Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 3315507 | Regulation of HLA class II expression and its role in autoimmune disease. | 1987 | Excessive HLA class II expression is found on the target tissues of the majority of human autoimmune diseases, together with activated (interleukin 2 receptor-expressing) T lymphocytes, suggesting that the target tissues act as antigen-presenting cells for infiltrating autoreactive cells, which in turn produce molecules that maintain class II expression. This vicious cycle has been shown to operate in Graves' thyroiditis, because interferon-gamma (IFN-gamma) induces class II expression on thyrocytes, and thyrocytes expressing class II antigens present their autoantigens to T cells cloned from thyroid tissue of Graves' disease patients. These results led us to consider whether the same mechanisms operate in other autoimmune diseases. In investigations into class II induction in other cell types we found that IFN-gamma is not the only regulator of HLA class II expression and that synergy exists among mediators regulating class II differentially on different cell types. This concept makes it possible to envisage selective diminution of class II antigens on target tissues without loss of class II on antigen-presenting cells. The study of mediators regulating class II expression on cells in vitro led us to ask whether the appropriate regulator molecules are important in disease states. To investigate this question we have developed the use of cDNA probes to analyse the expression of lymphokines, other cytokines, and receptors in small local biopsy samples of tissue from patients with autoimmune diseases. Results obtained so far indicate that mRNAs for many lymphokines are present in synovial fluid cell samples from patients with rheumatoid arthritis. | |
| 3769350 | Technetium-99m MDP vs technetium-99m dicarboxypropane diphosphonate. A clinical comparison | 1986 Feb | The performance of Tc-99m MDP vs Tc-99m dicarboxypropane diphosphonate (DPD) was evaluated in 20 patients with various skeletal bone diseases. Each patient was investigated twice, with an interval of three days between studies and using the same protocol, hence each case served as its own control. The results were: In a subjective interpretation by five independent and experienced investigators, the difference between agents was small, yet in favor of MDP. Region of interest (ROI) analysis of the pooled results in 74.4% of all cases shows a higher bone lesion to normal bone ratio (BL/NB), and in 79.3% of all cases, a better bone lesion to soft tissue ratio (BL/ST) with Tc-99m MDP. When considering pathology types separately, the BL/NB ratio of Tc-99m MDP was 17.7% higher than the one of Tc-99m DPD in metastases, 9.5% higher in rheumatoid arthritis, 2.8% higher in metabolic diseases, and 24% higher in bone fractures. Student's paired t test on the pooled BL/NB ratios shows a difference of 15.5% for Tc-99m MDP, significant at P = 0.00155. The overall results of our study favor Tc-99m MDP. | |
| 1772755 | Overlap syndromes and mixed connective tissue disease. | 1991 Dec | While the etiology of connective tissue diseases remains unknown, the classification of individual cases will continue to depend on identifying certain patterns of clinical and laboratory features. As many as 25% of connective tissue disease patients present with an overlap syndrome with features of systemic lupus erythematosus, systemic sclerosis, polymyositis, or dermatomyositis, with rheumatoid arthritis and Sjögren's syndrome evolving concurrently or consecutively during the course of the disease. The term overlap syndrome is applied to what appears to be a heterogeneous group of disorders, but in recent years there have been attempts to identify antibody markers within this population to identify subsets with particular patterns of disease expression. Thus, anti-U1-ribonucleoprotein is associated with overlap syndromes in which features of systemic lupus erythematosus are accompanied by features of systemic sclerosis or myositis; antibodies to polymyositis-scleroderma, Ku, and U2-ribonucleoprotein are associated with overlaps of systemic sclerosis and polymyositis, and anti-Jo-1 is associated with polymyositis and pulmonary fibrosis. A practical reason for subdividing cases in this way relates to prognosis and treatment, but at a more fundamental level it is hoped that the study of the origin of these antibodies and their antigen targets will provide clues to pathogenesis and even etiology. | |
