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ID PMID Title PublicationDate abstract
12163349 Induction of mitochondrial permeability transition by auranofin, a gold(I)-phosphine deriv 2002 Aug 1 Gold(I)-thiolate drugs are compounds that specifically interact with thiol and/or selenol groups and are essentially utilized in the treatment of rheumatoid arthritis. 2 Considering the importance of thiol groups in regulating mitochondrial membrane permeability, the effects of auranofin (S-triethylphosphinegold(I)-2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranoside), a second-generation gold drug, were studied on mitochondria isolated from rat liver. 3 Auranofin, at submicromolar concentrations, was able to induce the mitochondrial membrane permeability transition observed as swelling and loss of membrane potential. Both events are completely inhibited by cyclosporin A, the specific inhibitor of mitochondrial permeability transition. Calcium ions and energization by succinate are required for the occurrence of permeability transition. 4 By interacting with the active site selenol group, auranofin results as an extremely potent inhibitor of mitochondrial thioredoxin reductase, both isolated and in its mitochondrial environment. 5 It is concluded that auranofin, in the presence of calcium ions, is a highly efficient inducer of mitochondrial membrane permeability transition, potentially referable to its inhibition of mitochondrial thioredoxin reductase.
12052139 Pharmacogenetics and folate metabolism -- a promising direction. 2002 May Folate metabolism is the target of two major drug groups: folate antagonists (e.g., methotrexate) and thymidylate synthase inhibitors (for example, 5-fluorouracil). These agents are widely used in cancer chemotherapy, as treatment for rheumatoid arthritis, and for other conditions. The administration of these drugs in cancer chemotherapy can induce a state of acute folate depletion with sometimes life-threatening toxic sequelae. Recent studies suggest that polymorphisms in folate-metabolizing enzymes may modify the therapeutic effectiveness and toxicity of drugs targeting folate metabolism. This review briefly summarizes major drugs targeting the folate pathway and describes common polymorphisms in folate-metabolizing enzymes and transport proteins. Pharmacogenetic studies investigating the relevance of these polymorphisms with respect to patients' response to antifolate chemotherapeutic agents are discussed. Investigating genetic variability in folate metabolism in the framework of pharmacogenetics is a promising field. Findings to date illustrate the potential for targeting therapy based on patients' genotypes with improved outcomes and reduced toxicity.
11966457 Thiol-dependent enzymes and their inhibitors: a review. 2002 May Biological thiol-dependent enzymes have recently received extensive attention in the literature because of their involvement in a variety of physiopathological conditions. The active thiol groups of these enzymes are derived from the cysteine residues present. Hence, in a biological system, the selective reversible or irreversible inhibition of the activity of these enzymes by modification of the thiol moiety may potentially lead to the development of a chemotherapeutic treatment. Despite all the research efforts involved in the attempt to develop potential chemotherapeutic treatments for the major diseases involving cysteine proteases, there are in fact no such treatments available yet. However, AG7088 (1) an inhibitor of rhinovirus-3C is in phase II/III clinical trial for the treatment of common cold and VX-740 (2, pralnacasan) an inhibitor of caspase-1 is in phase II clinical trial as an anti-inflammatory agent for rheumatoid arthritis. Several other cysteine protease inhibitors (i.e., cathepsin K, and S) are in pre-clinical evaluation or pre-clinical development. Structure-based drug design approaches have been instrumental in the development of these inhibitors. Intensive biochemical studies on the cysteine proteases have shed some light on some potential targets for therapeutic development. In addition, new techniques and new ideas are constantly emerging. As such, an up-to-date review of the literature on thiol-dependent enzymes as potential targets and their inhibitors designed from peptidic, modified peptidomimetic scaffolds and from small heterocyclic molecules is presented.
