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ID PMID Title PublicationDate abstract
10594566 Circulating antibodies against alpha-enolase in patients with primary membranous nephropat 1999 Dec MN is characterized by the glomerular deposition of IgG4 immune complexes. This suggests that nephritogenic immune responses in MN are of the Th2 T helper cell type; however, the pathogenesis of MN is still unknown. In this study we examined sera from patients with primary MN for antibodies to renal proteins. A 47-kD protein in both human and porcine renal extracts was found by immunoblotting to react specifically with serum IgG from some patients. This protein was purified from porcine kidney and identified as alpha-enolase on the basis of its partial amino acid sequences. Sera from 87 patients with primary MN, 24 patients with secondary MN (15 rheumatoid arthritis patients, nine systemic lupus erythematosus patients), and 16 healthy subjects were examined by ELISA using purified alpha-enolase. In 60 (69%) patients with primary MN and 14 (58%) patients with secondary MN, the measured optical density values, and hence serum anti-alpha-enolase antibody levels, were greater than the mean + 2 s.d. of healthy subjects. Immunoblot analysis showed that IgG1 or IgG3 was the predominant subclass (Th1 T helper cell type subclass) of antibodies against alpha-enolase in patients with primary and secondary MN. Since circulating antibodies against alpha-enolase have recently been reported in patients with various autoimmune disorders, our results suggest that a number of patients with presumed primary MN may also have abnormalities in Th1 T helper cell-mediated immune responses.
10517974 Reactive oxygen species: the unavoidable environmental insult? 1999 Jul 16 Reactive oxygen species (ROS) are generated by a variety of sources from the environment (e.g., photo-oxidations and emissions) and normal cellular functions (e.g., mitochondrial metabolism and neutrophil activation). ROS include free radicals (e.g., superoxide and hydroxyl radicals), nonradical oxygen species (e.g., hydrogen peroxide and peroxynitrite) and reactive lipids and carbohydrates (e. g., ketoaldehydes, hydroxynonenal). Oxidative damage to DNA can occur by many routes including the oxidative modification of the nucleotide bases, sugars, or by forming crosslinks. Such modifications can lead to mutations, pathologies, cellular aging and death. Oxidation of proteins appears to play a causative role in many chronic diseases of aging including cataractogenesis, rheumatoid arthritis, and various neurodegenerative diseases including Alzheimer's Disease (AD). Our goal is to elucidate the mechanism(s) by which oxidative modification results in the disease. These studies have shown that (a) cells from old individuals are more susceptible to oxidative damage than cells from young donors; (b) oxidative protein modification is not random; (c) some of the damage can be prevented by antioxidants, but there is an age-dependent difference; and (d) an age-related impairment of recognition and destruction of modified proteins exists. It is believed that mechanistic insight into oxidative damage will allow prevention or intervention such that these insults are not inevitable. Our studies are also designed to identify the proteins which are most susceptible to ROS damage and to use these as potential biomarkers for the early diagnosis of diseases such as AD. For example, separation of proteins from cells or tissues on one- and two-dimensional gels followed by staining for both total protein and specifically oxidized residues (e.g., nitrotyrosine) may allow identification of biomarkers for AD.
