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ID PMID Title PublicationDate abstract
10342017 Risk factors for osteoporosis and fracture in patients attending rheumatology outpatient c 1999 Apr BACKGROUND: Bone mineral density (BMD) using dual energy X-ray absorptiometry (DXA) scanning is the best predictor of osteoporotic fracture but may not be cost effective for all patient groups. Risk factors (RF) other than BMD may be useful for fracture prediction. AIM: To assess the prevalence of RF for osteoporosis (OP) and fracture in patients attending a public hospital rheumatology clinic and to document physician awareness of these RF. METHODS: Two hundred and twenty rheumatology outpatients completed a self-administered questionnaire pertaining to known RF for OP and fracture. Initiatives were documented by the treating rheumatologist. RESULTS: One hundred and fifty-four females and 66 males completed questionnaires: 57% had an inflammatory disorder and 32% had received significant glucocorticoid therapy. Forty-five (68%) males and 126 (82%) females had three or more RF for OP and fracture. Diagnosis of rheumatoid arthritis or connective tissue disorder (CTD) was the variable most significantly associated with increasing numbers of RF. Antiosteoporotic medication (AOM) use at assessment (64/219, 29.2%) was accounted for primarily by the use of hormone replacement therapy in females between 45-54 years. Prednisolone use predicted intervention in 103 (48%) patients. CONCLUSION: Many rheumatology outpatients have multiple RF for OP and fracture. Infrequent AOM use could be explained by inadequate awareness of high risk patients and the lack of an ideal long term agent. With restricted outpatient resources, the feasibility of identifying high risk patients for OP and fracture would increase if the hierarchical status of RF was better understood.
10072521 A novel role of IL-15 in the development of osteoclasts: inability to replace its activity 1999 Mar 1 IL-15 shares many activities with IL-2 on stimulating lymphocytes, hematopoietic progenitor cells, and macrophages. However, the role of IL-15 in osteoclastogenesis has not been elucidated. The recent finding of abundant IL-15 in rheumatoid arthritis synovial fluids suggested a possible role for this cytokine in the pathological destruction of bone and prompted us to determine whether IL-15 stimulates osteoclast formation. IL-15 stimulated the formation of multinucleated osteoclast-like cells in rat bone marrow cultures. In stroma-free cultures, IL-15 increased the number of mononuclear preosteoclast-like cells in the early stage of osteoclast formation. The stimulation was observed even after treatment with IL-15 for only 24 or 48 h of culture. Moreover, low IL-15 concentration (0.1 ng/ml) strongly increased the level of calcitonin receptor mRNA of mononuclear preosteoclast-like cells. Although IL-15 is known as a potent stimulator of TNF-alpha, its activity was not abolished by addition of anti-TNF-alpha Ab. Interestingly, IL-2 and IL-7, which utilize some IL-15R components, had no effect on osteoclast differentiation, but pretreatment with IL-2 or IL-7 of bone marrow cells before the addition of IL-15 inhibited the enhancing activity of IL-15. In summary, IL-15 has a novel activity to stimulate the differentiation of osteoclast progenitors into preosteoclasts, which cannot be replaced by IL-2 but may use components in common with IL-2R to mediate its effects.
10063803 Light activates reduction of methotrexate by NADPH in the ternary complex with Escherichia 1999 Jan Methotrexate (MTX), a strong inhibitor of dihydrofolate reductase (DHFR), has been widely used for chemotherapy for many types of cancer as well as for juvenile rheumatoid arthritis. It mimics folate substrates and binds tightly to the active site of DHFR, perhaps in a conformation close to the transition state of the folate catalyzed reaction. Absorption, fluorescence and ultrasensitive Raman difference spectroscopies show that light-activated MTX reacts with NADPH in the enzyme active site, producing 5,8-dihydromethotrexate (5,8-dihydro-MTX) and NADP+. The reaction, which proceeds with a hydride transfer between C4 (pro-R side) of the nicotinamide ring and N5 of the pteridine ring, is similar to that between folate and NADPH except that the hydride is transferred to C6 in this case. Hence, MTX is catalytically competent in its excited state. Most experiments were performed on the Escherichia coli enzyme, but preliminary studies show that the reaction also occurs with human DHFR.