11812267 Progress in the development of selective nitric oxide synthase (NOS) inhibitors. 2002 Nitric oxide (NO), a molecular messenger synthesized by nitric oxide synthase (NOS) from L-arginine and molecular oxygen, is involved in a number of physiological and pathological processes in mammalians. Three structurally distinct isoforms of NOS have been identified: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). Although NO mediates several physiological functions, overproduction of NO by nNOS has been reported in a number of clinical disorders including acute (stroke) and chronic (schizophrenia, Alzheimer s, Parkinson s and AIDS dementia) neurodegenerative diseases, convulsions and pain; overproduction of NO by iNOS has been implicated in various pathological processes including septic shock, tissue damage following inflammation and rheumatoid arthritis. On the contrary, NO produced by eNOS has only physiological roles such as maintaining physiological vascular tone. Accordingly, selective inhibition of nNOS or iNOS vs eNOS may provide a novel therapeutic approach to various diseases; in addition selective inhibitors may represent useful tools for investigating other biological functions of NO. For these reasons, after the identification of N-methyl-L-arginine (L-NMA) as the first inhibitor of NO biosynthesis, design of selective NOS inhibitors has received much attention. In this article the recent developments of new molecules endowed with inhibitory properties against the various isoforms of NOS are reviewed. Major focus is placed on structure-activity-selectivity relationships especially concerning compounds belonging to the non-amino acid-based inhibitors.
11824969 Vascular endothelial growth factors C and D and their VEGFR-2 and 3 receptors in blood and 2002 Jan OBJECTIVE: To localize vascular endothelial growth factor C (VEGF-C) and VEGF-D in synovial specimens in relation to their VEGFR-2 and VEGFR-3 receptors in blood and lymphatic vessels. METHODS: Immunohistochemical staining and messenger RNA analysis from control and arthritic synovial membrane specimens. RESULTS: Quantitative RT-PCR disclosed that VEGF-C mRNA copy numbers were higher than VEGF-D mRNA copy numbers in the rheumatoid arthritis (RA), osteoarthritis, and control patient groups studied (p < 0.01). Immunohistochemical staining localized VEGF-C to synovial lining cell layer, pericytes, and smooth muscle cells of blood vessels. The number of VEGF-C positive cells was increased in the synovial lining of ankylosing spondylitis (AS) and RA compared to control synovium. However, in contrast to control synovial lining, little if any VEGF-D was detected in AS or RA synovial lining. VEGFR-2 expressing stromal blood vessels, also positive for the vascular endothelial marker PAL-E and the basement membrane marker laminin, were more abundant in RA and AS than in controls. Interestingly, the lymphatic endothelial receptor VEGFR-3 was also expressed in most synovial vessels, especially in the sublining capillaries and venules. CONCLUSION: VEGF-C is strongly expressed in the hypertrophic synovial lining of arthritic joints, whereas VEGF-D expression is very low in AS and RA. The expression of VEGF-C and VEGF-D in pericytes and smooth muscle cells suggests that these factors may have a role in maintaining vascular homeostasis. The VEGF receptors VEGFR-2 and VEGFR-3 are present in most of the sublining blood vessels. The expression of the lymphatic marker VEGFR-3 in the sublining blood vessels may relate to fluid filtration and/or fenestrations. The relatively few lymphatic vessels along with increased vascular permeability in RA may contribute to the development of tissue edema and joint stiffness.
15457469 Triptolide, an active component of the Chinese herbal remedy Tripterygium wilfordii Hook F 2004 Sep OBJECTIVE: The ethyl acetate (EA) extract of Tripterygium wilfordii Hook F (TWHF) and its major active component, triptolide, have been reported to be effective in the treatment of rheumatoid arthritis and other autoimmune inflammatory diseases. Nitric oxide (NO) has been recognized as an important mediator of inflammation. This study was therefore undertaken to examine the effects of the EA extract and triptolide on the production of NO and inducible NO synthase (iNOS) gene expression and transcription in vivo and in vitro. METHODS: Peritoneal macrophages from C57BL/6J mice treated orally with the EA extract of TWHF were assayed for NO production and iNOS messenger RNA (mRNA) expression by reverse transcriptase-polymerase chain reaction. The murine fibroblast cell line NIH3T3 was also assessed for NO production and iNOS mRNA expression, as well as for iNOS promoter activation, Oct-1 nuclear binding capacity, and Oct-1 protein content by transient transfection, electrophoretic mobility shift assay, and immunoblotting, respectively. RESULTS: NO production and iNOS mRNA expression by macrophages from C57BL/6J mice immunized with trinitrophenyl-bovine serum albumin in Freund's complete adjuvant were significantly inhibited by oral administration of the EA extract (52.3% and 59.8% of control, respectively, at one-eighth of the dose that is lethal for 50% of the animals [LD(50)] and 21.0% and 38.1% of control, respectively, at one-fourth the LD(50)). Moreover, the EA extract and triptolide significantly inhibited NO production in vitro in activated peritoneal macrophages, which reflected a decreased level of iNOS mRNA. Finally, triptolide inhibited promoter activity of the iNOS gene and induction of the activity of the regulator of iNOS transcription, Oct-1. CONCLUSION: The EA extract of TWHF and triptolide inhibit transcription of the iNOS gene. This may contribute to the antiinflammatory effects of this traditional herbal remedy.