10492503 The cyclooxygenase-2 inhibitors: safety and effectiveness. 1999 Sep OBJECTIVE: To review the development of cyclooxygenase-2 (COX-2) inhibitors and discuss specific agents that are currently under investigation or have been marketed. DATA SOURCES: Primary literature on selective COX inhibitors was identified from a comprehensive MEDLINE, English-literature search from January 1966 through September 1998, with additional studies selected by review of the references. Abstracts from recent meetings and package insert literature from approved agents were also used as source material. Indexing terms included COX-2 inhibitors, meloxicam, celecoxib, rofecoxib, flosulide, SC-58635, and MK-966. STUDY SELECTION: Human clinical, pharmacokinetic, and dose-ranging trials performed in Europe and the US and randomized comparative trials were reviewed. DATA SYNTHESIS: With the discovery of at least two COX isoforms, a better understanding of the mechanism of action and gastrointestinal toxicity of nonsteroidal antiinflammatory drugs (NSAIDs) has been realized. While COX-1 is involved in physiologic maintenance, COX-2 seems to be involved in inflammation, mitogenesis, and specialized signal transductions. Selective COX-2 inhibitors may allow maximum antiinflammatory activity while improving the safety profile associated with NSAID therapy. Celecoxib and rofecoxib have been approved by the Food and Drug Administration for the treatment of osteo- and rheumatoid arthritis; meloxicam is undergoing Phase III clinical trials. Preliminary data indicate that the selective COX-2 inhibitors provide analgesic and antiinflammatory efficacy comparable with older NSAIDs, with fewer adverse gastrointestinal effects. CONCLUSIONS: Specific COX-2 inhibitors offer promising benefits over older NSAIDs with regard to gastrointestinal safety while maintaining analgesic and antiinflammatory efficacy. Further study is required to determine long-term efficacy and safety in clinical use.
10479232 Essential fatty acids in health and chronic disease. 1999 Sep Human beings evolved consuming a diet that contained about equal amounts of n-3 and n-6 essential fatty acids. Over the past 100-150 y there has been an enormous increase in the consumption of n-6 fatty acids due to the increased intake of vegetable oils from corn, sunflower seeds, safflower seeds, cottonseed, and soybeans. Today, in Western diets, the ratio of n-6 to n-3 fatty acids ranges from approximately 20-30:1 instead of the traditional range of 1-2:1. Studies indicate that a high intake of n-6 fatty acids shifts the physiologic state to one that is prothrombotic and proaggregatory, characterized by increases in blood viscosity, vasospasm, and vasoconstriction and decreases in bleeding time. n-3 Fatty acids, however, have antiinflammatory, antithrombotic, antiarrhythmic, hypolipidemic, and vasodilatory properties. These beneficial effects of n-3 fatty acids have been shown in the secondary prevention of coronary heart disease, hypertension, type 2 diabetes, and, in some patients with renal disease, rheumatoid arthritis, ulcerative colitis, Crohn disease, and chronic obstructive pulmonary disease. Most of the studies were carried out with fish oils [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]. However, alpha-linolenic acid, found in green leafy vegetables, flaxseed, rapeseed, and walnuts, desaturates and elongates in the human body to EPA and DHA and by itself may have beneficial effects in health and in the control of chronic diseases.
10428222 Acetabular fracture associated with cementless acetabular component insertion: a report of 1999 Jun Acetabular fracture during insertion of a cementless acetabular component occurred in 13 patients. The preoperative diagnosis was osteoarthritis in 6 patients, rheumatoid arthritis in 2 patients, avascular necrosis in 3 patients, hip fracture nonunion in 1 patient, and developmental dysplasia of the hip in 1 patient. Several different components were used; however, the acetabulum was underreamed by 1 to 3 mm in all cases. The acetabular fracture was identified in 9 of 13 cases intraoperatively. The fracture was identified on postoperative radiographs for the other 4 cases. Fractures were treated by a variety of means, including the addition of augmentation screws in or around the cup, use of autograft bone at the fracture site, modified postoperative weight-bearing status, and immobilization. In 2 cases, the socket needed to be revised after it progressively migrated and failed. One patient had cup migration, and another had a radiolucent line about the cup but was not symptomatic enough to require revision. In 3 of these 4 cases, the fracture was not identified intraoperatively. Underreaming of the acetabulum and use of an oversized acetabular component has been recommended to improve the initial stability of the acetabular component during total hip arthroplasty. Impaction of an oversized component requires bone to undergo plastic deformation if the cup is to be fully seated. Theoretically, this technique provides improved component stability with enhanced osseous ingrowth into the cup. The 13 cases reported in this study demonstrate that acetabular fracture is a complication that may occur in association with uncemented hip arthroplasty, particularly if oversized components are used. The importance of recognizing acetabular fractures intraoperatively and the need to institute appropriate treatment to ensure a stable acetabular component is emphasized. In patients with osteoporotic bone, line-to-line reaming with use of a cementless acetabular component or insertion of a cemented socket may be considered to avoid this significant complication.
