Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
7787745 Immunosuppression-associated lymphoproliferative disorders in rheumatic patients. 1995 Feb The association between rheumatic disease and the occurrence of hematolymphoid neoplasms has been a subject of investigation for many years. Recently, we and others have reported the development in rheumatic patients of lymphoproliferative disorders that are similar to those occurring in patients with known immunocompromised states. The lymphoid neoplasms that develop in patients with immunosuppression are characterized by several features including the presence of EBV genome in the neoplastic cells. The fact that lymphomas with features of those occurring in immunosuppressed patients can occur in patients with rheumatic disease suggests that immune system impairment secondary to the rheumatic disease, the treatment given for the rheumatic disease, or to a combination of these factors, might play a role in the development of lymphoma in these patients. This review will first describe the characteristics of lymphoproliferative disorders that occur in patients with known immunocompromised states. It will then review general aspects of lymphomas in rheumatic patients with a focus on more recent reports that have described the development of immunosuppression-associated lymphoproliferative disorders in rheumatic patients. Studies that investigate the relative contribution of the rheumatic disease versus therapy for rheumatic disease in the development of lymphoma in this patient group are still needed.
7530962 HLA association of anti-Ro60 and anti-Ro52 antibodies in Sjögren's syndrome. 1994 Oct The possible pathological role of antibody subsets specific for different regions of 60-KD and 52-KD Ro/SSA proteins (Ro60 and Ro52) and La protein is unclear. Previously, we have shown that in patients with Sjögren's syndrome, the fine specificity of Ro60 and Ro52 antibodies, as characterized with synthetic peptides, varied considerably according to the origin of sera. We therefore looked for possible associations of HLA class I and class II alleles with Ro and La IgG antibodies in patients with primary Sjögren's syndrome (n = 24) and secondary Sjögren's syndrome associated with systemic lupus erythematosus (n = 25). Ro60 and Ro52 antibodies were tested by ELISA with the complete parent proteins and with 10 to 24 residue-long peptides of these proteins. Anti-Ro60 antibodies were more frequent in DR3-positive patients and in DQ1-negative patients whereas the presence of Ro52 and La IgG antibodies was significantly increased in patients with A1/B8/DR3 haplotype. Certain HLA associations observed with antibodies reacting with the whole Ro52 protein were not found with antibodies reacting with certain Ro60 and Ro52 peptides and, reciprocally, certain anti-peptide antibodies were linked to particular haplotypes whereas antibodies to the respective parent proteins were not linked to these haplotypes. Thus the production of antibody subsets reacting with different parts or presentations of Ro proteins is, at least in part, influenced immunologically by different HLA haplotypes, and this predisposition may play a role in the pathological development of the disease.
8843865 Distinct immunologic features of Finnish Sjögren's syndrome patients with HLA alleles DRB 1996 Oct OBJECTIVE: To determine whether there were differences in the circulating T lymphocyte subsets or clinical features of patients with primary Sjögren's syndrome (SS) who were positive for different HLA alleles. METHODS: Two- and three-color flow cytometry analyses were performed, using a whole blood lysing method. RESULTS: Patients with SS who had the HLA alleles DRB1*0301, DQA1*0501, and DQB1*0201 had lower levels of circulating V delta 1-positive T cell receptor gamma/delta (TCR gamma/delta) cells and higher levels of circulating CD45RO-positive TCR gamma/delta cells compared with patients with SS who did not have these alleles. The patient subgroup with these alleles also had higher levels of anti-SS-A/Ro and anti-SS-B/La. CONCLUSION: These results indicate that patients with primary SS may be immunologically divided into subgroups according to their HLA status. These immunologic changes in SS may also be typical of other autoimmune disorders in patients with the HLA-DR3 haplotype.
