Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The core protein and the transmembrane protein, encoded for the structural genes gag and env, respectively, of caprine arthritis-encephalitis virus were amplified by use of polymerase chain reaction, cloned into a pGEX-2T vector, and expressed in Escherichia coli as fusion proteins with the glutathione S-transferase at their C-terminus. The recombinant proteins were purified and evaluated by use of an ELISA. Sera from 269 goats were tested, and the results were compared with those obtained by use of immunoblot analysis. When results from both recombinant ELISA (r-ELISA) were compared, it appeared that the transmembrane glycoprotein was more immunoreactive than the core protein, because it was recognized by a higher percentage of sera from infected goats. When results of the 2 ELISA (p28 r-ELISA and p40 r-ELISA) were combined in parallel, they were comparable to those of the immunoblot test, with sensitivity of 100% and specificity of 98.3%. It was also found that use of both r-ELISA makes it possible to compare the variable immunoreactivity against gag and env viral antigens, which may be correlated with the disease state. The r-ELISA, using core and transmembrane proteins, appears to be highly sensitive and specific for detection of antibodies against caprine arthritis-encephalitis virus.
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PMID:Bacterial expression of the caprine arthritis-encephalitis virus gag and env proteins and their use in enzyme-linked immunosorbent assay. 757 48

The expression of immunoregulatory cytokines was investigated in freshly isolated synovial fluid mononuclear cells (SFMC) and peripheral blood mononuclear cells (PBMC) from patients with RA, using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay. IFN-gamma, TGF-beta, IL-10 and IL-12 (p40) transcripts were detected in SFMC of patients with early disease (<1 year duration) as well as in patients with long standing arthritis (>1 year). The expression of IFN-gamma, IL-10 and IL-12 mRNA was increased in SFMC compared with RA PBMC. In addition, the expression was higher in RA SFMC than in PBMC from health control individuals. Immunoassay analysis of the secreted IL-12 heterodimer demonstrated increased levels in RA SF compared with levels found in serum from RA patients and control individuals. High levels of TGF-beta mRNA were found in SFMC, but a significantly decreased TGF-beta/beta2-microglobulin (beta2-M) ratio was found compared with PBMC from both patients and control individuals. IL-4mRNA could not be detected, either in SFMC or in PBMC. Cytokine expression in RA PBMC did not differ from control PBMC, with the exception of a decreased TGF-beta/beta2-M ratio in RA patients with early disease. Our findings of IFN-gamma mRNA and IL-12, but undetectable levels of IL-4 mRNA, suggest that the synovitis is characterized by a type 1 immune response. The presence of TGF-beta and IL-10 mRNA indicates that immunosuppressive cytokines may also operate in the inflamed joint, although their level of expression may not be sufficient for down-modulation of immune activation.
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PMID:Expression of interferon-gamma (IFN-gamma), IL-10, IL-12 and transforming growth factor-beta (TGF-beta) mRNA in synovial fluid cells from patients in the early and late phases of rheumatoid arthritis (RA). 860 32

Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.
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PMID:Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses. 895 22

It has been reported that the mRNA of the type 1 cytokine, interferon-gamma (IFN-gamma)--but not the type 2 cytokine interleukin-4 (IL-4)--is detected in synovial tissues of rheumatoid arthritis (RA) patients, whereas both IFN-gamma and IL-4 mRNA are detected in reactive arthritis (ReA). To evaluate such data more extensively, we obtained 208 synovial specimens in a prospective study of 52 early synovitis patients (13 RA, 11 ReA, 28 undifferentiated oligoarthropathy) and analyzed type 1 and type 2 cytokine mRNA expression in specimens containing sufficient mRNA. Using a nested reverse transcriptase polymerase chain reaction technique, we measured the relative mRNA levels of 10 cytokines and CD3 delta chain. We detected IL-10, IL-15, and CD3 delta chain mRNA in all RA and ReA patients and frequently detected tumor necrosis factor-alpha, IL-1 beta, and IFN-gamma mRNA. IL-6 and IL-12 p40 mRNA were detected in approximately one-half of the patients. We also detected greater amounts of IL-2 and IFN-gamma mRNA in ReA than were detected in RA. However, we rarely detected IL-4 or IL-13 mRNA. Similar cytokine profiles were observed in undifferentiated oligoarthropathy. The amounts of cytokine mRNAs, except for IL-10, in specimens from the patients taking prednisone or second-line antirheumatic drugs tended to be less than in specimens from the patients taking neither prednisone nor second-line antirheumatic drugs. These results suggest that cytokine mRNA profiles in patients with RA, ReA, and undifferentiated arthritis in their early stages are skewed toward proinflammatory macrophage-derived and type 1 cytokines. IL-10--not IL-4 or IL-13--mRNA appears to be the major antiinflammatory cytokine mRNA. Drug therapy is associated with depressed proinflammatory and type 1 cytokine mRNA production. The differences in the expression of IL-2 and IFN-gamma mRNA between RA and ReA may reflect unique etiological or host factors associated with the early stages of these diseases.
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PMID:In vivo gene expression of type 1 and type 2 cytokines in synovial tissues from patients in early stages of rheumatoid, reactive, and undifferentiated arthritis. 915 45