10358752 The multifaceted regulation of interleukin-15 expression and the role of this cytokine in 1999 Interleukin-15 (IL-15) is a 14- to 15-kDa member of the 4 alpha-helix bundle family of cytokines. IL-15 expression is controlled at the levels of transcription, translation, and intracellular trafficking. In particular, IL-15 protein is posttranscriptionally regulated by multiple controlling elements that impede translation, including 12 upstream AUGs of the 5' UTR, 2 unusual signal peptides, and the C-terminus of the mature protein. IL-15 uses two distinct receptor and signaling pathways. In T and NK cells the IL-15 receptor includes IL-2/15R beta and gamma c subunits, which are shared with IL-2, and an IL-15-specific receptor subunit, IL-15R alpha. Mast cells respond to IL-15 with a receptor system that does not share elements with the IL-2 receptor but uses a novel 60- to 65-kDa IL-15RX subunit. In mast cells IL-15 signaling involves Jak2/STAT5 activation rather than the Jak1/Jak3 and STAT5/STAT3 system used in activated T cells. In addition to its other functional activities in immune and nonimmune cells, IL-15 plays a pivotal role in the development, survival, and function of NK cells. Abnormalities of IL-15 expression have been described in patients with rheumatoid arthritis or inflammatory bowel disease and in diseases associated with the retroviruses HIV and HTLV-I. New approaches directed toward IL-15, its receptor, or its signaling pathway may be of value in the therapy of these disorders.
10067375 [Tumor anemia. Overview of the role of human recombinant erythropoietin (r-hu-EPO) in trea 1999 Jan 28 The prevalence of anaemia in patients with cancer lies between 10 and 40%, depending on the type of tumor and chemotherapy. Anaemia has a significant impact on the quality of life, along with pain or disease progression. There are multiple causes but the physiopathology resembles that of inflammatory anaemia. The following mechanisms can be distinguished: a resistance of the erythroid precursor cells (BFU-e, CFU-e) to erythropoietin, an inappropriately decreased renal erythropoietin secretion for a given haemoglobin value and alterations of the iron metabolism leading to a functional iron deficiency. Recombinant human erythropoietin (r-hu-EPO) is safe and efficient in the treatment of anaemia of chronic renal failure and rheumatoid arthritis. In oncology different phase I and II studies have demonstrated an efficacy (increase of haemoglobin, decrease of transfusion requirements) in about 50% of all adult patients. A response to a subcutaneous r-hu-EPO treatment with a relatively high posology of 150 U/kg three times a week can be expected after one to two months. No single reliable parameter will predict a response to the r-hu-EPO treatment. Several phase III studies confirm that anaemia in cancer patients undergoing chemotherapy (notably with cisplatin) can be corrected in 40 to 60% of all cases and that the haemoglobin increase improves the quality of life. Finally, recent clinical trials suggest that an early r-hu-EPO treatment might prevent the occurrence of anaemia secondary to chemotherapy. Several parameters will have to be specified such as the precise definition of the groups at risk, the appropriate haemoglobin level to initiate a r-hu-EPO treatment, its optimal posology, as well as the role of the iron substitution and its route of administration. The impact of the r-hu-EPO treatment on the quality of life of cancer patients constitutes a priority for future studies, which will have define the exact role of r-hu-EPO in oncology management.