14566965 TNFalpha suppresses link protein and type II collagen expression in chondrocytes: Role of 2003 Dec Tumor necrosis factor alpha (TNFalpha) inhibits matrix synthesis by chondrocytes in rheumatoid arthritis and osteoarthritis; however, the underlying signaling pathways are poorly characterized. This study investigated the TNFalpha-activated pathways regulating expression of two key components of the cartilage matrix-link protein and type II collagen. In rat articular chondrocytes, TNFalpha decreased link protein and type II collagen mRNA to undetectable levels within 48 h. Levels of link protein mRNA recovered more readily than type II collagen mRNA following removal of the cytokine. TNFalpha-mediated reduction in mRNA of both matrix molecules occurred at the level of transcription and, for link protein, mRNA stability. Turnover of type II collagen and link protein mRNA was dependent on new protein synthesis. In both prechondrocytes and articular chondrocytes, TNFalpha induced concentration-dependent activation of MEK1/2 and NF-kappaB, but not p38 or JNK. Sustained activation of NF-kappaB was observed for up to 72 h following continuous or transient exposure to TNFalpha. Using pharmacological and molecular approaches, the MEK1/2 and NF-kappaB pathways were found to mediate inhibition of type II collagen and link protein gene expression by TNFalpha. Both prechondrocytes and articular chondrocytes are targets of TNFalpha. This study identifies pathways through which TNFalpha perturbs the synthesis and organization of articular cartilage matrix during inflammation.
12117682 Addition of interleukin 1 (IL1) and IL17 soluble receptors to a tumour necrosis factor alp 2002 Aug OBJECTIVES: To evaluate the usefulness of combination treatment with cytokine inhibitors. METHODS: A simplified model was set up to evaluate the effect of tumour necrosis factor alpha (TNFalpha) soluble receptors (sTNFR) used alone and in combination with soluble interleukin 1 receptor (sIL1R) and sIL17R on the production of markers of inflammation (IL6), of migration of dendritic cells (macrophage inhibitory protein-3alpha (MIP-3alpha)), and of matrix synthesis (C-propeptide of type 1 collagen (P1CP)). Synoviocytes were stimulated with supernatants of activated peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis (RA). Soluble receptors (sR) were preincubated at 1 gammag/ml alone or in combination with the supernatants before addition to RA synoviocytes. IL6, MIP-3alpha, and P1CP production was measured by enzyme linked immunosorbent assay (ELISA) in 48 hour synoviocyte supernatants. RESULTS: IL6 production decreased by 16% with sTNFR alone compared with no sTNFR (p<0.001) and by 41% with the combination of the three sR (p<0.001). MIP-3alpha production decreased by 77% with sTNFR alone compared with no sTNFR (p<0.001) and by 98% with the combination of the three sR (p<0.001). In the presence of sTNFR alone, P1CP production increased by 25% compared with no sR (p<0.01). The combination of the three sR increased P1CP production by 48% (p<0.01). CONCLUSION: The effect of sTNFR on IL6, MIP-3alpha, and P1CP production by RA synoviocytes stimulated by activated PBMC supernatants was further enhanced when combined with sIL1R and sIL17R.
