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)

Collagen-induced arthritis (CIA) in mice has been classified as a Thl-mediated disease. However, most evidence for this has been obtained by indirect experiments; for example, the administration of neutralizing anti-interferon-gamma (IFN-gamma) antibody reduced the severity of arthritis. To obtain direct evidence about the cytokine balance in CIA mice, we analyzed the cytokine-secreting cell in CIA mice at the single cell level using a dual color enzyme-linked immunospot (ELISPOT) assay, which enabled us to analyze interleukin-2 (IL-2)-secreting cells or IL-4-secreting cells or both simultaneously. Furthermore, to characterize the cytokine network in the pathogenesis of CIA, the frequency of the cells secreting IL-12, which induced the development of naive Th cells into Th1 cells, was analyzed. The results show that in the prearthritic phase, the number of IL-12-secreting cells in spleen and peritoneal exuded cells is increased, and Th1 cells in lymph node and spleen are dominant. In contrast, after the onset of clinical arthritis, the number of IL-12-secreting cells in spleen, lymph node, and peritoneal exuded cells is decreased, and there is a shift from a Thl-dominant to a Th2-dominant state in lymph node and spleen. The results indicated that the pathogenesis of CIA is associated with a disruption in the normal ratio of Th1/Th2 at cell level.
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PMID:Characterization of the cytokine network at a single cell level in mice with collagen-induced arthritis using a dual color ELISPOT assay. 1067 Jun 52

Interleukin-12 (IL-12) is a pleiotropic cytokine with proinflammatory, immunoregulatory, antitumor, and antimetastatic properties. It plays a crucial role in the development of the Th1 response and subsequent interferon-gamma production and enhancement of cell-mediated cytotoxicity. Recently, IL-12 has been used as an experimental therapy for cancer. Given the multiple immunomodulatory properties of IL-12, there are potential concerns associated with its clinical use. Of special interest are the possible side effects of IL-12 therapy in patients with autoimmune diseases, especially those that are T cell mediated, such as rheumatoid arthritis (RA). We present a case of severe RA exacerbation caused by treatment with IL-12 for metastatic cervical cancer. This is the first reported case of RA flare caused by exogenous IL-12.
Arthritis Rheum 2000 Feb
PMID:Rheumatoid arthritis exacerbation caused by exogenous interleukin-12. 1069 89

Previous studies have shown that immunization of mice with an immunodominant epitope from heat-shock protein 65 (hsp 65) (amino acids 261-271) can protect from the development of pristane-induced arthritis (PIA) and this protection is mediated by an antigen-specific T helper type 2 (Th2) cytokine response. Here we confirm these findings and show that frequent intranasal administration of this peptide exacerbates disease. In naive mice given peptide intranasally an antigen-specific T-cell population is systemically activated similar to that induced by peptide immunization in incomplete Freund's adjuvant. Thus, a paradox exists whereby apparently similar peptide-specific populations are either associated with protection from, or exacerbation of, PIA. However, comparison of cytokine profiles reveals differences between these two cell populations. Peptide inhalation induces the production of Th1-type cytokines (interferon-gamma) whereas intraperitoneal immunization leads to the production of Th2-type cytokines (interleukin-4, interleukin-5 and interleukin-10) by splenic T cells upon stimulation with peptide. Thus, for the application of nasal 'tolerance' in clinical medicine, it is important to identify antigens and dosing regimes that counteract but do not activate adverse immune responses.
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PMID:The route of administration of an immunodominant peptide derived from heat-shock protein 65 dramatically affects disease outcome in pristane-induced arthritis. 1071 62

The central role of CD4+ T cells and the balance between T helper (Th) subpopulations in the pathogenesis of autoimmune diseases have been extensively studied. Proteoglycan (aggrecan)-induced arthritis (PGIA) is a murine model for rheumatoid arthritis (RA), which is characterized by a Th1 dominance at the onset of the disease. In addition to CD4+ T cells, antigen-presenting B cells and autoantibodies seem to play an important role in the development and regulation of PGIA. To identify proteoglycan-specific CD4+ T cell subsets and Th1- and Th2-supported antibody isotypes during the progression of PGIA, spleen cells of proteoglycan-immunized BALB/c mice were harvested at different times of immunization, and at different stages of the disease, and their cytokine production and antigen-specific antibody isotype profiles were determined by enzyme-linked immunospot (ELISPOT) assays. Both Th1 and Th2 cytokine-producing cells, with the predominance of IL-4/IL-5-secreting cells, were detected during the prearthritic stage, and a shift toward a Th1 dominance was observed at the time of onset of arthritis. Tissue homogenates of acutely inflamed joints contained significantly higher levels of interferon-gamma than IL-4. The prearthritic period and both the acute and chronic phases of joint inflammation were characterized by IgG1 dominance in the sera and this correlated with the number of IgG1-secreting B cells in the spleen. However, the ratio of autoreactive IgG1/IgG2a-secreting cells decreased in arthritic animals. These results indicate the activation and possible regulatory roles of both Th1 and Th2 subsets in the autoimmune process, with the necessity of a relative increase of autoreactive Th1 cells for the induction of joint inflammation.
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PMID:Complex pattern of Th1 and Th2 activation with a preferential increase of autoreactive Th1 cells in BALB/c mice with proteoglycan (aggrecan)-induced arthritis. 1075 79