8192178 Age and sex associations of 40 autoimmune diseases. 1994 May Self-injury by the host's immune system is believed to be a factor in the etiology of many diseases. Much attention has been given to the part played by sex hormones in such processes. Current literature frequently maintains that females are more susceptible than males to autoimmune diseases. In order to gain information about this factor, a tabulation has been made of the sex incidence of 40 autoimmune diseases which occur at different periods of life: childhood, early adult life, mature adult life, and old age. To some extent the tabulations substantiate female preponderance, but in some there is no gender difference, and in others, particularly the autoimmune nephropathies, male preponderance is the rule. Findings in experiments with animal analogues of human autoimmune disease, showing that administration of estrogen augments the manifestations, whereas androgen treatment suppresses them, do not correlate closely with clinical experience.
8929481 Myelodysplastic syndromes and acute myeloid leukemia in connective tissue disease after si 1996 Nov Cytopenias are typical of patients with connective tissue disease (CTD) and are usually related to autoimmune phenomena. In some cases, cytopenia may be the result of treatment with cytotoxic agents. Although multi-drug therapy is known to produce myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) in patients with CTD, treatment with single-agent therapy, particularly methotrexate, has rarely been associated with secondary MDS or AML. Blood and marrow samples were studied from 3 men and 5 women with rheumatoid arthritis (5 cases), Behcet's disease (2 cases), and systemic lupus erythematosus (1 case) developing MDS or AML after methotrexate (5 cases), chlorambucil (2 cases), and cytoxan (1 case). The durations of CTD ranged from less than 6 months to more than 10 years. Five patients (63%) presented with MDS including refractory anemia (RA), refractory thrombocytopenia (RT), refractory anemia with excess blasts (RAEB), chronic myelomonocytic leukemia (CMML), and RAEB in transformation. Patients with RT, CMML, and RAEB in transformation developed AML. Of six patients presenting with or developing AML, four had AML with differentiation (FAB M2), one acute myelomonocytic leukemia (FAB M4), and one M4Eo. Inv 16 was seen in the M4Eo and t(8;21) in one case of M2. Four of six patients are alive up to 6 years after diagnosis of AML. One of three patients with MDS is alive 6 months after diagnosis of MDS. Cytopenias in patients with CTD may be due to therapy-related MDS or AML occurring in a setting of single-agent chemotherapy, including methotrexate.
8915784 Bone structure and turnover in the distal radius and iliac crest: a histomorphometric stud 1996 Nov In bone grafting procedures of the wrist, the distal radius would be a more convenient graft donor site than the conventionally used iliac crest. We compared tetracycline-labeled bone biopsies from these two sites in 18 white patients (12 males, 6 females, aged 26-66 years) undergoing bone grafting procedures of the wrist. Fourteen had had previous trauma, 1 osteonecrosis of the lunate, 2 mild rheumatoid arthritis, and 1 a brachial plexus palsy. The specimens were processed undecalcified and examined by routine histomorphometry for bone structure, static and dynamic bone turnover variables, and marrow cellularity. We found that bone from the distal radius had thinner cortices (p = 0.0001), lower bone volume (p = 0.01), thinner trabeculae (p = 0.029), greater trabecular separation (p = 0.015), and lower wall thickness (p = 0.0001), marrow cellularity (p = 0.0001), osteoid volume (p = 0.01), osteoid surface (p = 0.02), osteoid thickness (p = 0.0002), osteoblast surface (p = 0.001), eroded surface (p = 0.01), osteoclast surface (p = 0.012), mineral apposition rate (p = 0.0002), double-labeled surface (p = 0.0005), single-labeled surface (p = 0.006), bone formation rate (p = 0.0005), adjusted apposition rate (p = 0.0001), longer mineralization lag time (p = 0.012), and greater activation frequency (p = 0.003). Prolonged mineralization lag time in the radius was associated with thin osteoid seams and low adjusted apposition rates and was therefore attributable to a low level of osteoblast activity rather than to osteomalacia. We conclude that bone from the distal radius was structurally inferior to and had lower turnover than the iliac crest bone. We suggest that where a graft has to provide immediate structural integrity, the iliac crest is the preferred donor site. However, where bone graft is to be compacted into a small cavitary defect, distal radial bone may be an adequate alternative. A clinical study is needed to confirm this assumption.