9881774 Structural changes in the oligosaccharide moiety of human IgG with aging. 1998 Jul In order to elucidate the relationship between glycosylation of IgG and aging, oligosaccharide structures of human IgG purified from sera of men and women aged 18 to 73 years were investigated. Oligosaccharides were liberated quantitatively from IgG by hydrazinolysis followed by N-acetylation and were tagged with p-aminobenzoic acid ethyl ester. The oligosaccharide structures were then analyzed by HPLC in conjunction with sequential exoglycosidase digestion. All IgG samples were shown to contain a series of biantennary complex type oligosaccharides which consisted of +/-Galbeta1-4GlcNAcbeta1-2Manalpha1-6(+/-GlcNAcbeta 1-4)(+/-Galbeta1-4GlcNAcbeta1-2Man(alpha)1-3)Man(beta)1-+ ++4GlcNAcbeta1-4(+/- Fucalpha1-6)GlcNAc and their mono- and disialo glycoforms in different ratios. In female IgG samples only, the incidence of non-galactosylated oligosaccharides with non-reducing terminal GlcNAc residues increased with aging (r>0.8), whereas that of digalactosylated oligosaccharides decreased (r<-0.8). A weaker correlation was observed between aging and the incidence of neutral and monosialo oligosaccharides in female IgG (r=0.461 and r= -0.538, respectively) and between aging and the incidence of oligosaccharides with a bisecting GlcNAc in both male and female IgG samples (r=0.566 and r=0.440, respectively). In addition, a significant change with aging in the galactosylation of IgG oligosaccharides was observed in females in their thirties, fifties, and sixties (p<0.02, p<0.01, and p<0.04, respectively). These findings may contribute to our understanding of autoimmune diseases such as rheumatoid arthritis in which glycosylation is involved.
9858643 The effect on IgG glycosylation of altering beta1, 4-galactosyltransferase-1 activity in B 1998 Dec An absence of galactose on the N-linked oligosaccharides of immunoglobulin G (IgG) has been shown to affect the functional activity of the antibody molecule. In patients with rheumatoid arthritis there is an increased proportion of IgG which lacks galactose and correspondingly lower levels of beta1, 4-galactosyltransferase (beta4Gal-T) activity. The recent demonstration of several expressed beta4Gal-T genes in man raises the possibility that the enzyme responsible for the decreased IgG galactose is not the "classical" beta4Gal-T (beta4Gal-T1). To directly address the question of whether reduced beta4Gal-T1 would lead to reduced IgG galactose, the level of beta4Gal-T1 in a human IgG-secreting B cell line was specifically altered using stable transfection with sense (SpcDNA3-Gal-T1) or antisense (ASpcDNA3-Gal-T1) human beta4Gal-T1 cDNA. SpcDNA3-Gal-T1 B cell transfectants expressed up to a 2.5-fold higher level of beta4Gal-T enzyme activity for the exogenous neoglycoconjugate acceptor GlcNAc-pITC-BSA than did ASpcDNA3-Gal-T1 transfectants. Flow cytometric analysis with Ricinus communis agglutinin I (RCAI) revealed an overall greater number of Galbeta1,4GlcNAc structures in the fixed and permeabilized SpcDNA3-Gal-T1 B cell transfectants compared with the ASpcDNA3-Gal-T1 transfectants. Moreover, there was increased galactosylation of IgG secreted from the SpcDNA3-Gal-T1 transfectants relative to the ASpcDNA3-Gal-T1 B cell transfectants. Alteration of the level of the "classical" beta4Gal-T (beta4Gal-T1) in B cells therefore affects IgG glycosylation.