Our previous work showed that the cartilage proteoglycan aggrecan could induce an erosive polyarthritis and spondylitis in BALB/c mice and the G1 globular domain of the aggrecan (G1) contained the arthritogenic region. To elucidate whether autoreactive T cells to G1 are expressed in rheumatoid arthritis patients, we analyzed the frequency of human G1-specific T cells in the peripheral blood of five rheumatoid arthritis patients and tried to establish G1-reactive T cell lines from these rheumatoid arthritis patients. The results showed that the G1-specific T cells in PBL were detectable at the range of 4.97 +/- 0.5 x 10(-6) in peripheral blood lymphocytes. We have also generated 15 G1-specific T lymphocyte lines from these patients with a standard split-well method. All these cells expressed fine specificity to human recombinant G1, but not to unrelated antigen. All the 15 lines expressed a pan-T cell marker and 13 of them selectively used the alphabeta T cell receptor. Two of them used gammadelta T cell receptor. The 13 of these T cell lines was CD4 positive. One line expressed CD8. One line expressed both CD4 and CD8. Moreover, 14 out of 15 lines expressed the Th-1 cytokine profile, characterized by interferon-gamma positivity and IL-4 negativity. No Th-2 type cell line was generated. These data provide strong evidence in favor of the presence of autoreactive T cells in the rheumatoid arthritis patients. What is the mechanism(s) that these autoreactive T cells attack self-target and whether these G1-specific, Th-1 type T cell lines can induce arthritis in immune deficiency mice are currently under investigation.
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PMID:Isolation and characteristics of autoreactive T cells specific to aggrecan G1 domain from rheumatoid arthritis patients. 1076 82

We investigated the ability of lipopolysaccharide (LPS) as an adjuvant to induce autoimmune arthritis. LPS from Escherichia coli was intraperitoneally injected into DBA/1J mice together with the joint cartilage component type II collagen (CII) on day 0. Thereafter, the injection of CII and LPS was continued every 2 weeks up to day 56. The results showed that mice injected with CII plus LPS had signs of arthritis on day 55 and the joint inflammation reached a peak on day 75. Injection of CII or LPS alone induced no arthritis. Histologically, marked oedema of synovium and intense infiltration of inflammatory cells, including neutrophils, were observed 3 days after the onset of joint inflammation. Twenty-one days later, there were marked proliferation of synovial tissues with many mononuclear cells and destruction of cartilage. Anti-CII immunoglobulin G (IgG) and IgG2a antibodies were markedly produced in mice injected with CII plus LPS. Pronounced secretion of cytokines, including interleukins-12 and -1beta, interferon-gamma and tumour necrosis factor-alpha, was also observed in these animals. Arthritis was passively transferred into naive syngeneic mice with sera but not with lymphoid cells from mice given CII with LPS. Other types of LPS from Salmonella enteritidis, Salmonella typhimurium and Klebsiella pneumoniae as well as lipid A from E. coli, induced inflammation in joints when administered with CII. Polymixin B sulphate mixed with LPS or lipid A blocked the induction of joint inflammation. These results indicate that LPS appears to play an important role as an adjuvant in the induction of arthritis in which autoimmunity to CII is involved.
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PMID:Bacterial lipopolysaccharide acts as an adjuvant to induce autoimmune arthritis in mice. 1079 9

A 62-year-old white woman with chronic hepatitis C virus infection was diagnosed with systemic sarcoidosis during treatment with interferon-alpha. Seventeen cases of sarcoidosis associated with interferon treatment have been reported, with only 8 inpatients with chronic hepatitis C virus infection. Our patient, with no past history of sarcoidosis, developed subcutaneous sarcoid nodules, arthritis, uveitis, pneumonitis and heart involvement two months after she was started on treatment with interferon-alpha. Her symptoms resolved when she began corticosteroid therapy and interferon-alpha was stopped. This case report suggests that exogenous interferon-alpha may trigger or contribute to the development of this multisystem granulomatous disorder in which interferon-gamma and CD4 + T-lymphocyte are mainly involved. Patients should be monitored during and following interferon-alpha therapy, since the autoimmune diseases induced by interferon therapy do not always improve after cessation of treatment.
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PMID:[Systemic sarcoidosis during interferon-alpha therapy for chronic hepatitis C virus infection]. 1080 48

