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Biomedical subjects

R N Maini

Publications and source records attributed to R N Maini.

At least 145 records · Page 8Linked to original sources
PubMed1993

Serological and immunogenetic markers of extraglandular primary Sjögren's syndrome.

The clinical course of 48 patients with primary Sjögren's syndrome (primary SS) was reviewed. Forty-three north European patients were typed for HLA class I and class II alloantigens. In this population with primary SS HLA B8, DR3 and DRw52 all occurred more frequently than in the control population (P < 0.009, P < 0.0035, P < 0.02 respectively). The subgroup of primary SS patients with antibodies to Ro and/or La antigen had the greatest prevalence of DR3 (relative risk 33.4). The primary SS patients fall into two distinct groups: those with extraglandular disease in whom lymphopaenia, hypergammaglobulinaemia, antibodies to Ro and/or La and HLA DR3 were all more frequent and those patients with either glandular disease alone or only one extraglandular feature. There was no difference in disease duration between the two groups, although on average the latter group were 10 years older.

Adolescent↗
PubMed1993

The arthropathy of Sjögren's syndrome.

The clinical course of 48 patients with primary SS has been reviewed with particular reference to the articular manifestations. The incidence of arthritis and/or arthralgia was 54%. In a third of these patients it was a presenting feature and preceded sicca symptoms. The arthropathy tended to be polyarticular, the most frequent joint involved being the knee. It was symmetrical in 55% of cases. Joint symptoms or signs were intermittent, lasting less than a month in 55% of cases. The acute onset of purpuric vasculitis was associated with an acute arthritis in four out of the nine patients with such a vasculitis. Joint deformity was unusual, ulnar deviation occurring in only six patients. Hand X-rays obtained from primary SS patients revealed evidence of joint erosions in 33% of PIP joints, 27% of MCP joints and 12% of wrist joints.

Adult↗
PubMed1993

Increased limb involvement in murine collagen-induced arthritis following treatment with anti-interferon-gamma.

We have tested the effect of administering H22, a hamster neutralizing MoAb to murine interferon-gamma (IFN-gamma) in collagen-induced arthritis. Mice were immunized with human type II collagen in adjuvant on day 1 and boosted with soluble collagen on day 21. H22 was administered (250 micrograms, intraperitoneally) either during the induction of arthritis (on days 0, 6, 13 and 20) or around the time of disease manifestation (on days 21, 28, 35 and 42). Control mice received either an isotype-matched non-neutralizing MoAb or saline. Both treatment regimes gave similar results. Treatment with H22 did not significantly affect the incidence of arthritis, time of onset, degree of oedema, histopathological severity, or level of anti-type II collagen IgG. However, a highly significant increase (P < 0.01) in the number of limbs affected by arthritis was observed in the H22-treated group, irrespective of whether the antibody was administered during the induction of arthritis, or during the time of clinical manifestation of disease. From these results it was concluded that anti-IFN-gamma treatment caused an increase in the number of arthritic lesions, but did not affect the severity of each individual lesion.

Animals↗
PubMed1993

Autoantibodies in malaria, tuberculosis and hepatitis B in a west African population.

Following reports of associations between autoantibodies and living in the tropics, we have studied the seroprevalence and nature of anti-nuclear antibodies, anti-cardiolipin antibodies, antibodies to extractable nuclear antigens and anti-neutrophilic cytoplasmic antibodies in 351 West Africans with malaria, tuberculosis or hepatitis B, or in good health. Amongst healthy West Africans we found a seroprevalence of 7% for anti-nuclear antibodies with several staining patterns, and of 30.3% for anti-cardiolipin antibodies. Among patients with tuberculosis and malaria there was twice that frequency of anti-nuclear antibodies (predominantly speckled in pattern), and anti-neutrophil cytoplasmic antibodies (predominantly IgM) were demonstrated in a few cases. A possible association between IgG anti-cardiolipin antibodies and tuberculosis was observed (P < 0.05), but antibodies to double-stranded DNA were not elevated and no antibodies to extractable nuclear antigens were found in any of the patients or healthy individuals studied. Our findings suggest the need for caution in the interpretation of autoantibody tests in subjects from or living in the tropics, as well as in patients with tropical infections.