12195627 Estimation of Sjögren's syndrome among IBD patients. A six year post-diagnostic prevalenc 2002 OBJECTIVE: To study the prevalence of Sjögren's syndrome (SS), tear and saliva production and sicca symptoms in patients with inflammatory bowel disease (IBD) seen six years after IBD diagnosis. METHODS: In a population based cohort of 654 patients with IBD, 521 patients (80%) and a control group consisting of 68 healthy subjects were investigated. SS was diagnosed according to the European Criteria proposed by the American-European Consensus Group (US-EU criteria) and the European criteria. Maximum (supposing positive biopsies) and minimum prevalences (supposing negative biopsies) were estimated. RESULTS: Dryness of eyes and mouth were similarly distributed between patients with ulcerative colitis (UC) and Crohn's disease (CD) and between patients and controls. The prevalence of SS was 0-4.2% and 0-5.7% (minimum-maximum) according to the US-EU criteria and the European criteria, respectively. The controls fulfilled neither of the criteria. CONCLUSION: Sjögren's syndrome, sicca symptoms, tear and saliva production were not increased in patients with IBD compared to controls, indicating a lack of association between SS and IBD.
12910046 Aseptic meningitis associated with intravenous administration of dexchlorpheniramine. 2003 May Drug-induced aseptic meningitis has been reported mainly with the use of nonsteroidal anti-inflammatory drugs, antibiotics, intravenous immunoglobulins and OKT3 antibodies. We describe today a very unusual reaction on intravenous dexchlorpheniramine with this case of aseptic meningitis.
12436835 Treatment of xerostomia: a systematic review of therapeutic trials. 2002 Oct The results of the present systematic review of randomized controlled trials published in peer-reviewed journals demonstrate the presence of a wide variety of biases and the weakness of the existing literature of xerostomia treatment. The report of statistically significant efficacy on an outcome measure is only meaningful in the setting of a well-controlled, appropriately designed clinical trial. This points to the importance of evaluating the quality of the clinical trial closely when deciding if study results are applicable to a specific patient population. Future studies in the management of xerostomia will require an increased effort on the part of investigators to eliminate easily recognized flaws during the planning stages of a clinical trial. Minimizing bias in clinical studies will allow for easier interpretation and comparisons of different studies. Better clinical trial design is vital to provide maximal confidence in the efficacy of xerostomia interventions.
11850533 Up-regulation of M3-muscarinic receptors in labial salivary gland acini in primary Sjögre 2002 Feb M3-muscarinic receptors (M3R) mediate parasympathetic cholinergic neurotransmission to salivary and lacrimal glands, and autoantibodies to these receptors have been implicated in sicca symptoms and autonomic dysfunction in Sjögren's syndrome. We have investigated the expression of M3R in paraffin-embedded labial salivary glands (LSG) from seven patients with primary Sjögren's syndrome (pSS) and five healthy controls using high-resolution confocal microscopy and an affinity-purified goat polyclonal antibody raised against the COOH-terminal sequence of the human M3R. Immunolocalization of M3R was similar in control and pSS glands, with punctate staining of M3R in the basal membrane of acinar cells and in the luminal and abluminal membrane of myoepithelial cells. Bright, granular M3R staining was also detected in the cytoplasm and membranes of all intercalated and striated ducts, and infiltrating lymphocytes in pSS. All immunoreactivity was specifically blocked by the immunizing peptide. An increase in M3R expression specifically in acini in pSS was demonstrated by a 30% increase in receptor number per cluster and a 68% increase in the number of clusters in the membrane. This up-regulation is consistent with inhibition of parasympathetic neurotransmission, possibly by antagonistic autoantibodies to M3R. The up-regulation, rather than down-regulation, of M3R in acini of pSS LSG can explain the effectiveness of muscarinic agonists in treating sicca symptoms in pSS.
