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  • 1
    Language: English
    In: Best Practice & Research Clinical Rheumatology, August 2012, Vol.26(4), pp.505-533
    Description: The term ‘autoinflammatory disease’ was first proposed in 1999 to encompass some of the distinct clinicopathologic features of a group of monogenic conditions, characterised by recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells. It was subsequently observed that several of these conditions were caused by mutations in proteins involved in the innate immune response, including, among others, components of the NLRP3 inflammasome, cytokine receptors (tumour necrosis factor receptor 1 (TNFR1)) and receptor antagonists (interleukin 1 receptor antagonist (IL-1RA)). More recently, additional mechanisms linking innate immune-mediated inflammation with a variety of cellular processes, including protein misfolding, oxidative stress and mitochondrial dysfunction, have been recognised to play a role in the pathogenesis of some monogenic autoinflammatory conditions, and also in more common diseases such as type 2 diabetes (T2D), previously perceived as a metabolic disorder, but reclassified as a chronic inflammatory condition. NLRP3 inflammasome activation is induced by islet amyloid polypeptides (IAPPs) in T2D and this condition may, in future, be more commonly treated with targeted anti-cytokine therapies. Caspase 1 activation and release of IL-1β/IL-1 family members is central to the pathogenesis of many autoinflammatory syndromes, as evidenced by the effectiveness of anti-IL-1 biologics in treating these disorders. However, many patients continue to experience symptoms of chronic inflammation, and it will be necessary to translate discoveries on the immunopathology of these conditions into more effective therapies. For example, in tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), the pathogenesis may vary with each mutation and therefore future approaches to treatment of individual patients will require a more tailored approach based on genetic and functional studies.
    Keywords: Autoinflammation ; Fmf (Familial Mediterranean Fever) ; Traps (Tnf Receptor-Associated Periodic Fever Syndrome) ; Nlrp3 (Nod-Like Receptor Family, Pyrin Domain-Containing Protein 3) Inflammasome ; Biological Therapy ; Il-1β Tnf ; Ros (Reactive Oxygen Species) ; Metabolism ; Medicine
    ISSN: 1521-6942
    E-ISSN: 1532-1770
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  • 2
    Language: English
    In: Annals of the Rheumatic Diseases, March, 2014, Vol.73(3), p.A22(1)
    Keywords: Transcription Factors -- Research ; Transcription Factors -- Physiological Aspects ; Rheumatoid Arthritis -- Risk Factors ; Rheumatoid Arthritis -- Research ; Rheumatoid Arthritis -- Genetic Aspects ; Immune Response -- Research
    ISSN: 0003-4967
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  • 3
    Language: English
    In: Arthritis & Rheumatism, February 2012, Vol.64(2), pp.418-422
    Description: OBJECTIVETo characterize the role of histone deacetylase (HDAC) activity in rheumatoid arthritis (RA) and to evaluate the effects of MI192, a novel HDAC-3-selective inhibitor, compared with the established nonselective HDAC inhibitor trichostatin A (TSA), on proinflammatory cytokine production. METHODSActivity of HDAC and histone acetyltransferase was measured in peripheral blood mononuclear cells (PBMCs) from RA patients by spectrophotometric assay, prior to and after 12 weeks of etanercept therapy. The effects of HDAC inhibitor treatment on cytokine production in both RA and healthy PBMCs were assessed by enzyme-linked immunosorbent assay. RESULTSRA PBMCs exhibited significantly increased HDAC activity (P = 0.007) compared to PBMCs from healthy individuals, and the increase was unaltered after 12 weeks of etanercept therapy. TSA was a potent inhibitor of tumor necrosis factor (TNF) and interleukin-6 (IL-6) production in both RA and healthy PBMCs and of interferon-γ (IFNγ) production in healthy PBMCs; IFNγ was not produced by RA PBMCs. MI192 inhibited TNF production at high concentrations and dose-dependently inhibited IL-6 in RA PBMCs but not healthy PBMCs, across a dose range of 10 μM-5 nM. CONCLUSIONHDAC activity is dysregulated in RA PBMCs and is a potential target for therapeutic intervention, as it is not affected by conventional anti-TNF treatment with etanercept. Both the selective and the nonselective HDAC inhibitors (MI192 and TSA, respectively) were found to regulate cytokine production from PBMCs, but their effects were cell type and compound specific. HDAC inhibitors have potential in the treatment of RA, and HDAC-selective inhibition may improve the therapeutic margin of safety; however, further clinical characterization and evaluation for adverse effects is needed.
