cells. The effect of lymphokines on HLA class II regulation on joint cell was assessed. Gamma interferon was capable of augmenting HLA-DR to some extent, but paradoxically interleukin 2 at concentrations optimal for stimulating T cells, diminished HLA-DR expression.

Adult↗
PubMed1989

Factors predicting a poor life prognosis in rheumatoid arthritis: an eight year prospective study.

This prospective study evaluates the usefulness of clinical features and measurements of circulating immune complexes and autoantibodies for identification of patients with rheumatoid arthritis with a poor life prognosis. One hundred and seven hospital clinic patients, 64 with extra-articular manifestations, were followed up for a mean period of eight years, during which 50 deaths occurred. Comparison with an age and sex matched control population showed an increased incidence of deaths from myocardial infarction, pneumonia, and complications of rheumatoid arthritis. Patients with cutaneous ulcers, vasculitic rash, neuropathy, and scleritis had a higher mortality than patients whose disease was confined to the joints. Positive serological tests for precipitating antibodies to soluble cellular antigens and cryoglobulinaemia also predicted a poor prognosis. Eleven out of 12 patients (92%) with antibodies to soluble cellular antigens died compared with 21 out of 64 patients (33%) without antibodies. The presence of cryoglobulinaemia was associated with almost a twofold higher mortality. The laboratory measurements may reflect immunopathogenic mechanisms which lead to the occurrence of extra-articular disease features and reduce life expectancy.

Age Factors↗
PubMed1989

Arthritis associated with adjuvant mycobacterial treatment for carcinoma of the bladder.

A patient who developed an inflammatory polyarthritis following intravesical administration of bacillus Calmette-Guérin (BCG) used in the treatment of bladder cancer is described. An inflammatory synovitis comprising predominantly T lymphocytes was demonstrated on synovial biopsy. The synovitis resolved spontaneously within 14 days in this 'human model' of adjuvant arthritis.

Administration, Intravesical↗
PubMed1989

Anti-cardiolipin antibodies in infectious mononucleosis react with the membrane of activated lymphocytes.

To elucidate the mechanisms of autoantibody induction in infectious mononucleosis (IM), we have studied sera from 35 patients with IM with enzyme-linked immunosorbent assays using purified antigens. In the IM group 37% had IgM antibodies to cardiolipin above the normal range (mean plus 2 standard deviations of control sera). Significantly elevated frequencies of antibodies to actin (26%) and cytoskeletal antigens (97% versus 29% in normal sera) were also found, but levels of IgM rheumatoid factors, IgM antibodies to single-stranded DNA and antibodies to ribonucleoproteins (nRNP/Sm, Sm and La) were normal. Affinity purified anti-cardiolipin antibodies reacted with the cell membrane of transformed lymphocytes but not with resting cells, suggesting that cell activation was required for the expression of antigenic epitopes. Our data suggest that the autoantibody response in IM is restricted to two classes of autoantigens: cytoskeletal and cell membrane antigens. The appearance of antigenic epitopes on EBV-transformed lymphocytes could be a mechanism for the generation of anti-cardiolipin antibodies in infectious mononucleosis. Similar mechanisms could operate in autoimmune rheumatic disease.

Actins↗
PubMed1989

Coordinate expansion of 'fetal type' lymphocytes (TCR gamma delta+T and CD5+B) in rheumatoid arthritis and primary Sjögren's syndrome.

In the blood of 10 patients with rheumatoid arthritis (RA), the number of TCR gamma delta+T cells and CD5+B cells was 5.5% +/- 4.38 and 34.3% +/- 20.62 (mean +/- s.d.), respectively. In 12 patients with primary Sjögren's syndrome (SS) the mean +/- s.d. of these T and B cell subpopulations was 4.75% +/- 3.85 and 38.75% +/- 22.68. These values were significantly increased as compared with the circulating T and B cells from 22 healthy subjects in whom TCR gamma delta+T cells were 2.09 +/- 1.01 (P less than 0.001 for RA; P less than 0.004 for SS) and CD5+B cells were 18.09% +/- 4.47 (P less than 0.001 for RA and SS). This increase was not influenced by disease activity. Furthermore, there was a marked correlation (P less than 0.001) between the levels of TCR gamma delta +T cells and CD5+B cells. This novel finding of coordinate elevated levels of lymphocytes with fetal phenotypes in RA and primary SS suggests an immunological imbalance that may have implications in these diseases.

Antigens, Differentiation↗
PubMed1989

Antibodies in rheumatoid arthritis react specifically with the glycine alanine repeat sequence of Epstein-Barr nuclear antigen-1.

Antibodies to rheumatoid arthritis nuclear antigen (RANA) are four- to sixfold increased in sera from patients with rheumatoid arthritis (RA), whereas levels of antibodies to other EBV encoded antigens are slightly elevated or normal. We have demonstrated that the major epitopes recognised by anti-RANA antibodies are represented by a synthetic peptide, P62, corresponding to part of the internal repeat sequence which contains only the amino acids glycine and alanine. In an enzyme-linked immunosorbent assay, anti-P62 antibodies in rheumatoid arthritis sera were four fold higher than healthy and disease controls. By contrast, levels of antibodies to a cloned fusion protein, representing the C-terminus of EBNA-1 and excluding the IR3 region, were normal in RA, but elevated fivefold in nasopharyngeal carcinoma (NPC). Affinity purified anti-P62 antibodies reacted with EBNA-1 and RANA but also with a 60 kD protein present in tissue extracts which has been tentatively identified as cytokeratin. This suggests that the specific increase of anti-P62 antibodies in RA may be due to cross-reactions with autoantibodies to structural proteins with repeat sequences containing glycine. Such sequences are found in cytokeratin and proteoglycans, suggesting that anti-P62 (and hence anti-RANA) antibodies may be cross-reactive antibodies of pathogenic significance in RA, though not necessarily indicating an aetiological role for EBV.

Alanine↗
PubMed1989

Virus infection induces redistribution and membrane localization of the nuclear antigen La (SS-B): a possible mechanism for autoimmunity.

To investigate the possibility that anti-La (SS-B) antibodies in Sjögren's syndrome were induced by virus infection we studied the distribution of La in virus-infected human cell lines. Three monoclonal antibodies to La were used with monoclonal anti-Sm (derived from MRL/lpr lupus mice) and anti-rat immunoglobulin antibodies as controls. In uninfected cells La was predominantly in the nucleus. Twenty-four hours after infection of HEp-2 cells with adenovirus 2, the La and Sm antigens appeared to aggregate and accumulate in the periphery of the nucleus and, after 48 h, La was seen in the cytoplasm and cell membrane. No cytoplasmic or membrane expression of Sm was seen. Infection with adenovirus or cytomegalovirus caused a 2-13-fold increase in the concentration of La in three cell lines. Treatment of HE--2 cells with interferon-gamma (IFN-gamma) and infection with Epstein-Barr virus and cytomegalovirus caused cytoplasmic, but no definite membrane expression of La. The appearance of La on the surface of virally infected epithelial cells together with IFN-gamma induced class II expression could form the basis of a T cell dependent mechanism for anti-La autoantibody induction.

Adenoviridae Infections↗