Acute Disease↗
PubMed1993

Molecular mechanisms resulting in pathogenic anti-mouse erythrocyte antibodies in New Zealand black mice.

The New Zealand black (NZB) mouse strain is genetically predisposed to develop, at approximately 6 months of age, a spontaneous and severe autoimmune anaemia caused by production of pathogenic anti-mouse erythrocyte autoantibodies. In order to investigate the molecular mechanisms which lead to anti-mouse erythrocyte autoantibody production we have generated eight anti-mouse erythrocyte MoAbs producing hybridomas from splenocytes of 9- and 12-month-old NZB with spontaneous autoimmune anaemia. IgG2a was the predominant isotype, while IgM, IgG1 and IgG2b were each produced by one hybridoma cell line. All anti-mouse erythrocyte MoAbs were characterized for their antigen specificities. None of the MoAbs cross-reacted with ss- or dsDNA or with other species' erythrocytes, with the exception of one MoAb which cross-reacted with rat erythrocytes. None of the eight hybridomas was demonstrated to express surface or cytoplasmic CD5, suggesting that they derived from CD5- B lymphocytes. All hybridomas when implanted intraperitoneally into BALB/c mice caused anaemia. In order to define the genetic basis and investigate the molecular mechanisms resulting in pathogenic anti-mouse erythrocyte autoantibody production, the pattern of immunoglobulin variable region gene use has been studied. Five of the eight MoAbs whose IgVH genes were sequenced all have functionally rearranged genes from the VH J558 gene family. There is evidence for somatic point mutations in the complementarity-determining regions (CDR) of the IgVH genes in all of these five MoAbs when compared with the closest known germline gene. We suggest that these nucleotide sequence changes are likely to reflect selection by an antigen-driven mechanism. Furthermore, the data indicate that pathogenic anti-mouse erythrocytes are not derived from 'natural' autoantibodies.

Amino Acid Sequence↗
PubMed1993

Anti-mouse red blood cell monoclonal antibodies use functionally rearranged genes from the VH J558 family and are derived from the CD5- B-lymphocyte subpopulation.

The NZB mouse strain is genetically predisposed to develop, at approximately 6 months of age, a spontaneous and severe autoimmune anaemia caused by the production of pathogenic anti-mouse red blood cell (MRBC) autoantibodies. Although it is believed that the predisposition to autoimmune anaemia is multigenic in nature, the main pathogenic mechanism is attributed to anti-MRBC autoantibodies. We have generated eight anti-MRBC monoclonal antibody (mAb)-producing hybridomas derived from splenocytes of 9- and 12-month-old NZB mice with spontaneous autoimmune anaemia to dissect the molecular and cellular mechanisms resulting in the production of these pathogenic antibodies. The predominant immunoglobulin isotype was IgG2a, produced by five out of eight hybridomas (63%), while IgM, IgG1 and IgG2b were each produced by one hybridoma cell line (12%). Antigen specificity analysis of all eight hybridomas revealed that antibodies from seven out of eight hybridomas were monospecific for MRBC antigen(s). Only one hybridoma (clone 4-16-1) cross-reacted with rat RBC. None of the hybridomas produced antibodies reactive with single- or double-stranded DNA (ss- or dsDNA). Surface and cytoplasmic staining for the CD5 antigen revealed that none of the hybridomas was derived from CD5+ B lymphocytes. All hybridomas cause anaemia when implanted intraperitoneally into normal BALB/c mice. Molecular studies of five of the eight anti-MRBC mAb reveal that all use functionally rearranged genes from the VH J558 gene family. Three of these five mAb used FL16.1 DH genes while one had a CDR3 that resulted from a fusion between two DH genes (SP2.3 and SP2.2) from the SP family.