15211301 Evaluation of unstimulated flow rates of whole and palatal saliva in healthy patients wear 2004 Jun STATEMENT OF PROBLEM: The palate and upper lip are the regions of oral mucosa covered with the least amount of saliva. These areas are important for maxillary denture retention and stability. Thus, patients with xerostomia or hyposalivation may have problems with the stability of maxillary complete dentures. PURPOSE: The purpose of this study was to compare the unstimulated whole saliva (UWS) and palatal saliva (PS) flow rates of healthy patients wearing complete dentures and patients with Sjogren's syndrome (SS) and to determine whether xerostomia or hyposalivation has a negative influence on maxillary complete denture stability. A further aim was to determine the influence of new complete dentures on UWS and PS flow rates in healthy individuals. MATERIAL AND METHODS: Thirty-five complete denture wearers, 24 healthy individuals (controls) and 11 patients who fulfilled the diagnostic criteria for primary Sjogren's syndrome (as proposed by the European Community Study Group) were investigated. All participants were questioned about possible subjective oral complaints (xerostomia or instability of the dentures) through use of a standardized questionnaire. In the first part of the study, UWS and PS flow rates of the healthy subjects (controls) and of the SS patients were measured at the initial visit. The flow rate of UWS (mL/min) was collected by the "spitting" method; saliva was collected into preweighed vessels for 5 minutes while subjects were seated in an upright position. Patients were asked to refrain from smoking, eating, and drinking for 2 hours prior to the test session, to avoid swallowing, and to make as few movements as possible during the procedure. The PS flow rate (microL/min/cm2) was measured using previously weighed filter paper discs placed bilaterally in the region of the maxillary second molars, 15 mm palatally from the edentulous ridge, for 30 seconds. The measuring vessels and paper discs were weighed before and after each collection. In the second part of the study, new complete dentures were fabricated for healthy patients. Flow rates of UWS and PS were measured 7 days after the insertion to compare data with prefabrication values. Mann-Whitney and Wilcoxon rank sum tests and chi-square test were used to analyze the data (alpha=.05). RESULTS: The UWS flow rates were significantly lower in SS patients compared to healthy controls (0.36 +/- 0.33 vs 0.09 +/- 0.11 mL/min, P<.05), yet the PS flow rate for both groups was not significantly different. Although every SS patient had xerostomia, and 8 out of 11 had hyposalivation, no patient complained about denture instability. Neither UWS flow rate (0.36 +/- 0.33 mL/min and 0.39 +/- 0.35 mL/min) nor PS flow rate (1.66 +/- 0.99 microL/cm2/min and 1.86 +/- 0.45 microL/cm2/min) was different from the preinsertion values after 1 week of new denture insertion in healthy patients. CONCLUSION: Palatal mucous saliva may help stabilize the maxillary complete denture in patients with hyposalivation. The results suggest that neither UWS or PS flow rate are influenced by the placement of new dentures in complete denture wearers.
12806979 [Two cases of interstitial nephritis with primary Sjögren's syndrome successfully treated 2003 We have experienced two cases of interstitial nephritis with Sjögren's syndrome successfully treated by steroid therapy. Case 1. A 50-year-old woman was admitted because of rash and arthralgia of the limb. Although her renal function was normal, serum IgG was extremely high and gallium-67 scintigrams indicated abnormal uptake in both kidneys with swelling on CT scans. Renal biopsy specimens showed a patchy dense interstitial infiltration of lymphocytes, monocytes and partly plasma cells with tubular cell atrophy. To suppress an excessive immune reaction, oral prednisolone was administrated at a dose of 30 mg/day. Six weeks after inception of the therapy, re-biopsy specimens showed a decrease in interstitial infiltration, particularly plasma cells, and interstitial fibrosis did not progress. After 8 weeks, the serum IgG level was normalized. Case 2. A 57-year-old woman was found to have renal involvement(serum creatinine level: 2.2 mg/dl) and anemia. Clinical findings suggested primary Sjögren's syndrome with renal tubular acidosis. Renal biopsy specimens showed a moderate to severe interstitial infiltration of inflammatory cells. After inception of steroid therapy(prednisolone 40 mg/day), renal involvement and renal anemia gradually improved. The renal function has been kept stable(serum creatinine level: 1.5 mg/dl) for 9 years by low-dose steroid therapy. These two cases suggest that steroid therapy plays two important roles: controlling of the acute immune reaction that causes renal fibrosis to progress in case 1, and long-term preservation of the renal function by the continuous use of low-doses in case 2.
