Post-transcriptional regulation of pro-inflammatory gene expression.
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The cytokine tumour necrosis factor (TNF)alpha is a vital mediator of the innate immune response, and a pleiotropic regulator of cellular function. Its involvement in rheumatoid arthritis is illustrated by the clinical benefits of TNF alpha blockade. Post-transcriptional regulation (the control of mRNA stability and translation) appears to play a critical role in the regulation of TNF alpha expression by mitogen activated protein kinase signal transduction pathways and by anti-inflammatory agents. The aim of this article is to review some recent advances in our understanding of these processes, and to speculate on mechanisms of regulation of TNF alpha and other pro-inflammatory genes. (+info)
New variations of human CC-chemokine receptors CCR3 and CCR4.
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CCR3 and CCR4 are the members of CC chemokine receptor family expressed on Th2 type CD4+ T cells. In this study, variation screening of the entire coding regions of CCR3 and CCR4 was performed, and possible association with several autoimmune diseases was tested, using the genomic DNA from 304 Japanese healthy individuals and 272 Japanese patients with rheumatic diseases. One non-synonymous substitution was identified in CCR3 gene, whereas in CCR4 gene, two non-synonymous and two synonymous substitutions were detected. Among the synonymous substitutions, CCR4 1014(C-->T) was observed in 7.2% of the healthy individuals and 6.6% of the patients, and was considered as a single nucleotide polymorphism. All other variations were observed in only one or two individuals. No significant association was observed between any of the variations and any of the rheumatic diseases. Among these variations, CCR3-C218S substitution coded by 652(T-->A) substitution was localized in the region conserved among the G protein coupled receptor family. Reactivity of eosinophils to the monoclonal antibody against CCR3 and the chemotaxis to eotaxin were slightly reduced in this patient as compared with healthy controls or a patient with Behcet disease homozygous for the common allele, while CCR3 mRNA level was not different. These findings suggest that CCR3-C218S substitution may lead to the reduced function of CCR3 at the protein level. Further study will be of interest to test whether CCR3-C218S variation or any of the CCR4 variations has a significant role in rendering susceptibility to immunological diseases or resistance to HIV infection. (+info)
Single nucleotide polymorphisms in the coding regions of human CXC-chemokine receptors CXCR1, CXCR2 and CXCR3.
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Chemokines and their receptors have critical roles in inflammatory and immunological responses, and thus their genetic contribution to various human disorders needs investigation. In this study, systematic variation screening of the entire coding regions of CXCR1 (IL8RA), CXCR2 (IL8RB) and CXCR3 was carried out, using genomic DNA from a large number of Japanese healthy individuals and patients with rheumatic diseases. In addition to the previously reported variations in CXCR1 and in CXCR2, two non-synonymous, two synonymous substitutions and one nonsense mutation of CXCR1, one non-synonymous and two synonymous substitutions of CXCR2, two non-synonymous substitutions of CXCR3 were newly identified. The common single nucleotide polymorphisms (SNPs) at CXCR1 codon 827 and CXCR2 codon 786 were in strong linkage disequilibrium. In addition, familial analysis indicated that human CXCR3 is located on chromosome X. No significant association was observed between the variations and the tested rheumatic diseases. However, CXCR variations identified in this study will provide valuable information for the future studies in medical sciences as well as in human genetics. (+info)
Ninth Asia Pacific League of Associations for Rheumatology (APLAR) Congress, Beijing, China, 21-26 May, 2000.
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The Congress covered the broad field of rheumatology, with participants from China, the Asia Pacific League of Associations of Rheumatology (APLAR) region and the rest of the world. The programme consisted of a mix of plenary lectures, concurrent symposia, workshops, free paper sessions and poster presentations. Basic sciences were well represented, with the general theme of inflammatory cytokines being of particular interest. One plenary lecture and a number of other presentations addressed the problem of atherosclerosis and rheumatic diseases. Diseases prominent in the region, such as Behcet's disease and Takayasu's disease, were represented with large series. Other areas of interest were musculoskeletal infections in HIV-positive patients and the management of spondyloarthritis. Although the use of the most recently developed drugs is restricted in the APLAR region because of cost factors, there were symposia on the latest pharmacological advances such as COX-2 technology, leflunomide and anti-tumour necrosis factor (TNF) therapy. (+info)
Prevalence and spectrum of rheumatic diseases associated with proteinase 3-antineutrophil cytoplasmic antibodies (ANCA) and myeloperoxidase-ANCA.