    Keywords: Aged, 80 and Over–Blood ; Arthritis, Rheumatoid–Genetics ; Dose-Response Relationship, Drug–Metabolism ; Female–Pharmacology ; Histone Deacetylase Inhibitors–Genetics ; Histone Deacetylases–Metabolism ; Humans–Pharmacology ; Hydroxamic Acids–Metabolism ; Interferon-Gamma–Metabolism ; Interleukin-6–Drug Effects ; Leukocytes, Mononuclear–Metabolism ; Male–Metabolism ; Middle Aged–Metabolism ; Abridged ; Histone Deacetylase Inhibitors ; Hydroxamic Acids ; Interleukin-6 ; Trichostatin A ; Interferon-Gamma ; Histone Deacetylases ; Histone Deacetylase 3;
    ISSN: 0004-3591
    E-ISSN: 1529-0131
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  • 4
    In: Nature Reviews Rheumatology, 2014
    Description: Three monogenic diseases, with features of both autoinflammation and autoimmunity, were described for the first time in 2014. As well as providing insights into the molecular basis of several rare immunological disorders, the discoveries have implications for their diagnosis and treatment. Savic, S. & McDermott, M. F. Nat. Rev. Rheumatol. 11, 67-68 (2015); published online 23 December 2014; doi: 10.1038/nrrheum.2014.215
    Keywords: Gene Therapy – Health Aspects ; Immunologic Diseases – Care and Treatment ; Immunologic Diseases – Research;
    ISSN: 1759-4790
    E-ISSN: 17594804
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  • 5
    Language: English
    In: The Journal of Allergy and Clinical Immunology, August 2015, Vol.136(2), pp.502-505.e4
    Description: T-cell proliferative responses to phytohemagglutinin and anti-CD3 were within normal limits and lipopolysaccharide-induced CD62L shedding was normal; an autoimmune screen was negative. Because the diagnosis at this point was not obvious, and in view of the compelling family history, consent was sought...
    Keywords: Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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  • 6
    Language: English
    In: Annals of the Rheumatic Diseases March 2014, Vol.73(Suppl 1), p.A22
    Description: Rheumatoid arthritis (RA) is a polygenic disorder usually arising from combined genetic predisposition and environmental influences with associated dysfunctional immune responses. The X-box binding protein 1 (XBP1) transcription factor is a central regulator of the endoplasmic reticulum (ER) stress response. It is induced via activation of the IRE1 stress sensor as part of the unfolded protein response (UPR) and has been implicated in several diseases processes including RA. XBP1 can also be activated in direct response to Toll-like Receptor (TLR) ligation independently of the UPR but the pathogenic significance of this mode of XBP1 activation is not well understood. Our aim was to investigate the relevance of interactions between UPR and TLR signalling pathways in the serum and synovial fibroblasts (SFs) of patients with RA, using samples from healthy individuals and patients with osteoarthritis (OA) as controls
    ISSN: 0003-4967
    ISSN: 00034967
    E-ISSN: 1468-2060
    E-ISSN: 14682060
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  • 7
    Language: English
    In: Annals of the Rheumatic Diseases, 8 April 2015
    Description: To assess clinical and B cell biomarkers to predict relapse after rituximab in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) using retreatment on clinical relapse strategy.
    Keywords: B Cells ; Cyclophosphamide ; Dmards (Biologic) ; Granulomatosis With Polyangiitis ; Systemic Vasculitis
    ISSN: 0003-4967
    ISSN: 00034967
    E-ISSN: 1468-2060
    E-ISSN: 14682060
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  • 8
    Language: English
    Keywords: 616.079
    Source: The British Library
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  • 9
    Language: English
    In: Nature Reviews Rheumatology, Oct, 2009, Vol.5(10), p.529(2)
    Description: Biologic therapies that target interleukin (IL)-1 are known to dramatically improve symptoms of a group of rare, heritable chronic inflammatory diseases. The results of a phase III trial confirm the place of Canakinumab in the treatment arsenal for these disorders.
    Keywords: Canakinumab -- Usage ; Canakinumab -- Health Aspects ; Gene Mutation -- Health Aspects ; Gene Mutation -- Research ; Inflammation -- Risk Factors ; Inflammation -- Drug Therapy ; Inflammation -- Research
    ISSN: 1759-4790
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  • 10
    Language: English
    In: Blood, 01 March 2018, Vol.131(9), pp.974-981
    Description: To date, the pathogenic mechanisms underlying Schnitzler syndrome remain obscure, in particular, the interplay between the monoclonal protein and increased interleukin-1β (IL-1β) production, although interest in the contribution of genetic factors has been fueled by detection of somatic mosaicism in 2 patients with the variant-type Schnitzler syndrome. At 2 specialist UK centers, we have identified 21 patients who fulfilled diagnostic criteria for Schnitzler syndrome with urticarial rash, fever, arthralgia, and bone pain; 47% reported weight loss, 40% fatigue, and 21% lymphadenopathy. An immunoglobulin M (IgM) κ paraprotein was detected in 86%; the remainder had IgM λ or IgG κ. Patients underwent searches for germ line and somatic mutations using next-generation sequencing technology. Moreover, we designed a panel consisting of 32 autoinflammatory genes to explore genetic susceptibility factor(s) to Schnitzler syndrome. Genetic analysis revealed neither germ line nor somatic , , , or mutations, apart from 1 patient with a germ line p.V198M substitution. The proinflammatory cytokines and extracellular apoptosis-associated speck-like protein with caspase recruitment domain (ASC) measured in the serum of Schnitzler syndrome patients during active disease were significantly higher than healthy controls. Ninety-five percent of our cohort achieved a complete response to recombinant IL-1 receptor antagonist (anakinra). Our findings do not support a role for somatic mosaicism in disease pathogenesis; although elevated levels of ASC, IL-6, and IL-18 in patients' serum, and the response to anakinra, suggest that Schnitzler syndrome is associated with upregulated inflammasome activation. Despite its rarity, Schnitzler syndrome is an important diagnosis as treatment with IL-1 antagonists dramatically improves quality of life for patients.
    Keywords: Germ-Line Mutation ; Schnitzler Syndrome ; Interleukin 1 Receptor Antagonist Protein -- Administration & Dosage
    ISSN: 00064971
    E-ISSN: 1528-0020
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