Anemia↗
PubMed1993

The clinical implications of autoantibody detection in rheumatology.

The laboratory plays an increasing role in the diagnosis and clinical management of patients with rheumatic diseases. It is therefore essential that the results of laboratory tests are both accurate and reliable, and give clinicians correct information. It is also important to keep clinicians informed of the changes occurring in the rapidly evolving field of investigation of autoantibodies.

Autoantibodies↗
PubMed1992

Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis.

There is considerable evidence implicating tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of rheumatoid arthritis. This evidence is based not only on the universal presence of TNF-alpha in arthritic joints accompanied by the upregulation of TNF-alpha receptors but also on the effects of neutralizing TNF-alpha in joint cell cultures. Thus, neutralization of TNF-alpha in vitro results in inhibition of the production of interleukin 1, which like TNF-alpha, is believed to contribute to joint inflammation and erosion. To determine the validity of this concept in vivo, the effect of administering TNF-neutralizing antibodies to mice with collagen-induced arthritis has been studied. This disease model was chosen because of its many immunological and pathological similarities to human rheumatoid arthritis. TN3-19.12, a hamster IgG1 monoclonal antibody to murine TNF-alpha/beta, was injected i.p. into mice either before the onset of arthritis or after the establishment of clinical disease. Anti-TNF administered prior to disease onset significantly reduced paw swelling and histological severity of arthritis without reducing the incidence of arthritis or the level of circulating anti-type II collagen IgG. More relevant to human disease was the capacity of the antibody to reduce the clinical score, paw swelling, and the histological severity of disease even when injected after the onset of clinical arthritis. These results have implications for possible modes of therapy of human arthritis.

Animals↗
PubMed1992

Anti-type II collagen ELISA. Increased disease specificity following removal of anionic contaminants from salt-fractionated type II collagen.

The purification of type II collagen, for the detection of anti-type II collagen antibodies by ELISA procedures, involves removal of proteoglycans by guanidine-HCl, followed by pepsin solubilisation and salt fractionation. However, type II collagen purified in this way may contain contaminants, despite the apparent purity on SDS-polyacrylamide gels. In this paper we demonstrate how additional purification by DEAE chromatography reduces the degree of background binding in the type II collagen ELISA, leading to an increase in disease specificity. The contaminants included proteoglycan and bound serum IgG from both rheumatoid arthritis (RA) patients and healthy controls in ELISA. Furthermore, positive correlations were observed in the sera (n = 24) between degree of reactivity to the contaminants and to (1) purified proteoglycan (r = 0.50, P = 0.01) and (2) pepsin (r = 0.65, P = 0.001). Thus, inadequate purification of type II collagen produces false positive reactions in the collagen ELISA and gives rise to a high background. A lack of specificity has been frequently associated with this assay.

Adolescent↗
PubMed1992

Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases.

OBJECTIVE: Recently, 2 classes of cytokine inhibitors have been defined at the molecular level. The largest group comprises the extracellular domains of cell surface cytokine receptors, and includes both tumor necrosis factor receptors (TNF-R). The present study was conducted to investigate the role of TNF inhibitors in arthritis. METHODS: We measured p55 and p75 soluble TNF-R (sTNF-R) in serum and synovial fluid (SF) samples from patients with rheumatic diseases and compared their levels with levels of soluble interleukin-2 receptors (sIL-2R). Sensitive enzyme-linked immunosorbent assays (ELISA), specific for p55 and p75 sTNF-R and for sIL-2R, were used. RESULTS: Serum levels of p75 sTNF-R were 3-4-fold higher than levels of p55 sTNF-R, and both were significantly elevated in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) compared with healthy controls. RA SF levels of sTNF-R were 4-5-fold higher than levels in serum, suggesting local production in the joint, and were significantly higher than levels in the SF of patients with seronegative arthropathy or OA. Furthermore, levels of p55 and p75 sTNF-R, but not sIL-2R or TNF alpha measured by ELISA, were increased in the SF of patients with clinically active RA. The soluble TNF-R in RA and OA SF were functional since they inhibited TNF activity in a cytotoxicity assay in proportion to the levels of inhibitor present. Evaluation of serially obtained serum samples suggested that sTNF-R may be a useful parameter for monitoring RA disease activity. CONCLUSION: Biologically active soluble TNF-R are up-regulated in patients with rheumatic disease and are produced locally in the joints. Measurement of serum levels of TNF-R may be useful for monitoring of disease, and determination of SF levels could be of diagnostic value.