8830984 Mechanisms of cytokine induced bone resorption: role of nitric oxide, cyclic guanosine mon 1996 Jul We have examined the role of prostaglandins, nitric oxide (NO), and the NO induced effector molecule cyclic-guanosine monophosphate (cGMP) as mediators of cytokine effects on bone resorption in murine calvarial organ cultures. The combination of interleukin-1 beta (IL-1) and tumor necrosis factor alpha (TNF) stimulated NO production, PGE2 production, and bone resorption. The increase in bone resorption was inhibited by the NO synthase inhibitor L-NG-monomethyl arginine (LMMA) and by the cyclo-oxygenase inhibitor indomethacin, indicating that both factors act as mediators of bone resorption induced by IL-1 and TNF. In contrast, interferon gamma (IFN) inhibited bone resorption induced by IL-1, markedly stimulated NO production, but had no effect on IL-1 induced PGE2 production. The suppressive effect of IFN on bone resorption was reversed by LMMA, but enhanced by indomethacin confirming that the inhibitory effect of IFN on cytokine induced resorption is entirely attributable to high levels of NO production. While cytokine induced NO production was accompanied by increased production of cyclic guanosine monophosphate (cGMP), the cGMP agonist 8-bromo-cGMP had no significant effect on bone resorption, suggesting the effects of NO in bone resorption are mediated by other pathways. We conclude that the effect of cytokines on bone resorption are determined by a balance between levels of NO and PGE2; high NO concentrations inhibit bone resorption and antagonize the effects of PGE2, whereas lower concentrations act together with prostaglandins to enhance bone resorption. These observations may be of relevance to the pathogenesis of bone loss in inflammatory diseases such as rheumatoid arthritis (RA) where, IL-1 and TNF production are increased but IFN production is diminished, resulting in modest increases in NO and large increase in PGE production that are pro-resorptive.
8666898 The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human 1996 Apr 1 Interleukin 6 (IL-6) is considered an important mediator of acute inflammatory responses. Moreover, IL-6 functions as a differentiation and growth factor of hematopoietic precursor cells, B cells, T cells, keratinocytes, neuronal cells, osteoclasts, and endothelial cells. IL-6 exhibits its action via a receptor complex consisting of a specific IL-6 receptor (IL-6R) and a signal transducing subunit (gp130). Soluble forms of both receptor components are generated by shedding and are found in patients with various diseases such as acquired immune deficiency syndrome, rheumatoid arthritis, and others. The function of the soluble (s)IL-6R in vivo is unknown. Since human (h)IL-6 acts on human and murine target cells, but murine IL-6 on murine cells only, we constructed transgenic mice expressing the hsIL-6R. We report here that in the presence of hsIL-6R, mice are hypersensitized towards hIL-6, mounting an acute phase protein gene induction at significantly lower IL-6 dosages compared to control animals. Furthermore, in hsIL-6R transgenic mice, the detected acute phase response persists for a longer period of time. The IL-6/IL-6R complex prolongs markedly the Il-6 plasma half-life. Our results reinforce the role of the hsIL-6R as an agonistic protein, help to understand the function of the hsIL-6R in vivo, and highlight the significance of the receptor in the induction of the acute phase response.