15187033 Altered autoantigen structure in Sjögren's syndrome: implications for the pathogenesis of 2004 Jun 4 The etiology and pathogenic mechanisms underlying Sjögren's syndrome (SS) remain unclear. Recent studies have emphasized that the specific autoantibodies that occur in a high proportion of patients with SS may provide important insights into the circumstances that initiate and propagate tissue damage in this disease. Although autoantigens targeted in systemic autoimmune diseases share little in common in terms of structure, subcellular distribution, or function in normal cells, these molecules are unified by becoming clustered and concentrated in the surface blebs of apoptotic cells. Furthermore, their structure is altered during some types of cell death to generate structures not previously generated during development and homeostasis. This review highlights the susceptibility of SS autoantigens to undergoing such structural changes during activation of immune effector pathways, and synthesizes a model of SS incorporating these concepts. An understanding of the mechanisms responsible for activating the specific immune response in SS, and the role of specific immune effector pathways in propagating both the autoimmune response and tissue damage, is of potential therapeutic importance. Abbreviations used in this paper are: CTL, cytotoxic T-lymphocytes; ER, endoplasmic reticulum; GluR3, subunit III of the glutamate receptor; GrB, granzyme B; M3R, type III muscarinic receptor; NK cells, natural killer cells; PARP, poly(ADP-ribose)polymerase; SS, Sjögren's syndrome; SLE, systemic lupus erythematosus; and UV, ultraviolet.
12816697 [The clinical significance of SSA antigen and its different positive expressions]. 2003 Mar OBJECTIVE: To distinguish the difference among the pathogenesis of 60 000 SSA antigen mono-antigen peptides (MAPs), and to discuss the nosogenesis of anti-60 000 SSA antibodies in correlative rheumatic diseases. METHODS: MAPs were artificially synthesized according to the amino acid sequence of 20 positive epitopes and 1 control segment of 60 000 SSA antigen. ELISA against recombinant 60 000 SSA antigen MAPs were done to detect anti-MAPs antibodies in 59 sera with anti-SSA antibodies, and analyzing the relations of anti-MAPs antibodies and organism injuries. RESULTS: Anti-60 000 SSA antibodies are multiple clone autoantibodies. Different patients have different immune response to MAPs. Anti-MAP(1 approximately 21) antibodies have no relation to skin lesion; anti-MAP(2,14,15,21) antibodies have positive relation to salivary gland lesion; anti-MAP(7,16) antibodies have negative relation to kidney lesion; anti-MAP(6) antibodies have negative relation to heart lesion. CONCLUSIONS: The appearance of some anti-MAPs antibodies implies the lesions of some organs, while the appearance of some other anti-MAPs antibodies have the protection to some organs. We concluded that it is maybe the different anti-MAPs antibodies that result in different clinical manifestations.
12167735 Cerebral infarct mimicking glioma in Sjogren's syndrome. 2002 Aug A 50-year-old Chinese woman with a chronic 20-year history of ataxic gait associated with dry eyes and mouth, was admitted to hospital after a single episode of syncope. Magnetic resonance imaging scans showed a large left frontal hypodense lesion suggestive of a glioma. Craniotomy was performed and the lesion excised, with histology showing only infarcted tissue and no malignant cells. Further diagnostic evaluation revealed that the patient had primary Sjogren's syndrome, with demyelinating polyneuropathy. In the absence of risk factors for stroke, it was considered likely that the cerebral infarct was secondary to autoimmune-related vasculitis. Functional neuroimaging, such as magnetic resonance spectroscopy, should be considered in evaluating doubtful or unusual brain lesions in patients with autoimmune disease.
11914948 [Chronic myoepithelial sialadenitis - symptomatology, clinical signs, differential diagnos 2002 Feb In the differential diagnosis of mass lesions of the salivary glands, myoepithelial sialadenitis (MESA), i. e. benign lymphoepithelial lesion, carries particular importance because of its association with Sjoegren's syndrome and development of malignant lymphoma. In the present study, epidemiology and clinical findings were analysed in relation to presence of MESA, Sjoegren's syndrome and lymphoma development. MATERIAL AND METHOD: 67 patients, histopathologically classified by the salivary gland registry, were analysed retrospectively in regard to their clinical presentation, especially in regard to the chronical process of inflammation as present in MESA. RESULTS: MESA primarily affects women in the 5th and 6th decade and regularly the parotid gland; in 44.8 % of the cases, there is multiple organ presentation. Xerostomy (38.5 %) is usually present (in 88,9 % of all cases) before or at clinical onset of gland inflammation, whereas xerophthalmy (28.4 %) did not show such a correlation. In general, rheumatic diseases (23.9 %) precede the gland-symptoms in 77.8 % of the patients. In 31.3 % of the cases a Sjoegren's syndrome was present. 26.9 % of the patients developed a malignant Non Hodgkin's Lymphoma (88.9 % of the MALT-type). CONCLUSION: The most important clinical relevance of MESA lies in the higher probability to develop malignant lymphoma; this requires adequate staging-procedures and proper histopathological examination of sialogenic and nodal masses, especially over the course of the disease.
