Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coiled bodies are conserved subnuclear organelles that contain splicing snRNPs, a subset of nucleolar antigens, and the autoantigen p80 coilin. Most nuclei contain one to five nucleoplasmic coiled bodies, often with one or more located at the nucleolar periphery. Here we show that exposure of mammalian cells to low levels of the specific Ser/Thr protein phosphatase inhibitor, okadaic acid, results in the accumulation of p80 coilin and splicing snRNPs within nucleoli. Mutation of a single serine residue in p80 coilin to aspartate (S202D) also causes coiled bodies and splicing snRNPs to localize within nucleoli when the mutant is transiently transfected and expressed in HeLa cells. Neither okadaic acid nor the S202D coilin mutant causes nucleolar accumulation of serine-arginine-domain proteins. These data indicate that protein dephosphorylation is required to allow normal formation of nucleoplasmic coiled bodies and point to p80 coilin as a substrate whose phosphorylation state may regulate snRNP-nucleolar interactions. The data are consistent with a trafficking mechanism whereby splicing snRNPs cycle through the nucleolus.
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PMID:Inhibition of protein dephosphorylation results in the accumulation of splicing snRNPs and coiled bodies within the nucleolus. 901 10

Monoclonal antibodies (mAb) specific for the clonotype of an autoreactive T cell may be useful reagents in the modulation of autoimmune disease. We have previously reported the generation of a set of mAb specific for the clonotypic structure of a human T-cell clone recognizing an epitope of human cartilage gp-39. This glycoprotein was recently identified as a candidate autoantigen in rheumatoid arthritis. Here, we demonstrate for the first time that small amounts of immobilized anticlonotype mAb can induce anergy in the autoreactive clone. Following the anergic stimulus, T cells failed to proliferate upon restimulation as a result of a lack of interleukin-2 (IL-2) gene transcription. In addition, a diminished interferon-gamma (IFN-gamma) production was found. Our data indicate that anergy was not a result of T-cell receptor (TCR) downmodulation or the absence of free TCR. The anergic state was induced independent of costimulation or the presence of IL-2 and no protein synthesis was required for the induction of anergy. Anticlonotype mAb-induced anergy was prevented by cyclosporin A, suggesting that active signalling via the calcium/calcineurin pathway was required for the induction of anergy. In coculture experiments, anergic T cells were found to suppress the response of reactive cells from the same clone. This bystander suppression led to 90% inhibition of peptide-induced proliferation. Together, these findings suggest that mAb to the clonotypic structure of autoreactive T cells may be suitable reagents for the functional inactivation of these T cells in autoimmune diseases.
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PMID:T-cell anergy induced by clonotype-specific antibodies: modulation of an autoreactive human T-cell clone in vitro. 1023 45

Type 1 diabetes mellitus affects about 1 in 300 people in North America and Europe. Epidemiological studies indicate that the incidence and thus prevalence of type 1 diabetes is rising worldwide. Intervention in autoimmune type 1a diabetes could occur at the time of diagnosis or, preferably, prior to clinical presentation during the 'prediabetic' period (e.g. prevention). Prediabetes is best recognised by the detection of islet autoantibodies in the serum. Promising intervention strategies include monoclonal antibody therapies (e.g. anti-CD3, anti-CD25, anti-CD52 or anti-CD20 monoclonal antibodies), immunosuppression (e.g. calcineurin inhibitors, B7 blockade, glucocorticoids, sirolimus (rapamycin), azathioprine or mycophenolate mofetil), immunomodulatory therapies (e.g. plasmapheresis, intravenous immunoglobulin, cytokine administration, adoptive cellular gene therapy) and tolerisation interventions (e.g. autoantigen administration or avoidance, altered peptide ligand or peptide-based therapies). To date, islet and pancreas transplantation have essentially been reserved for patients with long-standing diabetes who have complications and are also in need of a concurrent kidney transplant. None of the therapies attempted to date has produced long-term remissions in new-onset type 1 diabetes patients and no therapies have been shown to prevent the disease. Nevertheless, with advances in our understanding of basic immunology and the cellular and molecular mechanisms of tolerance induction and maintenance, successful intervention therapies will be developed. The balance between safety and efficacy is critical. Higher rates of adverse events might be more tolerable in new-onset type 1 diabetes patients if the therapy is extremely effective at inducing a permanent remission. However, therapies must not harm the beta-cells themselves or any organ system that is a potential target of diabetes complications, such as the nervous system, retina, cardiovascular system or kidney. In the treatment of prediabetes, successful therapies should provide a level of safety similar to that of currently used vaccines and a high level of efficacy.
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PMID:Prevention strategies for type 1 diabetes mellitus: current status and future directions. 1253 19