8991630 Silicate antibodies in women with silicone breast implants: development of an assay for de 1996 Mar Silicon, in the form of sodium silicate (Na2SiO3), adsorbed onto bovine serum albumin (BSA)-precoated plates served as the solid-phase antigen in an enzyme immunoassay to detect silicate-reactive antibodies in the plasma of 40 symptomatic women with silicone breast implants, 91 asymptomatic women with silicone breast implants, 50 healthy control women, and 52 women with rheumatic diseases and without silicone breast implants, Silicate-reactive antibodies of immunoglobulin G (IgG) or IgM isotypes were detected in the plasma of 30% (12 of 40) of the symptomatic women with silicone breast implants; 9% (8 of 91) of the asymptomatic women with silicone breast implants; 5% (1 of 20) of the women without implants who had systemic lupus erythematosus; and 0% (0 of 32) of the women without implants who had either Sjögren syndrome, scleroderma, or rheumatoid arthritis. Only 2% (1 of 50) of the sera from the healthy control women contained silicate-reactive antibodies. Preincubation of sera with silicate and eight other metal compounds (including SiO2) demonstrated that the IgG and IgM antibodies bound specifically to silicate, because preincubation with Na2SiO3 inhibited more than 90% of the activity, whereas CrO3, Li2SO4, MgSO4, NiSO4, HgCl2, ZrOCl2, BeSO4, and SiO2 failed to inhibit the IgG or IgM antibody binding to the silicate-BSA plates. Furthermore, the F(ab')2 portion and not the Fc portion of the silicate-reactive IgG was reactive with BSA-bound silicate in the enzyme immunoassay. The assay for silicate-reactive antibodies was quantified by assigning arbitrary units to a standard curve composed of serial twofold dilutions of high-positive (ten times higher than the cutoff) silicate antibody sera. This novel assay is a useful method for detecting and quantifying humoral immune response to silicate.
8575432 Monoclonal antibodies specific for natural human neutrophil gelatinase B used for affinity 1995 Dec 15 Human gelatinase B was produced from peripheral blood neutrophils and purified by affinity chromatography on gelatin sepharose. This material was used as an antigen to prepare mouse monoclonal antibodies (mAb). The resulting hybridomas were selected on the basis of binding to biotinylated antigen and by a sandwich ELISA using gelatinase-B-specific polyclonal rabbit antiserum and pure natural antigen. Five of these mAb were selected for further characterization. They all displayed variable epitope specificity, binding capacity and inhibitory activity. Whereas mAb REGA-2D9 and REGA-3G12 showed the strongest binding to biotinylated gelatinase B and natural gelatinase B, respectively, mAb REGA-2F9 did not bind biotinylated antigen. None of the mAb displayed cross-reactivity to gelatinase A in a direct ELISA. The mAb REGA-1G8 was found to cross-react with human serum albumin. The binding capacity of the other four mAb with leukocyte gelatinase B was compared and a sensitive sandwich ELISA was developed with the antibodies REGA-3G12 and REGA-2D9 (detection limit 0.5 ng/ml). The mAb REGA-3G12 was unique in that it inhibited catalysis by gelatinase B. This was shown by assaying the degradation of nasal septum type II gelatin in the presence and absence of each of the five mAb. Furthermore, mAb REGA-3G12 inhibited the degradation of biotinylated gelatin in a microtiterplate solution assay. In addition to the potential use of the inhibitory mAb REGA-3G12 in the treatment of diseases with excessive gelatinase B production, several of the described mAb are useful as diagnostic probes to detect gelatinase B in body fluids and tissue samples of patients with multiple sclerosis, rheumatoid arthritis and cancer.