| 1742333 | Modulation of synovial fibroblast plasminogen activator and plasminogen activator inhibito | 1991 Nov 21 | Phorbol myristate acetate (PMA) added to human synovial fibroblast cultures caused a dose-dependent increase in the production of plasminogen activator inhibitor-type 1 (PAI-1). In addition, PMA inhibited endogenous and interleukin-1 (IL-1) induced plasminogen activator (PA) activity, while increasing mRNA PAI-1 levels. Other protein kinase C (PKC) activators, mezerein and teleocidin B4, caused similar effects. The simultaneous addition of the PKC antagonists, H-7 or staurosporine, prevented the inhibition of PA activity by PMA. This study shows that activation of PKC inhibits PA and stimulates PAI production in human synovial fibroblasts. These results suggest that activation of PKC may play an important role in regulating increased PA production associated with joint destruction in rheumatoid arthritis (RA). | |
| 1921498 | Eosinophilic fasciitis associated with use of L-tryptophan: a case-control study and compa | 1991 Sep | We investigated the relationship between use of L-tryptophan and development of eosinophilic fasciitis by two methods: a retrospective patient survey and a case-control study of patients with eosinophilic fasciitis diagnosed at the Mayo Clinic between 1977 and 1989. Before 1986, no traceable patients with eosinophilic fasciitis had taken L-tryptophan. Between Jan. 1, 1986, and July 31, 1989, 8 of 34 patients had ingested L-tryptophan (P less than 0.001). In the case-control study, traceable patients with eosinophilic fasciitis were matched with patients who had systemic sclerosis or rheumatoid arthritis and healthy control subjects who had undergone a general medical examination. Of the 60 matched control subjects, 2 had used L-tryptophan. Thus, the odds ratio was 19, indicating a 19-fold greater likelihood of use of L-tryptophan in patients with eosinophilic fasciitis than in the control group. A retrospective assessment of clinical features, response to treatment, and blinded review of biopsy specimens of skin and fascia in patients who had eosinophilic fasciitis with or without exposure to L-tryptophan disclosed no significant differences in the two groups. This retrospective study confirms a strong association between consumption of L-tryptophan and development of eosinophilic fasciitis in some patients. No clinical or histopathologic features were detected that distinguished this disorder on the basis of previous exposure to L-tryptophan. | |
| 2058454 | Leflunomide (HWA 486), a novel immunomodulating compound for the treatment of autoimmune d | 1991 Jan | Leflunomide has been shown to be very effective in preventing and curing several autoimmune animal diseases. Further, this agent is as effective as cyclosporin A in preventing the rejection of skin and kidney transplants in rats. Preliminary results from patients suffering from severe cases of rheumatoid arthritis demonstrated that clinical and immunological parameters could be improved with leflunomide therapy. Mode of action studies revealed that this substance antagonizes the proliferation inducing activity of several cytokines and is cytostatic for certain cell types. In this light, we could show that tyrosine phosphorylation of the RR-SRC peptide substrate and the autophosphorylation of the epidermal growth factor (EGF) receptor were, dose dependently, inhibited by leflunomide. EGF activates the intrinsic tyrosine kinase of its receptor, which stimulates the phosphorylation of a variety of peptides, the amino acid residue in all cases is tyrosine. These results indicate that much of leflunomide's activity could be due to the inhibition of tyrosine-kinase(s), which is an important general mechanism for the proliferation of various cell types. Thus, leflunomide, which is effective against autoimmune diseases and reactions leading to graft rejection, would seem to have a mode of action separating it from known immunosuppressive drugs. | |
| 2018389 | Oncogenes, growth factors, and autoimmune diseases (review). | 1991 Jan | Autoimmune diseases are benign proliferative diseases characterized by the expansion and activation of the autoreactive immune cells and the proliferation of connective tissue elements. Because both cytokines and oncogenes products are necessary for expansion of immune cells, it is possible that inappropriate activation of oncogenes might influence cytokine and lymphokine secretion as well as the expression of immune response genes necessary for the development of autoimmunity in a susceptible individual. At least four gene families of the immune system are involved in the induction and perpetuation of autoimmunity: 1) genes associated with the major histocompatibility complex, 2) germline immunoglobulin genes, 3) T cell receptor genes, and 4) complement genes. The hypothetical genetic locus responsible for the induction of autoimmunity is the "rheumogene". Oncogenes are obvious candidates for rheumogenes and activation of such genes may be