Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01889 (ankylosing spondylitis)
 5,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of natural killer (NK) cells can be modified by a number of factors that either increase or suppress cytotoxicity. We have investigated in detail the cytokine induced killing of a NK resistant renal carcinoma cell line Cur by human NK cells. Preincubation of peripheral blood mononuclear cells with interferon alpha (IFN alpha), interleukin 2 (Il-2), interleukin 1 (Il-1) and tumor necrosis factor alpha greatly increased the rate and magnitude of Cur killing. Positively selected CD16 (+) cells were found to respond to cytokine stimulation and to mediate Cur killing. The effects of Il-2 and IFNa could be upregulated by costimulation of effector cells with Il-1 or TNF alpha. It was shown that TNF alpha induced Il-2 receptor expression on CD16(+) cells alone and even more in combination with Il-2. Studies of NK cell function in various rheumatic diseases revealed reduced NK cytotoxicity in peripheral blood and synovial fluid (SF), both in rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). By contrast, normal NK function was found in patients with ankylosing spondylitis (AS) and psoriatic arthritis. A discordance with regard to the percentage of Leu 7 positive mononuclear cells and NK function in peripheral blood and SF was demonstrated. Minimal expression of Leu 7 positive cells and cytotoxicity was present in synovial membranes. NK function in rheumatic disease was largely independent of drug therapy. Natural killer (NK) cells are a subset of lymphocytes that mediate spontaneous cytotoxicity against certain tumor and virus infected cells without any known prior sensitation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of human natural killer cell function by cytokines and rheumatic disease. 307 75

Several studies have implicated tumor necrosis factor-alpha (TNF-alpha) in autoimmune diseases, such as rheumatoid arthritis (RA). To elucidate further the role of TNF-alpha in inflammatory arthritis, we generated transgenic mice harboring a truncated Peromyscus leucopus TNF-alpha (Pe-TNF) gene. An arthritic phenotype closely resembling human ankylosing spondylitis was observed only in transgenic lines expressing the Pe-TNF transgene at the mRNA level. We characterized the arthritic phenotype in detail by radiographic and histologic techniques. It consisted of severe axial skeletal kyphosis and ankylosis, accompanied by an inflammatory and fibrotic process at the end plates and enthesis. Peripheral joint lesions were absent in mice expressing the P. leucopus TNF-alpha gene, in contrast to the RA-like phenotype described in transgenic mice expressing a truncated human TNF-alpha gene. The Pe-TNF transgenic mouse model provides a unique opportunity to explore potential mechanisms whereby TNF-alpha may initiate an autoimmune arthritis resembling ankylosing spondylitis.
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PMID:Transgenic mice expressing a truncated Peromyscus leucopus TNF-alpha gene manifest an arthritis resembling ankylosing spondylitis. 956 23

In addition to HLA-B27, other genetic factors are thought to be involved in the pathogenesis of ankylosing spondylitis (AS). Because of the location of the TNF gene in the vicinity of the HLA-B locus, and the prominent role in inflammation of its product, we investigated the association between AS and two G to A transition polymorphisms located at position -238 and -376 in the promoter region of the TNF gene. The distribution of the TNF alleles was determined in 86 HLA-B27+ AS patients and 163 healthy controls. From the 86 AS patients, 33 suffered from acute anterior uveitis (AAU). No significant difference for the TNF-376 polymorphism in AS and healthy controls was observed. The frequency of the TNF-238A allele in HLA-B27+ AS patients was significantly decreased compared to random controls (p = 0.021). However, the frequency of the TNF-238A allele in HLA-B27+ AS patients was not significantly different from that observed in HLA-B27+ healthy individuals (p = 0.6). Assessment of association showed that the TNF-238G allele is in linkage disequilibrium with the HLA-B27 allele (delta = 0.053; P = 0.008). Therefore, we conclude that the association between TNF-238G and AS is secondary to the HLA-B27 gene and that TNF-238 and-TNF-376 alleles are not likely to be involved in the susceptibility to AS.
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PMID:Polymorphism within the tumor necrosis factor alpha (TNF) promoter region in patients with ankylosing spondylitis. 1002 81