8596147 The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: 1995 Nov OBJECTIVE: To determine the pharmacokinetics of methotrexate (MTX) with and without nonsteroidal antiinflammatory drugs (NSAID) at a 7.5 mg dose and higher usual maintenance doses of the drug. To determine the difference in pharmacokinetic variables when salicylate and nonsalicylate NSAID are administered with MTX at these doses. METHODS: Thirty patients receiving MTX chronically underwent a study of MTX pharmacokinetics after 7.5 mg doses of MTX with their usual NSAID and after the NSAID were withheld for 5 half-lives. Sixteen additional patients underwent pharmacokinetics studies with and without NSAID while receiving their usual weekly maintenance dose of MTX of 16.6 (3.6) mg (Mean +/- SD). RESULTS: No significant differences in pharmacokinetic variables were observed with and without NSAID at the 7.5 mg weekly dose of MTX. When patients received usual maintenance doses of MTX the renal clearance of MTX NSAID was 91.7 (26.4) ml/min versus 115.3 (34.4) ml/min without NSAID (p = 0.004). Creatinine clearance in patients taking usual maintenance doses increased from 77.5 (13.9) ml/min with NSAID to 95.3 (26.3) ml/min without NSAID (p = 0.05). A reduction in renal clearance of MTX was observed with maintenance dose MTX in both the 4 patients taking salicylates (p = 0.016) and the 12 patients taking nonsalicylate NSAID (p = 0.024). CONCLUSION: NSAID produce significant decreases in renal clearance of MTX and creatinine when patients consume their usual weekly dose of the drug, but not when they take a 7.5 mg dose. This effect is likely to achieve clinical relevance across the dose ranges used to treat patients with rheumatoid arthritis.
7579784 Epoetin alfa. A review of its clinical efficacy in the management of anaemia associated wi 1995 Aug Epoetin alfa is a recombinant form of erythropoietin, a glycoprotein hormone which stimulates red blood cell production by stimulating the activity of erythroid progenitor cells. This review discusses the use of the drug in the management of anaemia in diseases often associated with advancing age [renal failure, cancer, rheumatoid arthritis (RA) and other chronic diseases, and the myelodysplastic syndromes (MDS)] and in surgical patients. Intravenous and subcutaneous therapy with epoetin alfa raises haematocrit and haemoglobin levels, and reduces transfusion requirements, in anaemic patients with end-stage renal failure undergoing haemodialysis or peritoneal dialysis. The drug is also effective in the correction of anaemia in patients with chronic renal failure not yet requiring dialysis and does not appear to affect renal haemodynamics adversely or to precipitate the onset of end-stage renal failure. Response rates of 32 to 82% with epoetin alfa therapy have been reported in patients with anaemia associated with cancer or cytotoxic chemotherapy. Limited data in patients with anaemia associated with RA show correction of anaemia after epoetin alfa treatment. Response rates to the drug of 0 to 56% have been noted in patients with MDS. Epoetin alfa also reduces anaemia, increases the capacity for autologous blood donation and reduces the need for allogeneic blood transfusion in patients scheduled to undergo surgery. Hypertension occurs in 30 to 35% of patients with end-stage renal failure who receive epoetin alfa, but this can be managed successfully with correction of fluid status and antihypertensive medication where necessary, and is minimised by avoiding rapid increases in haematocrit. Although vascular access thrombosis has not been conclusively linked to therapy with the drug, increased heparinisation may be required when it is administered to patients on haemodialysis. Epoetin alfa does not appear to exert any direct cerebrovascular adverse effects. Thus, epoetin alfa is a well established and effective therapy for the management of anaemia associated with renal failure. It also improves haematocrit and quality of life in patients with anaemia associated with cancer or chemotherapy. Epoetin alfa increases the capacity for blood donation and reduces the decrease in haematocrit seen in patients donating autologous blood prior to surgery. It also reduces, but may not eliminate, the need for allogeneic blood transfusion.(ABSTRACT TRUNCATED AT 400 WORDS)
7473482 Pain coping mechanisms in fibromyalgia: relationship to pain and functional outcomes. 1995 Aug OBJECTIVE: To evaluate the factor structure of the Coping Strategies Questionnaire (CSQ) in patients with fibromyalgia (FM) and to compare the factors derived from this measure, along with the active and passive pain coping scales of the Pain Management Inventory (PMI) in predicting pain, depression, quality of well being (QWB), and pain behavior concurrently and over time. METHODS: One hundred twenty-two patients with FM were recruited from medical clinics, the community, and support groups. Eligible patients completed a battery of self-report measures of pain and psychosocial functioning at baseline assessment before random assignment to a clinical trial. A subset of 69 patients who completed the clinical trial were readministered the same battery 3 mo later. Data were analyzed within the baseline period, and from the baseline period to posttreatment to evaluate the predictive effects of coping strategies on clinical outcomes. RESULTS: Principal components analysis of the CSQ revealed Coping Attempts (CA) and Pain Control and Rational Thinking (PCRT) factors, which have been found in other patient populations with chronic pain. Hierarchical multiple regression analyses revealed that high active coping and low PCRT contributed to higher concurrent pain, while low active coping and high passive coping were related to greater concurrent depression and pain behavior, respectively. Controlling for baseline scores on criterion measures, longitudinal multiple regression analyses demonstrated that high active coping and low PCRT scores contributed to greater pain, greater depression, and lower QWB at posttreatment, while low PCRT alone predicted greater pain behavior. CONCLUSION: The results show the import of the pain coping construct in FM and highlight the negative contribution of low perceived control over pain and high active coping to a range of pain outcomes. The findings on low perceived control converge with data on other chronic pain populations, while the role of active coping appears to be detrimental in FM, in contrast to its positive effects in patients with rheumatoid arthritis.
