Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027121 (myositis)
 4,538 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper presents a brief review of several lines of evidence suggesting that chemokine receptors on dendritic cells play an important role in breaking tolerance to self and in inducing autoimmunity. First, we have shown that an idiotypic self-antigen obtained from malignant murine lymphomas, when covalently linked to selected chemokines or defensins that interact with receptors on immature dendritic cells (iDCs), has the capacity to break tolerance to self and induce humoral or cell-mediated anti-tumor responses. Since unlinked antigens mixed with the same chemokines or defensins or antigens fused with a mutant ligand deficient in receptor-binding capacity were not immunogenic, we propose that delivery of an antigen coupled to a ligand for receptors on iDCs promotes the processing and subsequent presentation of the antigen, resulting in immunoadjuvant effects. In a second study, we observed that two of five aminoacyl tRNA synthetases (aaRSs) - which act as autoantigens to which some patients with myositis have autoantibodies - were chemotactic for activated monocytes, T cells, and iDCs. These aaRSs interacted with either CC chemokine receptor (CCR)5 or CCR3, as was shown by desensitization with chemokines and the response of cell lines transfected with the chemokine receptor. Presumably, these autoantigens therefore have the capacity to attract inflammatory cells, including iDCs, to infiltrate affected muscle cells. These observations suggest the hypothesis that antigens delivered to receptors on iDCs are potent immunogens capable of breaking self-tolerance to tumor antigens to induce autoimmune diseases.
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PMID:Chemokine receptors on dendritic cells promote autoimmune reactions. 1211 Jan 38

Autoantibodies to histidyl-tRNA synthetase (HisRS) or to alanyl-, asparaginyl-, glycyl-, isoleucyl-, or threonyl-tRNA synthetase occur in approximately 25% of patients with polymyositis or dermatomyositis. We tested the ability of several aminoacyl-tRNA synthetases to induce leukocyte migration. HisRS induced CD4(+) and CD8(+) lymphocytes, interleukin (IL)-2-activated monocytes, and immature dendritic cells (iDCs) to migrate, but not neutrophils, mature DCs, or unstimulated monocytes. An NH(2)-terminal domain, 1-48 HisRS, was chemotactic for lymphocytes and activated monocytes, whereas a deletion mutant, HisRS-M, was inactive. HisRS selectively activated CC chemokine receptor (CCR)5-transfected HEK-293 cells, inducing migration by interacting with extracellular domain three. Furthermore, monoclonal anti-CCR5 blocked HisRS-induced chemotaxis and conversely, HisRS blocked anti-CCR5 binding. Asparaginyl-tRNA synthetase induced migration of lymphocytes, activated monocytes, iDCs, and CCR3-transfected HEK-293 cells. Seryl-tRNA synthetase induced migration of CCR3-transfected cells but not iDCs. Nonautoantigenic aspartyl-tRNA and lysyl-tRNA synthetases were not chemotactic. Thus, autoantigenic aminoacyl-tRNA synthetases, perhaps liberated from damaged muscle cells, may perpetuate the development of myositis by recruiting mononuclear cells that induce innate and adaptive immune responses. Therefore, the selection of a self-molecule as a target for an autoantibody response may be a consequence of the proinflammatory properties of the molecule itself.
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PMID:Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. 1223 11

Beta-chemokines attract and activate T cells and monocytes and have a key role in chronic inflammation. Certain beta-chemokines, such as monocyte chemoattractant protein-1 (MCP-1), have been reported to be upregulated in the idiopathic inflammatory myopathies (IIM). We studied the distribution of beta-chemokine receptors in polymyositis (PM), sporadic inclusion-body myositis (sIBM), dermatomyositis (DM), and control samples. CCR1-5 were localized to blood vessels in all samples. In addition, increased endothelial expression of CCR2A was observed in IIM. Subsets of inflammatory cells, identified as macrophages and T cells, in all three types of IIM expressed CCR2A, CCR2B, CCR3, CCR4, and CCR5. In contrast to an earlier report, we found CCR2B to be the most prominent MCP-1 receptor on inflammatory cells in IIM, especially in PM and sIBM. Strong CCR4 expression was present on myonuclei of regenerating muscle fibers. The prominence of the CCR2 receptors further underlines the importance of the interaction with their ligand MCP-1 in the immunopathogenesis of IIM and puts CCR2B forward as a potential target for future therapeutic intervention.
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PMID:Beta-chemokine receptor expression in idiopathic inflammatory myopathies. 1577 70

We have investigated the chemoattractant properties of self-antigens associated with autoimmune diseases and solid tumors. Many autoantigens induced leukocyte migration, especially by immature dendritic cells (iDC) by interacting with various chemoattractant Gi-protein-coupled receptors (GiPCR). Our initial observation that myositis-associated autoantigens, histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, were chemotactic for CC chemokine receptor 5 (CCR5)- and CCR3-expressing leukocytes, while other nonautoantigenic aminoacyl-tRNA synthesases were not, suggested that only self-antigens capable of interacting with receptors on antigen-presenting cells were immunogenic. We next determined that self-antigens associated with autoimmune diseases, e.g., multiple sclerosis or experimental autoimmune encephalomyelitis, type I diabetes, scleroderma, systemic lupus erythematosus, autoimmune uveitis, or experimental autoimmune uveitis (EAU), were chemotactic for GiPCR expressed by iDC. The majority of autoantigens were DC chemoattractants at 10-100 ng/ml, but did not induce DC maturation until they reached 1000-fold higher concentrations. Interphotoreceptor retinoid-binding protein and retinal arrestin (S-antigen) are targets of autoantibodies in human uveitis and are chemotactic for CXC chemokine receptor 5 (CXCR5)- and/or CXCR3-expressing iDC. However, although S-antigen does not induce EAU in wild-type mice, it is nevertheless a chemoattractant for murine iDC. These unexpected observations suggested that the chemotactic activity of these tissue-specific self-antigens could be involved in promotion of tissue repair and restoration. Thus, the primary role of autoantigens may be to alert the immune system to danger signals from invaded and damaged tissues to facilitate repair, and autoimmune responses subsequently develop only in subjects with impaired immunoregulatory function.
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PMID:Autoantigens act as tissue-specific chemoattractants. 1591 48

The etiologies of most autoimmune diseases are not completely understood. Aminoacyl-tRNA synthetases (AARS) are a family of heterogenous enzymes responsible for protein synthesis and whose secondary functions include a role in autoimmune myositis. A subset of patients with idiopathic inflammatory myopathies demonstrate autoantibody against specific cytoplasmic AARS and the human asparaginyl-tRNA synthetase (AsnRS) has been shown to be a potent chemokine that interacts with CCR3 chemokine receptors. One way in which a chemotactic cytoplasmic enzyme might contribute to tissue inflammation is if it were abundant in a specific injured tissue and thereby released to the microenvironment at times of cellular damage. To test this hypothesis, the relative levels of AsnRS mRNA were studied in six human tissues. A 1.6 kbF RNA probe identified highly variable levels of the corresponding mRNA in Northern blot analysis of human lung, brain, heart, skeletal muscle, pancreas and liver. The highest levels of signal were noted in muscle and pancreas. Polyclonal antibody raised against recombinant human AsnRS identified abundant antigenic material in the pancreas, in particular in islet cells. Thus, the local abundance of an endogenous pro-inflammatory autoantigen may provide one explanation for perpetuation or exacerbation of tissue specific immune-mediated pathologies.
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PMID:Do tissue levels of autoantigenic aminoacyl-tRNA synthetase predict clinical disease? 1608 68