10027640 Improved high-performance liquid chromatography determination of methotrexate and its majo 1999 Jan 8 A sensitive high-performance liquid chromatographic assay has been developed for measuring plasma concentrations of methotrexate and its major metabolite, 7-hydroxymethotrexate. Methotrexate and metabolite were extracted from plasma using solid-phase extraction. An internal standard, aminopterin was used. Chromatographic separation was achieved using a 15-cm poly(styrene-divinylbenzene) (PRP-1) column. This column is more robust than a silica-based stationary phase. Post column, the eluent was irradiated with UV light, producing fluorescent photolytic degradation products of methotrexate and the metabolite. The excitation and emission wavelengths of fluorescence detection were at 350 and 435 nm, respectively. The mobile phase consisted of 0.1 M phosphate buffer (pH 6.5), with 6% N,N-dimethylformamide and 0.2% of 30% hydrogen peroxide. The absolute recoveries for methotrexate and 7-hydroxymethotrexate were greater than 86%. Precision, expressed as a coefficient of variation (n=6), was <10% at each of five methotrexate concentrations in the range 2.5-50 ng/ml. The limits of quantitation of methotrexate were 1 and 2.5 ng/ml for methotrexate and 7-hydroxymethotrexate, respectively (using 1 ml plasma). A robust HPLC method has been developed for the reproducible quantitation of methotrexate in plasma of patients taking a weekly dose of methotrexate for rheumatoid arthritis.
9605921 Revisiting the role of tumor necrosis factor alpha and the response to surgical injury and 1998 May Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine with diverse biological actions. Studies originally identified TNF-alpha as a systemic mediator of endotoxemic shock, cachexia, and tumor regression. We now recognize that TNF-alpha is a member of a large family of proteins, including Fas ligand, whose actions are primarily paracrine in nature, and serve to regulate both cell proliferation and apoptotic death. Although clinical trials with TNF-alpha inhibitors in sepsis syndrome have been disappointing to date, and TNF-alpha administration has not proven widely successful as an antineoplastic agent, preliminary successes with TNF-alpha inhibition have been recently reported in more chronic inflammatory diseases, including rheumatoid arthritis and ulcerative colitis. The recent description of the TNF-alpha converting enzyme responsible for the processing of cell-associated to secreted TNF-alpha has opened a new therapeutic avenue to address inflammatory diseases dependent on the release of 17-kd secreted TNF-alpha. Similarly, inhibitors of nuclear factor kappa B activation can increase TNF-alpha-mediated apoptosis and have rejuvenated efforts to explore TNF-alpha's antineoplastic potential. The multiple and often conflicting TNF-alpha signaling pathways reveal a diversity to TNF-alpha's actions not fully appreciated in the past. Such investigations have opened a number of novel therapeutic interventions to either inhibit or potentiate the actions of TNF-alpha during surgical injury or acute inflammation.
9394833 Molecular mechanisms regulating induction of interleukin-6 gene transcription by interfero 1997 Nov The multifunctional cytokine interleukin-6 (IL-6) plays a central role in host defence mechanisms and hematopoiesis. Furthermore, dysregulation of IL-6 gene expression is associated with the pathogenesis of various immunologically related diseases such as myeloma, systemic lupus erythematosus, rheumatoid arthritis, psoriasis and Kaposi's sarcoma. The regulation of IL-6 gene expression occurs mainly at transcriptional level, although mechanisms of post-transcriptional regulation have also been described. In the present study we demonstrate that in HeLa cells, induction of IL-6 by interferon-gamma (IFN-gamma) is transcriptionally controlled, as shown by run on assays and analysis of the IL-6 mRNA stability. Gel-retardation experiments using antibodies specific for factors of the IRF family identified four protein-DNA complexes, which bind to the interferon regulatory factor (IRF) binding site at position -267 to -254, in nuclear extracts from IFN-gamma treated cells. Furthermore, transient transfection analyses of the 5'-flanking region of IL-6 gene linked to the chloramphenicol acetyltransferase (CAT) reporter gene demonstrated that the -267 to -254 IRF site is necessary for IL-6 induction by IFN-gamma. However, transfection experiments in which IRF-1 and I kappa B alpha were overexpressed show that full-scale transcriptional activation of the IL-6 promoter directing CAT expression requires the co-operation between IRF-1 and NF-kappa B at a low constitutive level.