12288679 Contraception in the later reproductive years: a valid aspect of preventive health care. 1995 Winter
7880126 Steroid induced osteoporosis: an opportunity for prevention? 1995 Jan OBJECTIVE: To determine the frequency with which osteoporosis prophylaxis is given to corticosteroid treated hospital inpatients. METHODS: All patients receiving systemic corticosteroids in a large teaching hospital over a three month period were identified through routine prescription monitoring by hospital ward pharmacists. Coprescription of antiosteoporotic therapy was recorded, along with other relevant details such as steroid dose, actual, or intended duration of therapy, and indication for therapy. RESULTS: Corticosteroids were prescribed to 214 patients over the study period, giving an average rate of 2.5 new prescriptions each day. Indications included: chest disease (n = 84; 39.2%), cancer (n = 17; 7.9%), inflammatory bowel disease (n = 16; 7.5%), rheumatoid arthritis/connective tissue disease (n = 16; 7.5%), and renal diseases (n = 7; 3.3%). One hundred and twelve patients (52.3%) were receiving short term steroid therapy (less than four months); 66 (37%) were receiving medium/long term steroid therapy (four months or more). In 36 cases (16.8%) the duration of therapy was unknown. Only 12 of the 214 patients (5.6%) received any form of osteoporosis prophylaxis. The prevalence of prophylaxis was similarly low in postmenopausal women (six of 93; 6.4%) and in patients receiving high dose long term steroid therapy (two of 25; 8%). CONCLUSIONS: Systemic corticosteroids are used frequently in hospital practice for a wide range of indications, but few patients receive co-prescription of prophylaxis against osteoporosis. This is true even in high risk groups such as postmenopausal women and those on high dose long term steroid therapy. Identification of individuals by the mechanism used in this study provides an opportunity by which all corticosteroid treated patients could be detected and offered osteoporosis prophylaxis before serious loss of bone density has occurred.
7547086 Single and multiple dose pharmacokinetics of tenidap sodium in healthy subjects. 1995 1. The absorption, protein binding, clearance and absolute bioavailability of tenidap sodium were studied after single and multiple dosing. 2. Thirteen healthy male volunteers received a single 120 mg oral dose of tenidap sodium and a 20 mg intravenous infusion of deuterated tenidap ([D3]-tenidap) on day 1. This was followed by a 6-day washout period (days 2-7) and then further daily doses of oral tenidap sodium 120 mg for 21 consecutive days (days 8-28) with an additional 20 mg intravenous infusion of [D3]-tenidap on day 28. Twelve subjects were eligible for pharmacokinetic evaluation. 3. Following multiple oral doses, the half-life of tenidap is approximately 23 h. 4. Following single and multiple dose administration, the absolute bioavailability is 85%. 5. Systemic clearance of [D3]-tenidap was 29% greater on day 28 than on day 1 indicating a significant increase in intrinsic clearance (CLint) of tenidap since protein binding of tenidap in plasma did not change during the study. Consistent with the increase in systemic clearance, the half-life of [D3]-tenidap decreased and the ratio of AUC(0,24h) day 28/AUC day 1 following oral dosing was less than one. Tenidap is subject to extensive hepatic metabolism, so the increase in CLint may indicate that tenidap induces its own metabolism. 6. Steady-state was achieved by the eleventh day of dosing. Since numerous studies in patients with rheumatoid arthritis have shown that multiple dosing with tenidap is clinically efficacious, this suggests that the pharmacokinetic differences observed between the first and twenty-first day of multiple tenidap dosing do not influence the clinical response.