necessary for the development of autoimmunity. Certain protooncogenes are activated in systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, progressive systemic sclerosis, and dermatomyositis, supporting this hypothesis. However, the activation of oncogenes in autoimmunity is not associated with gene translocation, deletions, point mutations, loss of regulatory sequences, or amplification, indicating that autoimmunity involves different mechanisms of oncogene activation than do many malignancies. Oncogene expression in autoimmune diseases tends to mimic the expression of oncogenes in normal activated lymphocytes, macrophages, and fibroblasts. Rheumogenes, if they exist, may be disordered regulatory genes which suppress or enhance the expression of cellular oncogenes in a non-malignant fashion. The existence of regulator gene demethylation and the presence of DNA-binding proteins specific for oncogene regulator sequences provide support for the concept of that regulator gene dysfunction, rather than oncogene activation per se is the more primary event in autoimmune diseases. | |
| 2303506 | Management of infection about total elbow prostheses. | 1990 Feb | Deep infection was a complication after twelve (7.3 per cent) of 164 primary total elbow replacements. Two additional patients who had an infection about an elbow prosthesis were referred for treatment after total elbow replacement elsewhere. A statistical analysis of all of these primary total elbow arthroplasties, including the two in patients who were referred from outside institutions, identified preoperative factors that placed a patient at significant risk for subsequent infection. The risk factors included a previous operation on the elbow, a previous infection in the region of the elbow, psychiatric illness, class-IV rheumatoid arthritis, drainage from the wound after operation, spontaneous drainage after ten days, and reoperation for any reason. Three modes of treatment were used for patients who had an established infection: débridement and salvage of the implant, resection arthroplasty, and arthrodesis. After early operative débridement and suppression of the infection with long-term antibiotic therapy, three patients were able to retain the prosthesis, with restoration of range of motion and function of the upper extremity. One prosthesis was reimplanted after a six-week course of intravenous administration of antibiotics. | |
| 2122642 | Extracellular phospholipase A2 activity in two in vivo models of inflammation. | 1990 | Two "in vivo" models of inflammation have been used to investigate the role of phospholipases A2 (PLA2) in inflammation. These models are casein-induced peritonitis in the rat and zymosan-induced peritonitis in the mouse. The extracellular PLA2 activities from peritoneal lavage fluid in these two models are similar: they are calcium dependent and have broad neutral pH optima. However, the relationship between extracellular PLA2 activity and cell influx in these models are not identical. In zymosan peritonitis, PLA2 activity preceded peak cell influx, reaching a maximum within 15 min after zymosan injection, while cell influx peaked by 8 hr. In casein-induced peritonitis, the PLA2 activity peaked at 24 hr, while cell influx continued through 48 hr. The origins of the PLA2 activities in both models remain unclear; one potential source is the plasma. Understanding the role of extracellular PLA2 activity in "in vivo" models, and investigating specific inhibitors in these models may aid in our understanding of the role of extracellular PLA2 in diseases such as rheumatoid arthritis, endotoxin shock and pancreatitis. | |
| 2625689 | An endoscopic comparison of the gastroduodenal injury seen with salsalate and naproxen. | 1989 Dec | Forty endoscopically normal healthy subjects were randomized to receive either BID salsalate (3500 mg/day) or BID naproxen (750 mg/day) for 14 days followed by repeat endoscopic examination. Gastroduodenal lesions were found in 55% (11/20) of the subjects taking naproxen, and 10% (2/20) of those taking salsalate (p = 0.002). Twenty-five percent (5/20) of the subjects taking naproxen and none of the subjects taking salsalate were noted to have severe gastric injury (p = 0.003). There was no difference between the 2 groups in subjective gastrointestinal system adverse experiences. Overall, 95% (19/20) of subjects taking salsalate reported at least 1 adverse experience compared with 60% (12/20) of those taking naproxen (p = 0.02). This was due primarily to the higher number of subjects taking salsalate reporting reversible tinnitus or hearing loss. There was no significant treatment difference in adverse experiences reported for any other organ system. The results of our study support previous observations in patients with rheumatoid arthritis that salsalate produces less gastroduodenal mucosal toxicity than the widely used antiinflammatory agent, naproxen. | |