Adult↗
PubMed1992

Localization of tumor necrosis factor receptors in the synovial tissue and cartilage-pannus junction in patients with rheumatoid arthritis. Implications for local actions of tumor necrosis factor alpha.

OBJECTIVE: We have previously described the location of tumor necrosis factor alpha (TNF alpha)-producing cells in synovial tissue and cartilage-pannus junction in rheumatoid arthritis (RA). To further understand the local actions of TNF alpha, we investigated the expression of TNF receptors (TNF-R) on cells in the same compartments in patients with RA. METHODS: The expression of both p55 TNF-R and p75 TNF-R was determined using alkaline phosphatase-conjugated mouse anti-alkaline phosphatase (APAAP) and double immunofluorescence staining techniques with monoclonal antibodies. RESULTS: In RA synovial membrane, both p55 TNF-R and p75 TNF-R were detectable in up to 90% of the cells in the lining layer, and were demonstrated on cells in deeper layers of the membrane, including vascular endothelial cells. Cells in lymphoid aggregates expressed both TNF-R, but with a predominant expression of p75 receptor. At the cartilage-pannus junction, the majority of pannus cells, especially those invading cartilage, expressed both the p55 and the p75 TNF-R. Sequential section and double immunofluorescence staining showed that the TNF-R-expressing cells were in the vicinity of TNF alpha-containing cells, and some TNF alpha-containing cells also expressed TNF-R. TNF-R-expressing cells were also detected in osteoarthritic and normal synovial tissue, but in smaller numbers and at a lower intensity. CONCLUSION: These results provide histologic evidence that both p55 TNF-R and p75 TNF-R are expressed by a variety of cell types in RA synovial tissue, reflecting the fact that a wide range of cells are potential targets for TNF alpha in this tissue. This study further supports the hypothesis that TNF alpha plays a major role in the pathogenesis of RA.

Arthritis, Rheumatoid↗
PubMed1992

Enhanced expression of tumor necrosis factor receptor mRNA and protein in mononuclear cells isolated from rheumatoid arthritis synovial joints.

We previously proposed the hypothesis that the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA) based on our observations that it is the dominant inducer of interleukin-1 (IL-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in RA synovial joint mononuclear (MNC) cells in culture. Since TNF-alpha acts via two membrane receptors, we have extended those studies to investigate the distribution of the p55 and p75 TNF receptors (TNF-R) in RA tissue. Surface receptor expression was quantitated by flow cytometry using monoclonal antibodies specific to the p55 (HTR-9) and the p75 (UTR-1) TNF-R. Both receptors were significantly increased on MNC isolated from the synovial membrane of RA patients compared to normal or RA peripheral blood MNC. Interestingly, the p75 TNF-R was increased both on large monocytic/macrophage-type cells and CD3+ lymphocytes. Furthermore, there was a significant increase in the proportion of CD3+ cells in RA synovial fluid expressing the p75 TNF-R, compared to matched peripheral blood MNC. In contrast to RA synovial MNC, p75 or p55 TNF-R expression was not significantly increased in osteoarthritis synovial MNC. In addition, Northern blot analysis indicated abundant expression of both p55 and p75 mRNA in RA synovial joint MNC. This was in contrast to normal peripheral blood MNC cells which contained little or no constitutive TNF-R mRNA; following stimulation with phytohemagglutinin and IL-2, a rapid and transient expression of both receptor mRNA was induced. These results, therefore, indicate that in RA synovial joint tissue there is up-regulation of both p55 and p75 TNF-R mRNA and surface protein expression, and with the presence of TNF-alpha in RA tissues, these results provide support to our hypothesis that TNF-alpha is of critical importance in the pathogenesis of RA.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