8051419 Tenidap modulates cytoplasmic pH and inhibits anion transport in vitro. I. Mechanism and e 1994 Sep 1 Tenidap is a novel anti-inflammatory and antiarthritic agent that in clinical studies of rheumatoid arthritis patients, displays symptomatic efficacy superior to nonsteroidal anti-inflammatory drugs (NSAIDs) and equivalent to combinations of NSAIDs and second line agents. Clinical and preclinical biochemical studies have demonstrated that tenidap combines cytokine modulation with suppression of prostaglandin biosynthesis. To better understand tenidap's mechanism of action, in vitro studies of intracellular pH (pHi) were conducted. In cells loaded with the pH-sensitive fluorescence dye 2',7'-bis-(2-carboxyethyl)-5-(and -6) carboxyfluorescein, tenidap, but not NSAIDs, caused a rapid and sustained acidification of the cytoplasmic compartment. Tenidap did not act as a proton ionophore, as it did not dissipate the low pH within lysosomes. Mammalian cells regulate pHi through the concerted action of a number of specific transport proteins, including sodium-proton antiporters and chloride-bicarbonate exchangers. Tenidap did not alter pHi via inhibition of the sodium-proton antiporter, but inhibited activity of chloride-bicarbonate exchangers, as did UK5099, a known anion-transport inhibitor that also lowers pHi. This similar activity suggests that the pHi change is coupled to anion transport inhibition. As a result of the pHi change, tenidap affected pH-dependent cellular activities. Tenidap inhibited mannose 6-phosphate receptor-mediated endocytosis, inhibited protein synthesis, and stimulated accumulation of the amino acid leucine. Effects on these cellular processes rapidly reversed when tenidap was removed from the culture medium. Tenidap's in vitro activities were highly dependent on the medium composition; protein content, pH, and bicarbonate concentration all were important factors that influenced activity. These results indicate that tenidap is a potent anion-transport inhibitor and modulator of pHi. Within the appropriate cell or tissue microenvironment, these activities may contribute to tenidap's novel therapeutic profile.
7821975 A human T-cell receptor recognizes 'O'-linked sugars from the hinge region of human IgA1 a 1994 Sep A receptor which binds secretory IgA (sIgA) is expressed on human T cells from patients with systemic lupus erythematosus, rheumatoid arthritis, Behcet's syndrome and IgA nephropathy and on normal T cells following phytohaemagglutinin (PHA) stimulation. The specificity of this receptor was initially probed with a panel of normal serum immunoglobulins in competitive inhibition assays with sIgA using two-colour immunofluorescence. While the receptor showed the strongest affinity for IgA1 (IC(50)10(-6) M), IgD which has a similarly glycosylated hinge region to IgA1, also bound to the receptor (IC50 10(-5) M). IgA2, which lacks the 'O'-glycosylated hinge region, did not significantly inhibit the binding at these concentrations suggesting that the IgA determinants for this receptor might be the oligosaccharides present in the hinge region of IgA1. IgA1 has up to 10 'O'-linked oligosaccharides and four N-linked oligosaccharides per molecule. In order to probe the role of the 'O'-linked hinge sugars in the binding event, a sugar library was prepared from IgA1 by a procedure designed to release 'O'-linked oligosaccharides preferentially, and to retain them in the natural closed ring formation. The sugars were released by hydrazinolysis at 65 degrees and the resulting oligosaccharide library analysed by high voltage paper electrophoresis (HVE) and P4 gel permeation chromatography. Competitive inhibition studies demonstrated that both the library and the individual 'O'-linked sugars associated with IgA1 were implicated in the binding of IgA1 to this receptor (IC50 between 1 x 10(-5) M and 6 x 10(-5) M). Within this range the individual sugars showed small differences in their affinity for the receptor in the following order: Gal beta 3GalNAc = NeuNAc2 alpha 3(6)Gal beta 3GalNAc > NeuNAc2 alpha 3(6)Gal beta 3[NeuNAc2 alpha 6]GalNAc > or = GalNAc.