9713901 A transmission/disequilibrium study of the DRB1*04 gene locus on chromosome 6p21.3 with sc 1998 Jul 27 Patients with schizophrenia rarely develop rheumatoid arthritis, an autoimmune disease that exhibits genetic association with the HLA DRB1*04 gene. We previously investigated the hypothesis that schizophrenia is negatively associated with DRB1*04, and found that only half the expected number of schizophrenic patients had this gene when compared with controls. We now report the results of DRB1*04 genotyping in pedigrees multiply affected with schizophrenia. Polymerase chain reaction amplification and sequence-specific oligonucleotide probes were used to determine the DRB1 genotypes of the 187 members of 23 pedigrees multiply affected with RDC schizophrenia. DQA1, DQB1 and DPB1 genotypes were similarly determined. We analysed data using the extended transmission/disequilibrium test and found a trend for the preferential non-transmission of DRB1*04 alleles from heterozygous parents to their schizophrenic offspring (16 of 23 alleles not transmitted, chi 2 = 3.5, p = 0.06). We found no evidence for a gene of major effect using GENEHUNTER for parametric and non-parametric linkage analysis. The results from this small sample need to be interpreted with caution, but they are in keeping with previous reports and suggest that HLA DRB1*04 alleles may be associated with a reduced risk of schizophrenia.
9686683 YKL-40, a mammalian member of the chitinase family, is a matrix protein of specific granul 1998 Jul YKL-40, also called human cartilage glycoprotein-39 (HC gp-39), is a member of family 18 glycosyl hydrolases. YKL-40 is secreted by chondrocytes, synovial cells, and macrophages, and recently it has been reported that YKL-40 has a role as an autoantigen in rheumatoid arthritis (RA). The function of YKL-40 is unknown, but the pattern of its expression in normal and disease states suggests that it could function in remodeling or degradation of the extracellular matrix. High levels of YKL-40 are found in synovial fluid from patients with active RA. Neutrophils are abundant in synovial fluid of patients with RA, and the cells are assumed to play a role in joint destruction in that disorder. Therefore, we examined whether neutrophils are a source of YKL-40. YKL-40 was found to colocalize and comobilize with lactoferrin (the most abundant protein of specific granules) but not with gelatinase in subcellular fractionation studies on stimulated and unstimulated neutrophils. Double-labeling immunoelectron microscopy confirmed the colocalization of YKL-40 and lactoferrin in specific granules of neutrophils. Immunohistochemistry on bone marrow cells showed that neutrophil precursors begin to synthesize YKL-40 at the myelocyte-metamyelocyte stage, the stage of maturation at which other specific granule proteins are formed. Assuming that YKL-40 has a role as an autoantigen in RA by inducing T cell-mediated autoimmune response, YKL-40 released from neutrophils in the inflamed joint could be essential for this response. In RA and other inflammatory diseases, YKL-40 released from specific granules of neutrophils may be involved in tissue remodeling or degradation.
9514210 Localization of parathyroid hormone-related protein in osteoclasts by in situ hybridizatio 1998 Mar Using immunohistology with two specific antisera raised against N-terminal parathyroid hormone-related protein (PTHrP) and in situ hybridization (riboprobe to common coding exon), evidence is provided for the expression of PTHrP by mouse, rabbit, and human osteoclasts derived from several in vitro and in vivo sources. In cocultures of mouse bone marrow and calvarial cells treated with 1,25-dihydroxyvitamin D3, the generated osteoclasts expressed both PTHrP messenger RNA (mRNA) and protein. In addition, PTHrP was detected in the majority of actively resorbing osteoclasts in sections of newborn and adult mouse long bones. Using an in vivo intramembranous bone formation model in rabbits, expression of PTHrP mRNA and protein was demonstrated in osteoclasts at active bone resorption sites as well as in actively synthesizing osteoblasts and bone lining cells. Localization of PTHrP was also demonstrated in osteoclast-like cells of human giant cell tumors from bone. In some of these tumors, a small proportion of the multinucleated cells expressed tartrate resistant acid phosphatase (TRAP), but not PTHrP mRNA or protein. Finally, both mRNA and protein for PTHrP were expressed in osteoclasts in sections of bone or joints from patients with Paget's disease, rheumatoid arthritis, and osteoarthritis. These observations raise the possibility that PTHrP might participate in osteoclast function.