Caprine arthritis encephalitis virus (CAEV) is a lentivirus of goats that leads to chronic mononuclear infiltration of various tissues, in particular, the radiocarpal joints. Cells of the monocyte/macrophage lineage are the major host cells of CAEV in vivo. We have shown that infection of cultured goat macrophages with CAEV results in an alteration of cytokine expression in vitro. Constitutive expression of interleukin 8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) was increased in infected macrophages, whereas transforming growth factor beta1 (TGF-beta1) mRNA was down-regulated. When macrophages were infected with a CAEV clone lacking the trans-acting nuclear regulatory gene tat, IL-8 and MCP-1 were also increased. No significant differences from cells infected with the wild-type clone were observed, suggesting that Tat is not required for the increased expression of IL-8 and MCP-1 in infected macrophages. Furthermore, infection with CAEV led to an altered pattern of cytokine expression in response to lipopolysaccharide (LPS), heat-killed Listeria monocytogenes plus gamma interferon, or fixed cells of Staphylococcus aureus Cowan I. In infected macrophages, tumor necrosis factor alpha, IL-1beta, IL-6, and IL-12 p40 mRNA expression was reduced in response to all stimuli tested whereas changes in expression of granulocyte-macrophage colony-stimulating factor depended on the stimulating agent. Electrophoretic mobility shift assays demonstrated that, in contrast to effects of human immunodeficiency virus infection of macrophages, CAEV infection had no effect on the level of constitutive nuclear factor-kappaB (NF-kappaB) activity or on the level of LPS-stimulated NF-kappaB activity, suggesting that NF-kappaB is not involved in altered regulation of cytokine expression in CAEV-infected cells. In contrast, activator protein 1 (AP-1) binding activity was decreased in infected macrophages. These data show that CAEV infection may result in a dysregulation of expression of cytokines in macrophages. This finding suggests that CAEV may modulate the accessory functions of infected macrophages and the antiviral immune response in vivo.
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PMID:Caprine arthritis encephalitis virus dysregulates the expression of cytokines in macrophages. 931 28

Understanding of the genetic basis of autoimmune diseases is currently incomplete. Cytokine gene polymorphisms warrant consideration as factors explaining variation in the human immune and inflammatory responses and as candidate susceptibility genes for related pathological states. Interleukin 12 (IL-12) is a key regulator of the polarisation of immune responses to T helper 1 or 2 categories and plays a role in autoimmune and infectious diseases. Using a bioinformatic strategy, we aligned cDNA and expressed sequence tag sequences to identify putative polymorphic regions of the IL-12 p40 gene. Position 1188 in the 3' untranslated region (UTR) was polymorphic with the frequency of the common allele around 80% in healthy UK Caucasoids. PCR genotyping of multiple Caucasoid groups and an African group showed significant population variation. In a case-control design, the polymorphism was not associated with rheumatoid arthritis, Felty's syndrome or large granular lymphocyte syndrome with arthritis or multiple sclerosis. A nonsignificant increase in the B allele frequency was observed in the rare large granular lymphocyte syndrome without arthritis (odds ratio 2.02 95% CI 0.95-4.3). This new genetic marker could be useful in anthropological studies and should be investigated in other autoimmune, allergic, inflammatory and infectious diseases.
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PMID:Genetic polymorphism of IL-12 p40 gene in immune-mediated disease. 1119 15

The Mycoplasma arthritidis mitogen (MAM) superantigen (SAg) is a potent activator of human and murine cells and is produced by an organism that is a cause of acute and chronic arthritis of rodents. It is phylogenetically unrelated to other bacterial SAgs and exhibits a number of unique features. We recently demonstrated that MAM differentially regulates the cytokine responses of different mouse strains following in vivo administration. Here we show that the presence in inbred C3H/HeJ mice of the mutant Lps(d) gene, which is associated with a defect in Toll-like receptor 4 (TLR4), influences MAM regulation of cytokine profiles in vivo. Whereas the levels of type 1 cytokines (interleukin-2 [IL-2], gamma interferon, IL-12, and tumor necrosis factor alpha) were depressed in cells from MAM-injected wild-type C3H/HeSnJ mice, they were elevated in cells from C3H/HeJ mice. Furthermore, the levels of type 2 cytokines (IL-4, IL-6, and IL-10) were elevated in Lps(n) C3H/HeSnJ mice but depressed in Lps(d) C3H/HeJ mice. The transcript for IL-12 p40 was highly expressed in C3H/HeJ but not C3H/HeSnJ mice. F(1) mice exhibited the same cytokine profile as C3H/HeJ mice, indicating that the mutant gene exhibited dominant-negative inheritance. In addition, C3H/HeJ mice were highly susceptible to toxic death in comparison with C3H/HeSnJ mice after injection with live M. arthritidis organisms. Our results suggest that MAM interacts with the lipopolysaccharide signaling pathway, possibly involving TLR4 or a combinatorial Toll complex.
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PMID:Presence of Lps(d) mutation influences cytokine regulation in vivo by the Mycoplasma arthritidis mitogen superantigen and lethal toxicity in mice infected with M. arthritidis. 1134 49