11995247 [Rheumatic syndromes during the course of HCV infection]. 2002 Feb The aim of the study was to evaluate clinical features and serological abnormalities in patients(pts) with rheumatological symptoms in the course of HCV infection (5 pts) and interferon-alpha treatment (2 pts). The diagnosis of hepatitis C was based on positive history on jaundice and risk factors of HCV infection, abnormal liver laboratory tests, the presence of anti-HCV and HCV-RNA and on results of liver biopsy. Among the patients with rheumatological features in the course of HCV infection seropositive arthritis in 4 pts, leucocytoclastic vasculitis, clinical and serological manifestations of mixed cryoglobulinemia-in 3 pts were observed. Glomerulonephritis, Raynaud's phenomenon and antinuclear antibodies were found in 2 pts. Sjögren's syndrome with anti-Ro/La antibodies, polyneuropathy and myalgia were observed in single cases. The most frequent therapy were corticosteroids alone or in combination with chlorochine or azathioprine. Arthritis, leucocytoclastic vasculitis and serological abnormalities: antinuclear antibodies, rheumatoid factor and low complement were seen in 2 pts with rheumatological features after the IFN-alpha treatment of HCV infection. Myalgia and xerostomia with anti-Ro antibody were found in one patient; lupus-like disease with anti-dsDNA antibody and autoimmune thyroiditis-in one patient. The therapy of these two cases was to withdraw interferon-alpha.
12672794 A novel function for a glucose analog of blood group H antigen as a mediator of leukocyte- 2003 Jun 13 The 4A11 antigen is a unique cytokine-inducible antigen up-regulated on rheumatoid arthritis synovial endothelium compared with normal endothelium. In soluble form, this antigen, Lewisy-6/H-5-2 (Ley/H), or its glucose analog, 2-fucosyllactose (H-2g), mediates angiogenesis. The Ley/H antigen is structurally related to the soluble E-selectin ligand, sialyl Lewisx, and is selectively expressed in skin, lymphoid organs, thymus, and synovium, suggesting that it may be important in leukocyte homing or adhesion. In the present study, we used H-2g as a functional substitute to demonstrate a novel property for Ley/H antigen in inducing leukocyte-endothelial adhesion. H-2g significantly enhanced the expression of human dermal microvascular endothelial cells (HMVECs) intercellular adhesion molecule-1 (ICAM-1), but not vascular cell adhesion molecule-1, E-selectin, and P-selectin. Immunoprecipitation and Western blotting showed glycolipids Ley-6, H-5-2, or the glucose analog H-2g quickly activated human microvascular endothelial cell line-1 (HMEC-1) Janus kinase 2 (JAK2) and that the JAK2 inhibitor, AG-490, completely inhibited HMVEC ICAM-1 expression and HL-60 adhesion to HMEC-1s. Use of a JAK/signal transducer and activator of transcription (STAT) profiling system confirmed that H-2g selectively activated STAT3 but not STAT1 and STAT2. AG-490 inhibited H-2g-induced Erk1/2 and PI3K-Akt activation, suggesting that JAK2 is upstream of the Erk1/2 and PI3K-Akt pathways. Furthermore, the JAK2 inhibitor AG-490, the Erk1/2 inhibitor PD98059, or the phosphatidylinositol 3-kinase inhibitor LY294002 or antisense oligodeoxynucleotides directed against JAK2, Erk1/2, or phosphatidylinositol 3-kinase blocked H-2g-induced HMVEC ICAM-1 expression and HL-60 adhesion to HMEC-1s. Hence, H-2g signals through JAK2 and its downstream signal transducers STAT3, Erk1/2, and phosphatidylinositol 3-kinase result in ICAM-1 expression and cell adhesion. Potential treatment strategies through the inhibition of JAK-dependent pathways to target H-2g signals may provide a useful approach in inflammation-driven diseases like rheumatoid arthritis.