Evaluation of the role of cytokines in autoimmune disease: the importance of TNF alpha in rheumatoid arthritis.

Cytokines and growth factors are involved in all important biological processes. Hence it is anticipated that they will be of importance in autoimmune disease. The pathogenesis of autoimmune diseases involves a number of stages, initiation, perpetuation and tissue damage, each of which involves different cell and molecular interactions. In this review, we will discuss an outline of the cytokine involvement in the various stages of autoimmune development, prior to focusing on the analysis of cytokines in rheumatoid arthritis. Cytokines exert their effect via high affinity cell surface receptors. Thus an understanding of cytokines involves the analysis of receptor expression, and also of cytokine inhibitors. Currently there is only adequate knowledge of these aspects in rheumatoid arthritis (RA), and as such the emphasis of this review is on RA. One of the major reasons for being interested in the role of cytokines in autoimmunity is to define possible therapeutic targets. There is now considerable evidence that TNF alpha is such a target in RA, and the effect of anti TNF alpha monoclonal antibody therapy in RA is discussed.

Animals↗
PubMed1992

Detection of cytokines at the cartilage/pannus junction in patients with rheumatoid arthritis: implications for the role of cytokines in cartilage destruction and repair.

Cytokine release at the cartilage/pannus junction (CPJ) may be involved in cartilage destruction and tissue repair in rheumatoid arthritis (RA). Tissue samples of CPJ from 12 RA patients were examined for the presence of cytokines using immunohistochemical techniques with immunoaffinity purified F(ab')2 antibodies raised against recombinant human cytokines. Twenty-four areas of distinct CPJ at which a discrete junction between cartilage and overlying pannus exists were observed. In all specimens, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha. IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor (TGF)-beta 1 were detected in cells in pannus particularly along the surface of cartilage and at the site of cartilage erosion. Double immunofluorescence staining showed that most cytokine containing cells also labelled with a macrophage marker (CD68). About 50% of blood vessel endothelial cells stained for GM-CSF. Twelve areas of diffuse fibroblastic CPJ, at which an indistinct margin is seen between cartilage and pannus were examined. At this site, TGF-beta 1 was the only cytokine detected in fibroblast-like cells. None of these cytokines were detected in synovial tissue at the normal synovium/cartilage junction. Chondrocytes from all 11 normal specimens as well as those from RA patients stained for IL-1 alpha, TNF-alpha, IL-6, GM-CSF and TGF-beta 1, especially those close to subchondral bone. However, IL-1 beta, interferon-gamma and lymphotoxin were not detected in either the normal synovium/cartilage junction or rheumatoid CPJ.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

The immune response to and expression of cross-reactive retroviral gag sequences in autoimmune disease.