Autoantigen-specific T cells have tissue-specific homing properties, suggesting that these cells may be ideal vehicles for the local delivery of immunoregulatory molecules. We tested this hypothesis by using type II collagen-specific (CII-specific) CD4(+) T hybridomas or primary CD4(+) T cells after gene transfer, as vehicles to deliver an immunoregulatory protein for the treatment of collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA). CII-specific T cells or hybridomas were transduced using retroviral vectors to constitutively express the IL-12 antagonist, IL-12 p40. Transfer of engineered CD4(+) T cells after immunization significantly inhibited the development of CIA, while cells transduced with vector control had no effect. The beneficial effect on CIA of IL-12 p40-transduced T cells required TCR specificity against CII, since transfer of T cells specific for another antigen producing equivalent amounts of IL-12 p40 had no effect. In vivo cell detection using bioluminescent labels and RT-PCR showed that transferred CII-reactive T-cell hybridomas accumulated in inflamed joints in mice with CIA. These results indicate that the local delivery of IL-12 p40 by T cells inhibited CIA by suppressing autoimmune responses at the site of inflammation. Modifying antigen-specific T cells by retroviral transduction for local expression of immunoregulatory proteins thus offers a promising strategy for treating RA.
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PMID:Antigen-specific T cell-mediated gene therapy in collagen-induced arthritis. 1139 Apr 15

Interleukin (IL)-12, being a major cytokine that induces T helper (Th) 1 differentiation and inflammatory response, has been postulated to be an important mediator of synovial inflammation in rheumatoid arthritis (RA). However, the regulation of IL-12 production in RA has not been elucidated. Our knowledge is mainly based on studies of the production of IL-12p40 and not the functional IL-12p70 heterodimer. We have studied the CD154-induced IL-12p40 and IL-12p70 production by synovial fluid (SF) macrophages from patients with RA. CD40 ligation induced the secretion of IL-12p40 but not IL-12p70. The observed increase in IL-10 and tumor necrosis factor (TNF)-alpha production indicated that SF macrophages responded to CD40 ligation. The expression of p40 mRNA was increased significantly and remained upregulated after CD40 ligation, whereas the increase of p35 transcript expression was observed only transiently and at a lower level. We further observed that dendritic cells (DCs) derived in vitro from SF macrophages produced IL-12p70. Most importantly, IL-4 and IL-13 primed SF macrophages to produce IL-12p70, whereas IFN-gamma was not observed to activate IL-12p70 production in these cells, in contrast with normal peripheral blood monocytes. These results provide novel information about the regulation of IL-12p70 production and the function of the cytokine network in RA.
Arthritis Res 2002
PMID:Regulation of CD154-induced interleukin-12 production in synovial fluid macrophages. 1222 12

The protective effect of pregnancy on putative Th1-mediated autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, is associated with a Th1 to Th2 immune shift during pregnancy. The hormone estriol increases during pregnancy and has been shown to ameliorate experimental autoimmune encephalomyelitis and collagen-induced arthritis. In addition, estrogens induce cytokine changes consistent with a Th1 to Th2 shift when administered in vitro to human immune cells and in vivo to mice. In a pilot trial, oral estriol treatment of relapsing remitting multiple sclerosis patients caused significant decreases in enhancing lesions on brain magnetic resonance imaging. Here, the immunomodulatory effects of oral estriol therapy were assessed. PBMCs collected longitudinally during the trial were stimulated with mitogens, recall Ags, and glatiramer acetate. Cytokine profiles of stimulated PBMCs were determined by intracellular cytokine staining (IL-5, IL-10, IL-12 p40, TNF-alpha, and IFN-gamma) and cytometric bead array (IL-2, IL-4, IL-5, IL-10, TNF-alpha, and IFN-gamma). Significantly increased levels of IL-5 and IL-10 and decreased TNF-alpha were observed in stimulated PBMC isolated during estriol treatment. These changes in cytokines correlated with reductions of enhancing lesions on magnetic resonance imaging in relapsing remitting multiple sclerosis. The increase in IL-5 was primarily due to an increase in CD4(+) and CD8(+) T cells, the increase in IL-10 was primarily due to an increase in CD64(+) monocytes/macrophages with some effect in T cells, while the decrease in TNF-alpha was primarily due to a decrease in CD8(+) T cells. Further study of oral estriol therapy is warranted in Th1-mediated autoimmune diseases with known improvement during pregnancy.
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PMID:Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. 1463 44


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