9344881 Beta 2-microglobulin induces stromelysin production by human synovial fibroblasts. 1997 Oct 20 beta 2-Microglobulin (beta 2-m) is a major constituent of amyloid fibrils in hemodialysis-associated amyloidosis (HAA), a serious complication in patients on long-term hemodialysis. The most distinctive pathological feature of HAA is the deposition of amyloid fibrils with subsequent articular inflammation and destruction. However, the pathological role of beta 2-m is not well known at present. We investigated the effects of beta 2-m on the production of proteinases from synovial fibroblasts isolated from patients with rheumatoid arthritis. beta 2-m stimulated synovial fibroblasts to produce stromelysin, a neutral matrix metalloproteinase (MMP-3). The production of MMP-2 and of a tissue inhibitor of metalloproteinase-1 (TIMP-1) were not enhanced by beta 2-m-treated synovial fibroblasts. Stromelysin is capable of degrading several components of the extracellular matrix and believed to be the key enzyme causing articular destruction in inflammatory joint diseases. Our results suggest a novel role for beta 2-m in articular inflammation and destruction mediated by stromelysin in HAA.
9215847 Irradiation in the setting of collagen vascular disease: acute and late complications. 1997 Jul PURPOSE: Based on reports of greater toxicity from radiation therapy, collagen vascular diseases (CVDs) have been considered a contraindication to irradiation. We assessed the complications of radiation therapy in patients with CVD. PATIENTS AND METHODS: A total of 209 patients with documented CVD were irradiated between 1960 and 1995. One hundred thirty-one had rheumatoid arthritis (RA), 25 had systemic lupus erythematosus (SLE); 17 had polymyositis or dermatomyositis; 16 had scleroderma; eight had ankylosing spondylitis; five had juvenile RA; three had discoid lupus erythematosus; and four had 4 mixed connective tissue disorders (MCTD). The mean follow-up duration of curative cases was more than 6 years. Doses ranged from 10 to 87.6 Gy, with a median of 45 Gy. RESULTS: Overall, 263 sites were assessable in 209 patients. Significant (> or = grade 3) acute toxicity was seen in 10% of irradiated sites. Severe late effects were associated with significant acute reactions and with non-RA CVDs (6% v 21% at 5 years). No difference was seen in late effects according to timing of CVD onset, presence of concurrent vascular insults, radiation dose, or other technical factors, or by measures of disease activity. CONCLUSION: RA does not appear to have an elevated rate of late toxicity. While non-RA CVD is significantly associated with increased radiation late effects at standard doses, radiation-related mortality remains exceedingly rare. The choice of therapeutic modality in this radiosensitive group of patients should be made on a case-by-case basis.
9101503 Intravenous cyclophosphamide pulses in pyoderma gangrenosum: an open trial. 1997 Apr OBJECTIVE: To evaluate the potential efficacy of intravenous bolus cyclophosphamide (IVCY) in patients with pyoderma gangrenosum. METHODS: Consecutive patients with a diagnosis of pyoderma gangrenosum seen in a period of 3 years in tertiary care referral center were included. Patients received IVCY 500 mg/m2 of body surface area, every month until reaching a maximum of 6 doses, or healing of their ulcers or a lack of response after 3 doses. Patients were assessed every month during the time they received IVCY and every 3 months thereafter. The assessments included number and size of ulcers, and a safety profile of the study drug. Complete remission was defined as 100% ulcer healing, partial remission as a decrease > or = 50% but less than 100%, and therapeutical failure if the size of the ulcer increased or decreased < 50%. RESULTS: Nine patients were included, 6 were men, the mean age was 46 yrs (range 24-76). The mean disease duration was 3.3 yrs (range 1 week to 9 yrs). Four patients had idiopathic pyoderma gangrenosum, 3 had associated rheumatoid arthritis, and 2 had associated systemic lupus erythematosus. Complete remission was observed in 7 patients, partial in one, and failure in one. Relapses were observed, 3 months after the last IVCY (2 cases) and 12 months after the last IVCY (one case). Transitory thrombocytopenia and leukopenia developed in one patient and nausea and vomiting in another. CONCLUSION: IVCY appears effective in controlling the lesions of pyoderma gangrenosum and inducing remission for a substantial period in many individuals.