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OBJECTIVES: To evaluate the prevalence and association of antineutrophil cytoplasmic antibodies (ANCA) and their subtypes [proteinase 3 (PR3)-ANCA, myeloperoxidase (MPO)-ANCA] with distinct clinical features in various clinicopathological syndromes. METHODS: All consecutive ANCA-positive patients seen at the combined unit for rheumatology for Bad Bramstedt and the University of Lubeck between 1989 and 1999 were analysed. ANCA were detected by an immunofluorescence technique and ANCA subspecificities were determined by ELISA. Clinical features at presentation and diagnoses were recorded according to standardized procedures. RESULTS: Among 4620 patients tested, 333 were cytoplasmic ANCA-positive and 291 were perinuclear ANCA-positive. cANCA/PR3-ANCA were strongly associated with Wegener's granulomatosis (WG), whereas pANCA/MPO-ANCA were associated with a diverse disease spectrum. Further investigation of PR3-ANCA-positive (n=80) and MPO-ANCA-positive patients (n=40) revealed a greater extent of disease [disease extent index (DEI); median 8 vs 5, P<0.01] and more frequent involvement of the upper/lower respiratory tract and the eyes in PR3-ANCA-positive than in MPO-ANCA-positive patients. Fewer than 5% of WG patients were MPO-ANCA-positive. Compared with matched PR3-ANCA-positive WG patients, the MPO-ANCA-positive WG patients had a lower DEI (median 5 vs 8) and had a lower frequency of peripheral neuropathy. CONCLUSIONS: ANCA testing is useful due to its high sensitivity and specificity, especially for cANCA/PR3-ANCA in WG. We found a divergence in the disease spectrum between PR3- and MPO-ANCA-positive patients, characterized by higher DEI and extrarenal manifestations in the PR3-ANCA group. MPO-ANCA was rarely found in WG and was associated with less organ involvement. (+info)
A patient with severe palindromic rheumatism and frequent episodes of pain.
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A 44-year-old man began to experience episodes of joint pain with erythema in his knees, elbows, shoulders, and hands in April 1996. He was diagnosed as having palindromic rheumatism. Due to the increasing frequency and severity of these episodes, he was admitted to our hospital in May 1999. Heat therapy to the affected area produced a rapid improvement in symptoms. In addition, the continued use of physical therapy during symptom-free periods tended to reduce the frequency and severity of pain attacks. We present this case and discuss treatment options in patients with palindromic rheumatism. (+info)
Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies.
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OBJECTIVES: To review the autoimmune and rheumatic manifestations of patients with malignancy. METHODS: A Medline search of all published papers using keywords related to malignancies, autoimmunity, rheumatic diseases, and paraneoplastic syndromes. RESULTS: Patients with malignant diseases may develop autoimmune phenomena and rheumatic diseases as a result of (a) generation of autoantibodies against various autoantigens, including oncoproteins (P185, 1-myc, c-myc, c-myb), tumour suppression genes (P53), proliferation associated antigens (cyclin A, B1, D1, E; CENP-F; CDK, U3-RNP), onconeural antigens (Hu, Yo, Ri, Tr), cancer/testis antigens (MAGE, GAGE, BAGE, SSX, ESO, SCP, CT7), and rheumatic disease associated antigens (RNP, Sm). The clinical significance of the various autoantibodies is not clear. Anti-oncoprotein and anti-tumour suppression gene antigens are detected before the diagnosis of the cancer or in the early stages of the malignant disease, suggesting a potential diagnostic or prognostic role. Anti-onconeural antibodies are pathogenic and are associated with specific clinical neurological syndromes (anti-Hu syndrome and others). (b) Paraneoplastic syndromes, a wide range of clinical syndromes, including classic autoimmune rheumatic diseases that develop among patients with cancer. (c) Rheumatism after chemotherapy, a clinical entity characterised by the development of musculoskeletal symptoms after combination chemotherapy for malignancy. CONCLUSION: Autoimmune and rheumatic features are not rare among patients with malignancies. They are the result of various diverse mechanisms and occasionally they may be associated with serious clinical entities. (+info)
Prevalence and clinical significance of antikeratin antibodies and other serological markers in Lithuanian patients with rheumatoid arthritis.
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OBJECTIVES: To assess the clinical value of several serological markers in Lithuanian patients with rheumatoid arthritis (RA) compared with control patients with rheumatic disease and age matched healthy controls. METHODS: Serum samples from 96 patients with RA of approximately 8 years' duration, 90 rheumatic disease controls, and 37 healthy subjects were tested. Antikeratin antibody (AKA), antineutrophil cytoplasmic antibody (ANCA), and antinuclear antibody (ANA) titres were estimated by indirect immunofluorescence (IIF) and serum samples positive for ANA and ANCA were further studied by enzyme linked immunosorbent assay (ELISA). IgA and IgM rheumatoid factors (RF) were measured by ELISA. RESULTS: A positive AKA test was highly specific for RA (diagnostic specificity 97%), being found in 44% of the patients. Although both RF tests had a higher sensitivity, they were less specific for RA. ANCA was detected in 33% of patients with RA but lacked diagnostic specificity. AKA and ANCA were associated with more erosive disease and the presence of extra-articular manifestations. Positivity for AKA, IgA RF, and ANCA was significantly associated with disease activity and worse functional capacity. However, in multiple regression analysis only positivity for AKA was significantly correlated with functional disability (p=0.0001), evaluated by the Steinbrocker functional classification, and no single marker had any relation with radiological damage. CONCLUSION: Although AKA showed the highest disease specificity, all serological markers studied except ANA exhibited interesting associations with important clinical and paraclinical parameters of RA. (+info)