9306258 Nitric oxide is a regulator of bone remodelling. 1997 Sep Nitric oxide (NO) is known to be implicated in the metabolism of bone, especially as a mediator of cytokine effects on the remodelling of bone tissue. In this study we examine whether NO affects the osteoblast activation or the osteoclast differentiation of primary mouse osteoblast-like and osteosarcoma ROS 17/2.8 cell lines. Primary osteoblast and ROS 17/2.8 cells released NO upon stimulation of interleukin-1 beta, tumour necrosis factor-alpha, and interferon-gamma. Sodium nitroprusside, a donor of nitric oxide, increased the activity of alkaline phosphatase in ROS 17/2.8 cells as well as the number of calcified nodule formations in primary mouse osteoblast-like cells. Sodium nitroprusside also completely inhibited 1 alpha, 25-(OH)2D3-induced osteoclast generation in a high concentration (100 microM). However, a low concentration of sodium nitroprusside (3-30 microM) significantly increased the generation of osteoclasts. These results indicated that NO appears to be an important regulatory molecule in the processes of bone formation and resorption. Hence, NO may be involved in the pathogenesis of bone loss in diseases associated with cytokine activation, such as periodontal disease and rheumatoid arthritis.
9335312 Oral administration of unsaturated fatty acids: effects on human peripheral blood T lympho 1997 Oct Oils enriched in certain polyunsaturated fatty acids suppress joint pain and swelling in rheumatoid arthritis (RA) patients. Because T lymphocyte activation is important to propagation of joint tissue injury in patients with RA, we examined the effects of fatty acids administered by mouth in vivo on proliferation of human lymphocytes activated through the T cell receptor complex. T cell proliferation was reduced after oral administration of 2.4 g gammalinolenic acid in capsules of borage seed oil. Oral administration of oils enriched in linoleic acid, the parent n-6 fatty acid, and alpha linolenic acid, the parent n-3 fatty acid, did not influence growth of stimulated cells. Fatty acid analyses indicated that suppression of lymphocyte proliferation after gammalinolenic acid administration was associated with increased plasma and peripheral blood mononuclear cell concentrations of gammalinolenic acid and dihomogammalinolenic acid.
9266252 [Studies on Fas ligand expression in patients with systemic lupus erythematosus]. 1997 Jul The Fas/Fas ligand (FasL)-mediated apoptosis may play a role in the induction and maintenance of T cell tolerance. To investigate the role of FasL in the apoptosis of lymphocytes in autoimmune diseases, gene and protein expression of FasL were examined in peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), and from healthy donors by a newly-designed semiquantitative reverse transcription (RT)-PCR and flow cytometry. Although no significant difference in FasL gene expression was obtained among three groups, SLE patients exhibited a wide distribution of the values. In SLE patients, there was a significant correlation between FasL gene expression by PBMC and some clinical parameters including SLE Disease Activity Index (SLEDAI) score, anti-DNA antibody titer and complement titer (CH50). More interestingly, a marked increase in FasL gene expression was observed in untreated SLE patients, whereas a significant decrease was observed in prednisolone-treated SLE patients. Flow cytometric analysis revealed the expression of FasL on T cell subsets from SLE patients and on anti-CD3 mAb-stimulated T cells from healthy donors. In vitro experiments, dexamethasone inhibited FasL gene expression by PBMC from healthy donors in a dose-dependent manner and with time of incubation. These results clearly indicate that FasL is up-regulated in active SLE patients, reflecting in vivo T cell activation, and that corticosteroids directly down-regulate FasL gene expression by human PBMC.