| 2600938 | Elevation of a tumor associated antigen CA 19-9 levels in patients with rheumatic diseases | 1989 Nov | We investigated the incidence and characteristics of an elevated tumor associated antigen CA 19-9 in patients with rheumatic diseases. Serum concentration of CA 19-9 was increased in 13 of 39 patients (33.3%) with definite or classical rheumatoid arthritis (RA), in 6 of 19 patients (31.6%) with systemic lupus erythematosus (SLE), in 3 of 9 patients (33.3%) with progressive systemic sclerosis (PSS) and in 9 of the other 35 patients (25.7%). Malignant neoplasm was not detected in any of the patients with rheumatic diseases. Pretreatment of mouse serum with patients' sera did not reduce the measured CA 19-9 values obtained by the conventional assay. The CA 19-9 antigen found in sera from patients with RA was present in a non-IgG fraction, and had the same molecular weight as that in one patient with pancreatic cancer, as determined by gel filtration. These results demonstrated that serum CA 19-9 levels were increased in some patients with rheumatic diseases. | |
| 2478093 | Increased numbers of CD5+ B lymphocytes in schizophrenic patients. | 1989 Oct | Autoimmune mechanisms have been postulated to play a role in the pathogenesis of schizophrenia. Recently, increased numbers of B lymphocytes expressing the CD5 (Leu-1) surface antigen have been observed in patients with certain autoimmune diseases. In the present study, approximately 30% of schizophrenic patients (11/34) were found by cytofluorometric methods to have similarly increased levels of circulating CD5+ B cells compared with 6% (2/33) of healthy individuals and 5% (1/20) of patients with bipolar affective disorder. In schizophrenic patients with a "high" CD5+ B-cell phenotype, the percentage of B cells expressing the CD5 surface marker (mean +/- SEM, 52.4% +/- 3.5%) was comparable to that reported for patients with rheumatoid arthritis and significantly greater than that reported for patients with bipolar affective disorder (25.7% +/- 2.5%) and healthy controls (31.0% +/- 1.8%). Schizophrenic patients with high levels of CD5+ B cells had increased numbers of total B cells compared with control subjects and patients with low levels of CD5+ B cells. An elevation in CD5+ B cells may delineate a subgroup of schizophrenic patients whose disease has an underlying autoimmune and/or genetic cause. | |
| 2576330 | Drug interactions with non steroidal anti-inflammatory drugs (NSAIDs). | 1989 | Drug interactions occur when the pharmacologic profile of one drug is altered by the administration of another drug. These interactions may be due to changes in absorption, distribution, metabolism or excretion. NSAIDs are associated with drug interactions but only a proportion are clinically relevant. Many are due to displacement of a drug from its plasma protein binding sites by NSAIDs which are tightly protein-bound. They may not occur with all NSAIDs but might be selective: most NSAIDs do not have clinically important interactions with oral hypoglycemic agents whereas phenylbutazone, azaprozone & aspirin prolong their half-life. Similarly phenylbutazone and azaprozone prolong coumadin's half-life. Lithium clearance may be decreased by indomethacin, piroxicam, phenylbutazone and diclofenac. Methotrexate (MTX) may be displaced from its binding protein sites by NSAIDs. This is generally not clinically relevant with low doses of MTX as utilized in rheumatoid arthritis patients with normal renal function. NSAIDs also may reduce renal blood flow, tubular excretion of drugs & renal prostaglandin production and may attenuate the effect of anti-hypertensive drugs. Renal failure & hyperkalemia have been reported in patients receiving triamterene & indomethacin. The clinician should be aware of important drug-drug interactions prior to prescribing NSAIDs. Continued scrutiny of these effects are indicated to increase the safety profile. | |
| 3265150 | Analgesic action of amfenac Na, a non-steroidal anti-inflammatory agent. | 1988 Sep | Amfenac Na is a new non-steroidal analgesic anti-inflammatory drug which is clinically used for ailments such as rheumatoid arthritis and pain and/or inflamation after surgery. In this paper, amfenac Na is studied on the bradykinin induced-flexor reflex and the simultaneous recording of the cortical somatosensory-evoked response (SER) and the electromyogram of digastric muscle (d-EMG) evoked by a tooth pulp stimulation. Amfenac Na at doses of 0.1-1 mg/kg p.o. suppressed hindlimb flexor reflexes induced by bradykinin infusion in the rat. This effect was the most potent among the drugs used; the order of potency was as follows: amfenac Na greater than floctafenine greater than loxoprofen much greater than piroxicam = emorfazone greater than mefanamic acid. Similarly, the intravenous injection of amfenac Na completely suppressed the flexor reflex with a dose as low as 0.1 mg/kg; the potency was almost equal to that of morphine. On the SER and d-EMG evoked by tooth pulp stimulation, a high dose (100 mg/kg i.v.) of amfenac Na showed very weak inhibition, whereas morphine (10 mg/kg i.v.) suppressed those responses. These data suggest that amfenac Na showed a very potent analgesic effect comparable to morphine, and that the site of action is mainly the periphery. | |