DBA/1 mice deficient in expressing the interferon-gamma (IFN-gamma) membrane receptor (IFN-gammaR KO mice) are more susceptible to collagen-induced arthritis (CIA) than wild-type mice, indicating that endogenous IFN-gamma plays a protective role in the pathogenesis of CIA. In IFN-gammaR KO mice, nitric oxide (NO) production during CIA is impaired. Because NO is known to exert immunosuppressive and anti-inflammatory effects in certain model systems, the protective effect of IFN-gamma might be mediated by NO. Here, we tested in wild-type mice whether inhibition of NO production by metabolic inhibitors, aminoguanidine (AG) and L-N-(1-iminoethyl)lysine (L-NIL), could mimic the ablation of the IFN-gamma receptor. A high-dose regimen of AG supplied in the drinking water inhibited NO production, disease development, and anticollagen antibody production but was also associated with transient body weight loss. At a dose and time regimen that still inhibited NO production but did not cause body weight loss, AG failed to affect disease scores. Treatment with L-NIL, which more specifically than AG affects inducible NO production, caused a slight increase in anticollagen antibody production although not significantly affecting disease occurrence. These data indicate that the diminished capacity of the IFN-gammaR KO mice to produce NO following immunization with collagen is unlikely to account for their higher susceptibility to CIA.
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PMID:The effects of NO synthase inhibitors on murine collagen-induced arthritis do not support a role of NO in the protective effect of IFN-gamma. 1091 98

Factor H and the FHL-1/reconectin protein are two human plasma proteins that act as important regulators of the alternative complement pathway. Each protein is encoded by a unique transcript, but both mRNAs are derived from the factor H gene by means of alternative processing. In order to address potential functional differences between the two proteins we analysed their expression in hepatic and non-hepatic cells and studied their regulation by inflammatory mediators. We demonstrate that factor H and FHL-1/reconectin transcripts which are regulated by the same gene promoter and are initiated at the same transcription start site are differently expressed. Expression of the molecules is induced and regulated by the inflammatory mediators interferon-gamma (IFN-gamma) and the anti-inflammatory glucocorticoid dexamethasone. Both factor H and FHL-1/reconectin are expressed and secreted by synovial fibroblasts and are present in synovial fluid derived from patients suffering from rheumatoid or reactive arthritis. The local synthesis in synovial fibroblasts and their induction by IFN-gamma and dexamethasone, but not by tumour necrosis factor-alpha, suggests for each of the two complement regulators a protective role in RA.
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PMID:Different regulation of factor H and FHL-1/reconectin by inflammatory mediators and expression of the two proteins in rheumatoid arthritis (RA). 1093 Nov 60

Proinflammatory cytokines including interferon-gamma (IFNgamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha) are implicated in the pathogenesis of acute graft-versus-host disease (aGVHD). Cytokine gene polymorphism is associated with functional differences in cytokine regulation and altered clinical performance in a variety of diseases. Polymorphism in the IFNgammaIntron1 microsatellite (CA)n repeat has been linked with in vitro IFNgamma production and renal transplant rejection. The IL-6(-174)(G/C) single nucleotide polymorphism has been linked to in vitro and in vivo IL-6 production, juvenile chronic arthritis, and renal transplant rejection. This study examined the potential association of GVHD with IFNgamma and IL-6 polymorphisms in 80 sibling bone marrow transplant (BMT) donor/recipient pairs. Patients homozygous for the IFNgammaIntron1 allele 3 had more severe (grade III-IV) aGVHD. Patients possessing the IL-6(-174)G allele had a trend toward higher grades of aGVHD, and those homozygous for the IL-6(-174)G allele were more likely to develop chronic GVHD (cGVHD). The associations of previously identified aGVHD severity-associated cytokine gene polymorphisms (TNFd and IL-10(-1064)) with severe aGVHD were reconfirmed. Logistic regression analysis confirmed the association of severe aGVHD with recipient genotype at IFNgammaIntron1 (odds ratio [OR] 3.92; P =.02), IL-10(-1064) (OR 4.61; P =.026) and TNFd (OR 3.29; P =.039), and that of cGVHD with recipient IL-6(-174) genotype (OR 4.25; P =.007), in addition to age, gender mismatch, and underlying disease. Assessment of cytokine genotype may potentially allow more accurate prediction of GVHD and appropriate adjustment of GVHD prophylaxis, as well as indicating novel areas for future studies of GVHD pathogenesis.
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PMID:Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. 1152 Aug 12


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