9058645 The effects of traditional antirheumatic herbal medicines on immune response cells. 1997 Mar OBJECTIVE: Clinically, some traditional Chinese herbal medicines have been thought to be effective in treating rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus. To examine the mechanism by which such herbal remedies might be effective, we investigated the ability of Tripterygium wilfordii Hook-f (TWHf) and tetrandrine (TTD) to affect human immune responsiveness in vitro. METHODS: We measured the ability of these agents to affect cytokine secretion from monocytes or T cells, prostaglandin E2 (PGE2) secretion from monocytes, IgG production from B cells, and the phagocytosis of bacteria by neutrophils. RESULTS: These studies revealed that both TWHf and TTD significantly inhibited interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-8 secretion from monocytes, IgG secretion from B cells, and phagocytosis of bacteria by neutrophils; however, only TWHf inhibited IL-2 and IL-4 production from lymphocytes, and PGE2 secretion from monocytes. CONCLUSION: TWHf and TTD exert a powerful suppressive effect on human immune responses. This action might account for their therapeutic effectiveness in rheumatic diseases, and might support broader and more rigorous clinical trials.
9518310 [The role of radiotherapy in the management of benign lymphoepithelial lesions]. 1997 Benign lymphoepithelial lesion (BLL) is observed as a diffuse or nodular enlargement of major salivary gland. In 80% it appears in woman in the sixth and seventh decade. The histopathologic appearance consist of a triad of parenchymatous atrophy, interstitial lymphocytic infiltration and epimyoepithelial islands. This disease co-exists in 50% of cases with connective tissue disorders. In patients with BLL the risk of the development of a malignant lymphoma may be as high as 40:1 in comparison to the control group. From 1960 to 1991 ten women with BLL in salivary glands were treated in Oncology Centre in Kraków. The disease was localized in parotid glands (8 pts), in submandibular glands (1 pt) and in parotid and submandibular gland (1 pt). In this group 3 patients were treated for the rheumatoid arthritis and in 1 women presented symptoms of Sjögren' syndrome. Exclusive surgical treatment was performed in 2 patients, 7 patients were treated with irradiation, and 1 patient received combined therapy: surgery and radiotherapy. The doses of irradiation were from 12 to 36 Gy given in 6 to 18 fractions. Complete remission was observed in 2 patients who received only surgical treatment. In group of 8 patients treated with irradiation and surgery and irradiation we have observed local control in six women after 1 series and in two women after 2 series of irradiation. During the observation malignancies developed in 4 patients between 11 to 39 months after radiotherapy. One patient developed cancer of salivary gland. In remaining 3 patients it was observed malignant lymphomas. Our results of therapy of BLL in salivary gland are similar to presented by the other authors and indicate the efficiency of local (surgical or irradiation) treatment.
11837669 Cross--reactivity of the V3-speciflc antibodies with the human C1q. 2001 Nov It has been previously shown that the sequence similarity between a portion of the envelope glycoprotein 120 (gp120) from the human immunodeficiency virus type-1 (HIV-1) and several types of human collagen and collagen-like molecules exists. That observation led to the suggestion that the antibodies against the third hypervariable region (V3) of HIV-1 gp120 (V3-specific antibodies) might have a role in the autoimmune phenomena observed in HIV-infected persons. In this study we have examined the cross-reactivity of the V3-specific antibodies purified from sera of HIV-infected individuals, sera obtained from the rheumatoid arthritis and systemic lupus crythematosus patients, as well as from the sera of healthy volunteers with the separate chains of a subcomponent of the first component of the human complement system, Clq. Our results show that the V3-specific antibodies are present in the sera of the HIV-infected individuals, patients suffering of the systemic autoimmune diseases as well as in the sera of healthy volunteers. Whereas these antibodies appeared in the HIV+-sera after antigen challenge, those present in the HIV- -sera probably represent the antibodies that are cross-reactive with the antigen. V3-reactive antibodies can be purified by affinity chromatography and they were highly specific for the V3-peptide. Additionally, they showed cross-reactivity with the separate chains of the human Clq as well as with the chicken collagen type VI. Possible physiological implications are discussed.
11737074 Lymphopenia in occupational pulmonary silicosis with or without autoimmune disease. 2001 Dec An increased prevalence of autoimmune diseases such as rheumatoid arthritis has been demonstrated in silica-exposed patients. The aim of this study was to determine the peripheral blood lymphocyte phenotype in a population of silicotic workers employed in the slate mines of the district. Silicosis was assessed in 58 patients according to the International Labor Office's criteria. Clinical and biological data including flow cytometric evaluation of the lymphocyte subsets were compared with those from 41 healthy volunteers. The silicotic patients had a higher prevalence of autoimmune diseases (6/58 versus 0/41: P < 0.05) and of elevated antinuclear antibody titres compared to the control group. A very significant decrease of total lymphocyte count (P < 0.001) involving B, T and Natural Killer cells was found in silicotic patients as compared with matched healthy volunteers. A significant increase in the percentage of activated T cells (12.3%) was observed in the silicotic group as compared to 6.5% in the control group (P = 5 x 10(-5)). Our results show that in silicotic patients, the absolute number of circulating lymphocytes is diminished with an increased proportion of activated T cells. Whether these findings could predispose to the development of autoimmune disorders is discussed.