Prednisone alone or a lower dose of prednisone in combination with azathioprine induces remission and enhances survival in autoimmune hepatitis. Treatment failure, incomplete response, drug-induced side effects, and relapse after drug withdrawal are unsatisfactory outcomes that justify the search for new therapies. Potent new drugs promise greater blanket immunosuppression than current regimens, and insights into the pathogenic mechanisms of the disease make site-specific interventions possible. Cyclosporine and tacrolimus are calcineurin inhibitors that impair the transcription of interleukin 2, reduce the expression of cytokines, and diminish T lymphocyte proliferation. Mycophenolate mofetil antagonizes the synthesis of purines and depletes stores of guanine nucleotides necessary for DNA synthesis and expansion of T cell clones. Controlled clinical trials are warranted to establish the role of these new drugs in the treatment of autoimmune hepatitis. Promising site-specific therapies include peptides that competitively block autoantigen presentation, agents such as cytotoxic T lymphocyte antigen 4 that inhibit the second co-stimulatory signal of immunocyte activation, T cell vaccination, oral tolerance therapy, and cytokine manipulation with monoclonal antibodies and recombinant supplements. Confident animal models of experimental autoimmune hepatitis are necessary to mature these interventions. In conclusion, promising immunosuppressive agents that alter cytokine expression and T lymphocyte proliferation may be of value in the treatment of autoimmune hepatitis. Critical mechanisms of immunocyte activation, cytotoxic T cell expansion, and cytokine modulation are the targets of site-specific interventions.
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PMID:Emerging treatments for autoimmune hepatitis. 1456 Nov 79

The cause of common polygenic autoimmune diseases is not understood because of genetic and cellular complexity. Here, we pinpoint the action of a subset of autoimmune susceptibility loci in the NOD mouse strain linked to D1mit181, D2mit490, D7mit101, and D15mit229, which cause a generalized resistance to thymic deletion in vivo that applies equally to Aire-induced organ-specific gene products in the thymic medulla and to systemic antigens expressed at high levels throughout the thymus and affects CD4(+), CD4(+)8(+), and CD4(+)25(+) thymocytes. Resistance to thymic deletion does not reflect a general deficit in TCR signaling to calcineurin- or ERK-induced genes, imbalance in constitutive regulators of apoptosis, nor excessive signaling to prosurvival genes but is distinguished by failure to induce the proapoptotic gene and protein, Bim, during in vivo encounter with high-avidity autoantigen. These findings establish defects in thymic deletion and Bim induction as a key mechanism in the pathogenesis of autoimmunity.
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PMID:Generalized resistance to thymic deletion in the NOD mouse; a polygenic trait characterized by defective induction of Bim. 1558 70

The treatment of autoimmune hepatitis is evolving as the pathogenic pathways that underlie the disease are defined, new immunosuppressive agents are tested, and site-specific molecular interventions become feasible. Prednisone alone or at a reduced dose combined with azathioprine is the conventional treatment. Patients with HLA genotype DRB1*0301 have a poorer treatment response and a more frequent need for liver transplantation than those with HLA genotype DRB1*0401. Therapy to the point when liver test results and histological findings are normal reduces, but does not eliminate, the occurrence of relapse. Treatment failure warrants reassessment with regard to the accuracy of the original diagnosis and the exclusion of variant forms of hepatitis or concomitant alternative diseases. Ciclosporin might be effective as short-term, front-line therapy in infants and adults, and calcineurin inhibitors might salvage patients who are refractory to corticosteroid regimens. Mycophenolate mofetil can induce an improvement in laboratory test results and reduce the requirement for corticosteroids. Sirolimus is effective for treatment of de novo autoimmune hepatitis that develops after liver transplantation. Synthetic peptides that block autoantigen presentation, cytokine manipulations, oral tolerance regimens, T-cell vaccination, and gene therapy are all interventions that will be able to emerge after a reliable animal model of the human disease has been developed.
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PMID:Current therapy for autoimmune hepatitis. 1740 88

Spontaneous equine recurrent uveitis (ERU) is an incurable autoimmune disease affecting the eye. Although retinal-autoantigen specific T-helper 1 cells have been demonstrated to trigger disease progression and relapses, the molecular processes leading to retinal degeneration and consequent blindness remain unknown. To elucidate such processes, we studied changes in the total retinal proteome of ERU-diseased horses compared to healthy controls. Severe changes in the retinal proteome were found for several markers for blood-retinal barrier breakdown and whose emergence depended upon disease severity. Additionally, uveitic changes in the retina were accompanied by upregulation of aldose 1-epimerase, selenium-binding protein 1, alpha crystallin A chain, phosphatase 2A inhibitor (SET), and glial fibrillary acidic protein (GFAP), the latter indicating an involvement of retinal Mueller glial cells (RMG) in disease process. To confirm this, we screened for additional RMG-specific markers and could demonstrate that, in uveitic retinas, RMG concomitantly upregulate vimentin and GFAP and downregulate glutamine synthetase. These expression patterns suggest for an activated state of RMG, which further downregulate the expression of pigment epithelium-derived factor (PEDF) and begin expressing interferon-gamma, a pro-inflammatory cytokine typical for T-helper 1 cells. We thus propose that RMG may play a fatal role in uveitic disease progression by directly triggering inflammatory processes through the expression and secretion of interferon-gamma.
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PMID:Retinal Mueller glial cells trigger the hallmark inflammatory process in autoimmune uveitis. 1744 70