9154454 Allele-specific variation in the degeneracy of major histocompatibility complex (MHC) rest 1997 Apr 15 The role of peptides in determining immune responses for both allorecognition and antigen-specific recognition has been clearly documented. The importance of different regions of the major histocompatibility complex (MHC) class II molecule in contributing to recognition has been demonstrated by studies involving site-directed mutagenesis and exon shuffling. These studies have indicated that the N-terminal region of the MHC class II molecule has a role to play in contributing to the T-cell receptor (TCR)-MHC-peptide interaction. Variation in the importance of different regions of the MHC class II molecule may be dependent on different aspects of this interaction, such as restriction specificity and affinity of the responding T-cell clone, and the nature of the bound peptide. We demonstrate here that the degree of T-cell degeneracy may be allele dependent. Thus, a series of exon-shuffled molecules were generated by shuffling the first and second variable region of a particular DR beta 1 molecule with the third variable region of a different DR beta 1 molecule. A panel of transfectants, which expressed these hybrid molecules, was then generated and used as antigen-presenting cells (APCs). A panel of peptide-specific T-cell clones was generated using the native HLA-DR molecules as the restricting elements. For the majority of restricting alleles, HLA-DRB5*0101, HLA-DRB1*1101, and HLA-DRB1*0701, all three variable regions were required for recognition. The exception to this observation was HLA-DRB1*0401, which was degenerate. Such degeneracy may facilitate the breakdown of self-tolerance through the cross-reactive recognition of other alleles in DR4/DR"x" heterozygotes. Such an observation as this may contribute to our understanding of the etiopathology of rheumatoid arthritis, an autoimmune disease strongly associated with HLA-DRB1*0401.
9161931 Current views on the pharmacological properties of the immunomodulator, lobenzarit disodiu 1997 Mar Lobenzarit disodium (LBZ) is an immunomodulator and antioxidative drug developed and used successfully in Japan for the treatment of rheumatoid arthritis (RA). Studies in animals and humans have shown striking differences between the pharmacological profile of LBZ and nonsteroidal antiinflammatory drugs commonly used in the treatment of RA. LBZ does not inhibit the biosynthesis of prostaglandins and leukotrienes and is ineffective on acute inflammatory reactions induced in animals. Therefore, its usefulness in RA is ascribed to immunopharmacological properties of the drug. Currently, evidence is available that B- and T-lymphocytes are targets of LBZ's actions which regulates the functions of these cells. LBZ reduces IgE titers in serum of sensitized mice by activating suppressor T-lymphocytes and inhibiting anaphylactic shock induced by ovalbumin. These results provide evidence in favor of the potential use of LBZ in the treatment of allergic diseases, which must be elucidated in controlled double-blind clinical trials. The suppressive effects of LBZ on the function of activated B cells as well as in the production of anti-DNA antibody have been reported. These findings suggest that LBZ may be effective in the treatment of other autoimmune diseases such as lupus erythematosus that are also characterized by the production of autoantibodies from activated B cells. Recently, an open clinical trial in patients with systemic lupus erythematosus supports this point of view. Other potential therapeutic uses of LBZ are in autoimmune-related diabetes and in autoimmune liver disease which are documented in this review. LBZ also selectively antagonizes the contractile responses of isolated rabbit aorta strips induced by thromboxane A2-mimetic U-46619. This result provides evidence in favor of an antagonist of LBZ at the level of TxA2 receptors and supports the potential usefulness of LBZ in some cardiovascular disorders such as cardiopulmonary diseases and thrombosis. LBZ is a scavenger of oxygen-free radicals such as hydroxyl radicals, superoxide, peroxyl and singlet oxygen. This property contributes substantially to its pharmacological and therapeutic profile as well as its mechanism of action.