To examine the immune response to retroviral gag sequences in autoimmune disease, we measured antibody levels to synthetic peptides representing the major epitopes on HTLV-1 p19 gag and a homologous sequence on the endogenous retrovirus, HRES-1, in sera from 121 patients with autoimmune disease and 52 healthy controls. In the absence of HTLV-1 antibodies, using a conventional diagnostic assay, significantly elevated levels of antibodies to the HTLV-1 peptide were found in 23% of multiple sclerosis and 20% of anti-Sm antibody positive systemic lupus erythematosus patients. Elevated antibody levels to HRES-1 were found in 32% of Sjögren's syndrome and 19% of multiple sclerosis patients. Evidence of reactivity with both HTLV-1 and HRES-1 was found in human sera and cross-reactivity demonstrated with affinity purified rabbit anti-peptide antibodies. Expression of HRES-1, detected by antibodies and Northern blots, was found in lymphoblastoid cells, salivary gland biopsy sections and salivary gland epithelial cells in culture. This study confirms previous reports of low levels of anti-retroviral gag antibodies in autoimmune disease. The cross-reactions support the concept that reports of elevated HTLV-1 antibodies may be due to an endogenous agent such as HRES-1. The expression of HRES-1 salivary gland may explain its antigenicity in a small proportion of Sjögren's syndrome patients as well as suggesting mechanisms whereby it may contribute to the chronic inflammation of autoimmune disease.

Amino Acid Sequence↗
PubMed1992

Localization of interleukin-1 alpha, type 1 interleukin-1 receptor and interleukin-1 receptor antagonist in the synovial membrane and cartilage/pannus junction in rheumatoid arthritis.

Using monoclonal antibodies and immunohistochemical techniques we have investigated the presence and distribution of interleukin-1 alpha (IL-1 alpha), type 1 IL-1 receptor (IL-1R1) and of interleukin-1 receptor antagonist (IL-1ra) in synovial tissue from 18 rheumatoid arthritis (RA) and eight osteoarthritis (OA) patients and in eight normal synovial tissue samples. IL-1 alpha and IL-1R1 were found in all of the samples examined. In RA, there were a large number of synovial cells expressing IL-1 alpha and IL-1R1, with 85 and 90% positive cells in the lining layer, 45 and 80% in the interaggregate area, and 90% of the vascular endothelial cells. In the lymphoid aggregates, 20% of the cells contained IL-1 alpha and 70% expressed IL-1R1. IL-1 alpha and IL-1R1 expressing cells showed a similar distribution in OA synovial membrane, but there was a smaller number of positive cells in the deeper area; and the staining intensity was lower. In contrast to IL-1 alpha and IL-1R1, IL-1ra was found only in 10/18 RA, 5/8 OA and 2/8 normal tissue samples. IL-1ra was detected in 35% of RA and 45% OA lining layer cells; 25% RA and 35% OA vascular endothelium; 10% RA and 15% OA interstitial cells and 30% cells in RA lymphoid aggregate. The staining intensity in both RA and OA tissues was comparably low. The presence of IL-1ra in RA and OA tissues was confirmed by Northern blot analysis for IL-1ra mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1992

TNF alpha--a pivotal role in rheumatoid arthritis?

This review seeks to describe data which support the concept that TNF alpha has a pivotal role in the pathogenesis of RA. There is now compelling evidence from in vitro studies and in animal models that this is the case. The in vitro studies suggest that the direct pathogenic effects of TNF alpha are amplified by its potential to act as a potent paracrine molecule, by inducing other pro-inflammatory molecules such as IL-1, and GM-CSF. It has yet to be established whether similar paracine effects of TNF-alpha are observed in the collagen type II mouse, or in human TNF alpha transgenic mice, where (as discussed in this review), TNF alpha undoubtedly has a pathogenic involvement. During the ongoing inflammation in RA, TNF alpha (and other mediators?) induce the production of soluble TNF-R which can act as natural inhibitors. This process is, however, inadequate within the inflamed synovium, due to the fact that cytokine interactions are very local, through autocrine and paracrine mechanisms. In this environment there is a continuous competition between the interactions of surface or soluble receptor with TNF alpha. It may well be that soluble TNF-Rs play a more important role in the periphery where they act as an essential clearance mechanism for the ligand. If, as the available data suggest, TNF alpha does indeed have a pivotal role in the pathogenesis of RA, this needs to be verified by demonstrating that removal of TNF alpha locally in the synovial joint of RA patients has a significant effect on clinical parameters of disease, and the progression of the disease process itself.

Arthritis, Rheumatoid↗