11567892 Avian air sac and plasma proteins that bind surface polysaccharides of Escherichia coli O2 2001 Oct Some serovars of Escherichia coli, mainly O2 and O78, are responsible for air sac and systemic infections in farm-raised turkeys (Meleagris gallopavo) and chickens (Gallus gallus). We looked in air sac surface fluid from young turkeys to identify proteins that bind surface polysaccharides of pathogenic respiratory E. coli O2. Turkey air sac surface fluid was subjected to affinity chromatography on Toyopearl AF-Epoxy-650M, coupled with either lipopolysaccharide (LPS) or lipid-free polysaccharide (LFP) purified from an avian pathogenic E. coli O2 isolate. A multimeric protein termed lipid-free polysaccharide binding protein-40 (LFPBP-40) composed of six covalently associated subunits of approximately 40 kDa was isolated by elution from LFP by EDTA or L-rhamnose. An analogous protein in air sac fluid proteins bound to intact E. coli O2 and eluted with L-rhamnose or N-acetylglucosamine (GlcNAc). The N-terminal amino acid sequence of LFPBP-40 DINGGGATLPQHLYLTPDV was related to the N-terminus of fragment 3 of a partially characterized human protein possessing T cell stimulation activity in synovial membrane of rheumatoid arthritis patients. However, endogenous amino acid sequences were unrelated to other known proteins. LFPBP-40 was immunoreactively distinct from pulmonary collectins and ficolins. These studies demonstrate a novel avian respiratory soluble lectin that can bind surface polysaccharides of pathogenic E. coli responsible for respiratory disease.
11502610 Health Assessment Questionnaire modifications: is standardisation needed? 2001 Sep BACKGROUND: Physical disability is part of the end point measures in rheumatoid arthritis clinical trials. The Stanford Health Assessment Questionnaire Disability Index (HAQ DI) is often used for this purpose but lacks international uniformity owing to variations in the translated and adapted questionnaires and variations in its calculation. To study the consequences of these variations the previous Dutch HAQ (HAQ90) was revised, resulting in a new Dutch HAQ (HAQ99). OBJECTIVE: To compare DI scores from the two versions, and to study the consequences of applying different calculation methods for the DI score. METHODS: 78 patients completed both the HAQ99 and the HAQ90. To compare the use of different category score calculation methods a post hoc analysis on prospectively collected data obtained in clinical trials was performed. RESULTS: No statistically significant differences were observed between the DI scores of the HAQ90 and the HAQ99 using the alternative method (that is, without correcting for aid and devices). However, correcting for the use of aid or devices or not did result in statistically significant different DI scores. The systematic shift when using the maximum or mean item score for calculation of the category score resulted in non-comparable absolute DI scores. CONCLUSION: The use of HAQ DI questionnaires with different numbers of items and/or categories does not hinder international comparability, except when these variations interfere with the calculation method of the DI (as in the case of questionnaires without a section correcting for devices). For the sake of international uniformity the HAQ or any validated translation should be used and calculated in a standard way, including correcting for the use of aid and devices, and taking the maximum within each category as the category score.