9135557 Selective migration of highly differentiated primed T cells, defined by low expression of 1997 Feb Low expression of CD45RB on CD45RO+ T lymphocytes defines a subset of highly differentiated T lymphocytes that accumulate in vivo within the affected joints of patients with rheumatoid arthritis (RA). Although it is known that CD45RO+ T lymphocytes migrate to sites of inflammation in vivo, it is not clear whether within this subset the CD45RBlo cells are selectively recruited or develop in situ within the joint. Using a transwell system we show that a small proportion of resting T lymphocytes migrated across unactivated human umbilical vein endothelial cells (HUVEC). These migrating cells were CD45RO+ and enriched for low CD45RB expression. In addition, both the CD45RO+CD45RBlo subset and migrating cells expressed increased levels of beta 1 and beta 2 integrins and CD44. The percentage of CD45RO+CD45RBlo T lymphocytes was increased in the circulation of patients with acute Epstein-Barr virus (EBV) infection. These in vivo activated cells also expressed increased levels beta 1 and beta 2 integrins and CD44, and showed an enhanced rate of transmigration compared with resting T lymphocytes. Transmigration of T lymphocytes was increased using the chemokines RANTES and lymphotactin and the cytokine interleukin-15 (IL-15). In addition, infection of the HUVEC with cytomegalovirus (CMV) led to an enhanced movement of T lymphocytes. In all of these cases the selective migration of the CD45RBlo subset was maintained. Thus although the rate of T-lymphocyte transmigration could be influenced by a number factors, the CD45RO+CD45RBlo subset has a migratory advantage suggesting that more differentiated CD45RO+CD45RBlo T lymphocytes are selectively recruited to sites of inflammation.
9203029 New perspective on Behçet's disease. 1997 There are many distinct differences between Behçet's disease of Silk Route and that of outside Silk Route; genetic factors, role of neutrophils, and severity of this disease. We have thus emphasized that we prefer the term "Behçet's syndrome" rather than "Behçet's disease". In this chapter, Behçet's disease seen along the Silk Route will be mainly discussed. HLA-B51 molecules themselves may be responsible, at least in part, for the neutrophil hyperfunction in Behçet's disease; a significant correlation was observed between the neutrophil hyperfunction and the possession of HLA-B51 phenotype, regardless of the presence of the disease, in both humans and HLA-B transgenic mice. T cells in this disease, proliferated vigorously in response to a specific peptide of human heat shock protein (HSP)-60; however, T cells from normal subjects or patients with rheumatoid arthritis, did not. This peptide has the amino acid sequence of 336-351 of human HSP-60, which is similar, but not identical to specific peptide of mycobacterial HSP-65. We have further analyzed T cell receptor (TCR) usage of HSP-responsive T cells by means of TCR V beta subfamily specific monoclonal antibodies and polymerase chain reaction and single strand conformation polymorphism-based technique. We found that T cells with specific TCR V beta subfamilies proliferated and increased in number in response to the peptide by an antigen-specific fashion. The result of recurrent exposure to the HSP may break the tolerance to self-HSP, and provoke T cell responses to self- and microbial-HSP. Such T cells produced Th1-like proinflammatory and/or inflammatory cytokines. This leads to tissue injury, possibly via delayed-type hypersensitivity reaction, macrophage activation, and activation and/or recruitment of neutrophils. Our data shed a new light on the autoimmune nature of Behçet's disease; a novel multistep molecular mimicry mechanisms may induce and/or exacerbate Behçet's disease by bacterial antigens that activate T cells previously educated by self-peptides of HSP. This would lead to positive selection of autoreactive T cells in this disease.