| 3048809 | Two calcium-binding proteins associated with specific stages of myeloid cell differentiati | 1988 Jun | Using a monoclonal antibody to macrophage migration inhibition factor (MIF), two proteins were isolated from supernatants of Concanavalin A-stimulated human peripheral blood mononuclear cells which seem to have complexed to a third component carrying the MIF activity. They are therefore designated MIF-related proteins or MRP-8 and MRP-14 according to their apparent molecular weights. Partial amino acid sequences have been determined and their cDNA have been cloned and expressed in Escherichia coli. Both are calcium-binding proteins and MRP-8 seems to be largely homologous to the cystic fibrosis antigen (Dorin et al., 1987). Antisera were raised in the rabbit against the recombinant proteins and their expression in cells and tissues studied using immunohistological techniques. The proteins are only found in blood granulocytes and monocytes. In culture the number of positive monocytes sharply increased and then declined with time, suggesting that their expression is associated with early stages of monocyte/macrophage differentiation and absent from resident macrophages in all tested tissues. In acute inflammatory reactions, e.g. gingivitis, MRP-8 is never seen in the tissue, whereas MRP-14 is expressed by intravascular monocytes and perivascular macrophages. In contrast, in chronic inflammation, e.g. rheumatoid arthritis, MRP-8 is also expressed by macrophages in the tissue. From this it is concluded that MRP-8 and MRP-14 are expressed sequentially at defined stages of monocyte/macrophage differentiation and that dysregulation of this process in chronic inflammation is mirrored by the presence of MRP-8-positive macrophages in the tissue. | |
| 3282679 | Potentiation of Balb/3T3 fibroblast proliferative response by interleukin-1 and epidermal | 1988 May | Balb/3T3 fibroblasts respond to interleukin-1 (IL-1) by proliferating in a dose-dependent fashion. Increasing proliferative responses were observed with increasing IL-1 concentration in serum-free medium when the medium was supplemented with insulin, transferrin, and selenium. This response was evident only if the cell culture medium also contained the cyclooxygenase inhibitor indomethacin. When another fibroblast mitogen, epidermal growth factor (EGF) was cocultured with either purified monocyte-derived IL-1 beta or recombinant IL-1 beta, there was a potentiation of proliferation above the expected additive response. Unexpectedly, the response to recombinant IL-1 alpha was only additive with EGF. This suggests that IL-1-mediated activation of synovial fibroblasts in rheumatoid arthritis may be compounded by EGF as well as by other fibroblast mitogens secreted by cells found in the joint. The results further suggest that IL-1 and EGF interactions may play a significant role in wound healing, scarring, and bone resorption. In addition, these results imply that there may be different cellular activation pathways brought to bear in vivo which may depend, in part, on the IL-1 isotype available. | |
| 3422543 | The affected-pedigree-member method of linkage analysis. | 1988 Feb | This paper describes a generalization of the affected-sib-pair method of linkage analysis to pedigrees. By substituting identity-by-state relations for identity-by-descent relations, we develop a test statistic for detecting departures from independent segregation of disease and marker phenotypes. The statistic is based on the marker phenotypes of affected pedigree members only. Since it is more striking for distantly affected relatives to share a rare marker allele than a common marker allele, the statistic also includes a weighting factor based on allele frequency. The distributional properties of the statistic are investigated theoretically and by simulation. Part of the theoretical treatment entails generalizing Karigl's multiple-person kinship coefficients. When the test statistic is applied to pedigree data on Huntington disease, the null hypothesis of independent segregation between the marker locus and the disease locus is firmly rejected. In this case, as expected, there is a loss of power when compared with standard lod-score analysis. However, our statistic possesses the advantage of requiring no explicit assumptions about the mode of inheritance of the disease. This point is illustrated by application of the test statistic to data on rheumatoid arthritis. | |