8137557 Soluble CD23 and interleukin-4 levels in autoimmune chronic active hepatitis and systemic 1994 Apr A variety of cytokines secreted by cells of the immune system could contribute to the induction or persistence of the inflammatory processes in autoimmune and infectious diseases. Soluble CD23 (sCD23) and interleukin-4 (IL-4) are the recently characterized factors implicated in B cell-T cell function in human disease. In this study we examined the circulating levels of sCD23, IL-4, and soluble interleukin-2 receptors (sIL-2R) from patients with hepatitis B surface antigen-positive (HBsAg+) acute viral hepatitis (AVH), HBsAg+ chronic active hepatitis (HBsAg+ CAH), and autoimmune chronic active hepatitis (AICAH) and from autoimmune rheumatic disease patients, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The sCD23 was found in sera from 16 of 16 patients with AICAH (159.0 +/- 40.8 ng/ml), in 3 of 32 patients with AVH (4.1 +/- 15.6), 5 of 30 patients with HBsAg+ CAH (6.9 +/- 17), 8 of 25 patients with SLE (19.4 +/- 37.2), 2 of 21 patients with RA (4.7 +/- 16.3), and none of the 50 age-matched healthy controls. However, sIL-2R was detected more frequently in sera from all hepatitis and rheumatic disease patients. In AICAH, sCD23 levels correlated positively with IL-4 (r = 0.44, P = 0.001) but not with sIL-2R. Markedly elevated levels of sCD23 and IL-4 in serum are prominent and characteristic features of AICAH disease, which could play an important role in the pathogenesis or induction and perpetuation of the inflammatory response in this disorder.
1401080 Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response 1992 Oct Interleukin 4 (also known as "B cell stimulatory factor-1"), a cytokine product of T lymphocytes and mast cells, stimulates synthesis of the extracellular matrix proteins, types I and III collagen and fibronectin, by human dermal fibroblasts in vitro. Stimulation of collagen by human recombinant (hr)IL-4 was also demonstrated in several fibroblastic synovial cell lines obtained from patients with rheumatoid arthritis and osteoarthritis. The stimulatory effect of hrIL-4 on fibroblast collagen synthesis was specifically neutralized by rabbit anti-hrIL-4 Ig. IL-4 specifically increased the steady-state levels of types I and III procollagen and fibronectin mRNAs, with no effect on cytoplasmic beta-actin mRNA. Quantitative analysis of the levels of Pro alpha 1(I) collagen transcripts in IL-4-treated fibroblast cultures was also corroborated by antisense RNA-mRNA hybridization and RNAse resistant hybrids which showed that IL-4-treated fibroblasts expressed higher levels of Pro alpha 1(I) collagen transcripts. Nuclear run-off transcription experiments indicated that IL-4 stimulated the rates of mRNA biogenesis. Based on these observations we conclude that IL-4 exerts its effect on collagen and fibronectin synthesis at the pretranslational level, resulting in synthesis of these extracellular matrix proteins. These and other data suggest that IL-4 may be a "fibrogenic cytokine" that could be important in promoting biogenesis of extracellular matrix proteins in normal wound healing and in pathological fibrosis in which mast cells and T lymphocytes play a central role.