12903410 [Modulation of the inflammatory response through complement-neutrophil activation feedback 2000 Dec To identify the regulatory effect of sodium selenite and vitamin E on the complement-neutrophil-reactive oxygen(ROS) activation feedback (CNAF) mechanism mediated inflammatory response, we detected ROS production and complement activation in vitro tests by chemiluminescence technique and complement fixation and recognized the regulation of the inflammatory response in vivo mouse vasculitis models of skin, lung, and liver. Convincing results were observed as both in vitro and in vivo experiments showing inhibition of CNAF mechanism with sodium selenite and vitamin E could effect the reduced ROS production and complement activation. The incidence (100%) for vasculitis in control group decreased to 20%-57% in sodium selenite and vitamin E treated groups. Elucidation of the ancillary mechanism of CNAF enhancing inflammatory response is a promising area for new therapeutic developments in the modulation of inflammatory response. As in a clinical approach, a remarkable therapeutic effect with sodium selenite was observed during an epidemic episode of epidemic hemorrhagic fever in Henan province. The mortality rate of fulminant cases was reduced from 100% of untreated control cases to 36.6% by treatment with sodium selenite. The results of present studies strongly suggest that antioxidants such as selenium and vitamin E as well as others like flavonoids can exhibit a novel anti-inflammatory action via this CNAF mechanism. It is expected in the future an increasing number of patients with severe infections or inflammatory disorders in which excessive complement activation and adverse ROS production have been implicated, e. g. ischemia-reperfusion injury, severe sepsis and diverse inflammatory vascular injuries like rheumatoid arthritis, hepatitis and inflammatory bowel diseases should benefit from this newer concept guided adjuvant therapies which make use of nutrient antioxidants like selenium, vitamin E and others.
11732263 [Neurological deficits in patients with primary and secondary anticardiolipin syndrome]. 2001 Mar 27 patients (22 women, 5 men); age 17 to 56 yr. (mean age 37 yr.) were included in this study, 4 had primary antiphospholipid syndrome and 18 secondary antiphospholipid syndrome in the course of systemic connective tissue disease and in 5 cases increased levels of anticardiolipid antibodies were found which did not meet the criteria necessary for diagnosis of secondary antiphospholipid syndrome. The mean duration of the disease was 8 yrs. Among primary antiphospholipid syndrome patients two had ischaemic stroke, one migraine-like headache and seizures. 18 patients had lupus erythematosus, two mixed connective tissue disease, one rheumatoid arthritis, one Sjögren syndrome, one Behçet disease. In 55% of patients migraine-like headache, polyneuropathies, encephalophaties, stroke, seizures and vision disturbances were present. In 18.5% of patients EEG exam revealed focal lesions with tendency for generalisation. On brain stem auditory evoked potentials examination, in 11.1% of patients conductivity lesions in mesencephalon and pons were found, visual evoked potentials, in 11.1% of patients in visual tracts. In 37% of patients, neuropathy was found on EMG exam. Neurological symptoms are one of the most frequent disorders in systemic connective tissue disease associated with the presence of anicardiolipin antibodies.
11724453 Polyunsaturated fatty acids, inflammation, and immunity. 2001 Sep The fatty acid composition of inflammatory and immune cells is sensitive to change according to the fatty acid composition of the diet. In particular, the proportion of different types of polyunsaturated fatty acids (PUFA) in these cells is readily changed, and this provides a link between dietary PUFA intake, inflammation, and immunity. The n-6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds, which have important roles in inflammation and in the regulation of immunity. Fish oil contains the n-3 PUFA eicosapentaenoic acid (EPA). Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators. In addition, EPA is a substrate for cyclooxygenase and lipoxygenase and gives rise to mediators that often have different biological actions or potencies than those formed from AA. Animal studies have shown that dietary fish oil results in altered lymphocyte function and in suppressed production of proinflammatory cytokines by macrophages. Supplementation of the diet of healthy human volunteers with fish oil-derived n-3 PUFA results in decreased monocyte and neutrophil chemotaxis and decreased production of proinflammatory cytokines. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease. Clinical studies have reported that fish oil supplementation has beneficial effects in rheumatoid arthritis, inflammatory bowel disease, and among some asthmatics, supporting the idea that the n-3 PUFA in fish oil are anti-inflammatory and immunomodulatory.