| 3335628 | Autoantibodies to the heat-shock protein hsp90 in systemic lupus erythematosus. | 1988 Jan | Patients with systemic lupus erythematosus (SLE) develop multiple autoantibodies to self-antigens. Analysis of autoantibody systems in this and related autoimmune disorders can provide information of etiologic and pathogenetic significance. We report here a previously unrecognized autoantibody to the 90,000-D heat-shock protein, hsp90, a molecule thought to have important functions in the cellular response to stress, virus-induced transformation, steroid hormone receptor action, and cellular activation. Autoantibodies to hsp90 were exclusively of the IgG class, and were detected in approximately 50% of unselected patients with SLE and 2/6 patients with idiopathic polymyositis. Anti-hsp90 antibodies were not detected in sera from 10 normal subjects, 10 patients with rheumatoid arthritis, or 7 patients with scleroderma. The identity of this major intracytoplasmic antigen was established by its specific removal from nonionic detergent cell lysates following immunoabsorption with monospecific rabbit anti-hsp90, and by demonstration of increased synthesis following a 10-min 45 degrees C heat shock. These data define the frequent occurrence of a novel autoantibody to a major heat-shock protein in patients with SLE. | |
| 3494777 | Auranofin increases the affinity of phorbol dibutyrate receptors in chronic lymphocytic le | 1987 May 1 | Previous studies have shown that auranofin (AF), a lipophilic gold I complex, modulates metabolic events in leukocytes stimulated by phorbol esters, whose major cellular binding site is now known to be the Ca++/phospholipid-dependent protein kinase (protein kinase C). In these experiments we have investigated the effect of AF on the binding of phorbol dibutyrate (PDBu) to human chronic lymphocytic leukemia (CLL) B cells. AF enhanced binding of PDBu to its receptor in CLL cells by a) causing an increase in the affinity of PDBu receptors from Kd 20.3 nM to 7.3 nM, and b) enhancing translocation of PDBu receptors to the cell membrane. The increase in PDBu binding induced by AF in whole cells was only partially reversible by EGTA or the intracellular Ca++ antagonist TMB-8. Studies performed with quin-2-labeled cells showed that 100 microM AF caused a mean (+/- SD) rise in cytosolic Ca++ levels from 0.41 (0.12) to 0.85 (0.33) (n = 5). Thus the mechanism by which AF increases binding of PDBu to its receptor appears to be partially dependent on Ca++. These effects of AF occurred at cellular levels achieved in mononuclear cells during chrysotherapy of patients with rheumatoid arthritis. | |
| 3495035 | [The role of T-lymphocytes in organ-specific autoimmune diseases]. | 1987 Mar 14 | Chronic debilitating diseases such as multiple sclerosis, demyelinating inflammatory polyradiculoneuropathy, rheumatoid arthritis, diabetes mellitus type I, Hashimoto thyroiditis, forms of uveitis and interstitial nephritis, share many characteristics. They are all organ-specific inflammatory diseases of unknown etiology but with strong evidence of tissue-destructive activity of the cellular immune system in the organs respectively affected, i.e. the central or peripheral nervous system, the joints, the islets of Langerhans, the thyroid gland, the retina, or the tubulo-interstitial renal tissue. Recognized animal models of all these diseases are experimentally induced autoimmune conditions that are transferable with autoreactive T-lymphocytes, in contrast to autoantibodies in humoral autoimmune diseases. In recent years, disease-transferring T-lymphocytes, have been successfully grown as lines and clones in vitro, thus finally proving the primary pathogenic role of autoreactive T-lymphocytes in these animal models. Such T-cell lines are valuable tools in further defining autoantigens, studying mechanisms of T-cell activation in vitro, following T-cell migration and organ-specific homing in vivo, and analyzing effector functions in the infiltrated organs. In addition, questions concerning the breakdown of immunological selftolerance and the basic principles of resistance to disease can be addressed, and possibilities of treatment can be approached. Although the basic etiology of the human organ-specific immune diseases is still unknown, these animal models have helped to throw light on some of the pathogenic mechanisms common to these various diseases. |