11477284 Inhibition of neutrophil responses by cyclosporin A. An insight into molecular mechanisms. 2001 Jul OBJECTIVE: Cyclosporin A (CsA) is an effective agent in rheumatoid arthritis (RA), slowing joint damage progression. Its therapeutic effect on T lymphocytes has been studied extensively, but there is little information available about neutrophils, the cells responsible for a substantial proportion of inflammation. A study was performed to investigate the in vitro effects of CsA on neutrophil functions triggered by several agonists and determine whether the drug could counteract the binding of formyl-methionyl-leucyl-phenylalanine (fMLP) to its receptor and/or modulate changes in the intracellular Ca(2+) concentration ([Ca(2+)]i). METHODS: CsA was added to neutrophils 5-50 min before the incubation steps for neutrophil function assays (chemotaxis, superoxide anion production, lysozyme release), calcium measurements and receptor binding experiments. RESULTS: CsA appeared to be particularly effective in lowering chemotaxis, superoxide anion production and lysozyme release induced by different agonists. However, it did not significantly affect either basal or agonist-stimulated neutrophil [Ca(2+)]i and the interaction between fMLP and its receptor. CONCLUSIONS: Because of its in vitro inhibition of neutrophil functions, CsA appears to have considerable potential as an anti-inflammatory drug. Moreover, as it is also a potent immunosuppressive agent, it may reduce the progression of joint damage in RA. More work remains to be done to clarify the molecular mechanism of CsA action on neutrophils.
11375112 Neuroendocrine regulation of autoimmune/inflammatory disease. 2001 Jun Interactions between the immune and nervous systems play an important role in modulating host susceptibility and resistance to inflammatory disease. Neuroendocrine regulation of inflammatory and immune responses and disease occurs at multiple levels: systemically, through the anti-inflammatory action of glucocorticoids released via hypothalamic-pituitary-adrenal axis stimulation; regionally, through production of glucocorticoids within and sympathetic innervation of immune organs such as the thymus; locally, at sites of inflammation. Estrogens also play an important role in immune modulation, and contribute to the approximately 2- to 10-fold higher incidence of autoimmune/inflammatory diseases seen in females of all mammalian species. During inflammation, cytokines from the periphery activate the central nervous system through multiple routes. This results in stimulation of the hypothalamic-pituitary-adrenal axis which, in turn through the immunosuppressive effects of the glucocorticoids, generally inhibits inflammation. Recent studies indicate that physiological levels of glucocorticoids are immunomodulatory rather than solely immunosuppressive, causing a shift in patterns of cytokine production from a TH1- to a TH2-type pattern. Interruptions of this loop at any level and through multiple mechanisms, whether genetic, or through surgical or pharmacological interventions, can render an inflammatory resistant host susceptible to inflammatory disease. Over-activation of this axis, as occurs during stress, can also affect severity of infectious disease through the immunosuppressive effects of the glucocorticoids. These interactions have been clearly demonstrated in many animal models, across species, strains and diseases, and are also relevant to human inflammatory, autoimmune and allergic illnesses, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, allergic asthma and atopic skin disease. While many genes and environmental factors contribute to susceptibility and resistance to autoimmune/inflammatory diseases, a full understanding of the molecular effects on immune responses of combinations of neuropeptides, neurohormones and neurotransmitters at all levels has opened up new therapeutic approaches and are essential for the design of future therapies based on such principles.
11325425 Preparation of gellan sulfate as an artificial ligand for removal of extra domain A contai 2001 Jun 12 The extra domain A containing fibronectin (EDA(+)FN) concentration in plasma of rheumatoid arthritis (RA) is abnormally higher than the normal level. We synthesized various gellan-sulfate (GS) candidates as artificial ligands for removing EDA(+)FN from plasma. The interaction between these artificial ligands and EDA(+)FN was evaluated using affinity constants (KA), which were determined by surface plasmon resonance measurement. The KA (3.6 x 10(8) per M) of GS-25 [degree of substitution for sulfonation (DS) = 25%] with EDA(+)FN was higher than those of other molecules: GS-16 (DS=16%) at 8.3 x 10(7) per M, and GS-35 (DS = 35%) at 1.7 x 10(8) per M. Furthermore, GSs displayed selectivity of EDA(+)FN for binding with plasma FN (KAEDA(+)FN)/KA(plasma FN)>2). The removal ratio in plasma was measured by using GS-immobilized gel. Removals of 66, 11, 7.7, 6.2, 6.9, and 12% for EDA(+)FN, plasma FN, fibrinogen, albumin, immunoglobulin G (IgG) and antithrombin III from the patient-model plasma were, respectively, achieved with GS-25-immobilized gel. These results suggest that GS may be used as a selective artificial ligand for EDA(+)FN removal from plasma in RA treatment.