Many of the genes in the class III region of the human MHC encode proteins involved in the immune and inflammatory responses. We have sequenced a 30-kb segment of the MHC class III region lying between the heat shock protein 70 and TNF genes as part of a program aimed at identifying genes that could be involved in autoimmune disease susceptibility. The sequence analysis has revealed the localization of seven genes, whose precise position and order is cen-G7-G6-G6A-G6B-G6C-G6D-G6E-tel, five of which are fully encoded in the sequence, allowing their genomic structures to be defined. Three of them (G6C, G6D, and G6E) encode putative proteins that belong to the Ly-6 superfamily, known to be GPI-anchored proteins attached to the cell surface. Members of the family are specifically expressed and are important in leukocyte maturation. A fourth gene, G6B, encodes a novel member of the Ig superfamily containing a single Ig V-like domain and a cytoplasmic tail with several signal transduction features. The G6 gene encodes a regulatory nuclear chloride ion channel protein, while the G6A gene encodes a putative homologue of the enzyme N omega,N omega-dimethylarginine dimethylaminohydrolase, which is thought to be involved in regulating nitric oxide synthesis. In addition, three microsatellite markers, 9N-1, 82-2, and D6S273 are contained within the sequence, the last two of which have been reported to be strongly associated with the autoimmune disease ankylosing spondylitis.
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PMID:Genes encoding three new members of the leukocyte antigen 6 superfamily and a novel member of Ig superfamily, together with genes encoding the regulatory nuclear chloride ion channel protein (hRNCC) and an N omega-N omega-dimethylarginine dimethylaminohydrolase homologue, are found in a 30-kb segment of the MHC class III region. 1038 26

The objective of this study was to investigate TNF promoter region polymorphisms for association with susceptibility to ankylosing spondylitis (AS). The TNF -238 and -308 polymorphisms were genotyped in 306 English AS cases and 204 ethnically matched healthy B27-positive controls, and 96 southern German AS cases, 58 B27-positive and 251 B27-negative ethnically matched controls. Additionally, the TNF -376 polymorphism was genotyped in the southern German cases and controls. In the southern German AS patients a significant reduction in TNF -308.2 alleles was seen, compared with B27 positive controls (odds ratio 0.4, P = 0.03, 95% confidence interval 0.2-0.9), but no difference in allele frequencies was observed at TNF -238. Significant association between AS and both TNF -238 and TNF -308 was excluded in the English cases. These results confirm previous observations in the southern German population of association between TNF promoter region polymorphisms and AS, but the lack of association in the English population suggests that these polymorphisms themselves are unlikely to be directly involved. More likely, a second, non-HLA-B, MHC locus is involved in susceptibility to AS in these two populations.
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PMID:Interethnic studies of TNF polymorphisms confirm the likely presence of a second MHC susceptibility locus in ankylosing spondylitis. 1119 71

Rheumatoid arthritis (RA) is a chronic destructive arthritis leading to joint destruction as a consequence of chronic inflammatory processes. Established therapy with slow-acting disease-modifying anti-rheumatic drugs (DMARDs), as with low-dose methotrexate (MTX), leads to a significant improvement of disease symptoms, but are unable to stop joint destruction. Novel therapeutic agents like monoclonal antibodies (mAb), cytokine receptor-human immunoglobulin constructs or recombinant human proteins have been tested in RA and in other chronic arthritides like ankylosing spondylitis or psoriatic arthritis with convincing success. In particular, clinical trials testing anti-TNF alpha agents either alone or in combination with MTX have proven the feasibility and efficacy of these novel approaches.
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PMID:TNF inhibitors in the treatment of arthritis. 1124 72

Pro-inflammatory cytokines, such as interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha), released from inflammatory foci, can activate the hypothalamus to produce corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP). These hypothalamic peptides in synergy increase ACTH production by the pituitary gland and hence corticosteroid (CS) secretion by the adrenal cortices. CS dampens inflammation. The pituitary also produces prolactin (PRL), which is pro-inflammatory, and macrophage inhibitory factor (MIF), which by counteracting the anti-inflammatory and immunosuppressive effects of CS, is pro-inflammatory. Lewis rats develop a variety of induced-autoimmune inflammatory conditions, such as streptococcal cell wall arthritis, whereas the histocompatible F344 Fisher rats are resistant to this condition. Lewis rats have a defective hypothalamic-pituitary adrenal (HPA) response to a variety of hypothalamic stimuli, but have augmented systemic secretion of AVP. Patients with rheumatoid arthritis (RA) have deficient CS with exaggerated PRL responses to inflammatory stimuli. Within inflammatory foci, CRH is pro-inflammatory. AVP, which augments autologous mixed lymphocyte reactions, can replace the IL-2 requirement for gamma IFN production by T cells via V1a receptors, and potentiates primary antibody responses, is also pro-inflammatory. Lewis rats have significantly high plasma levels, hypothalamic content, and in vitro release of AVP in comparison to the inflammatory disease-resistant Fischer rats. Immunoneutralization of AVP attenuates inflammatory responses. In Sprague-Dawley rats, AVP potentiates PRL secretion. Preliminary studies in patients with RA have shown that the circulating levels of AVP are significantly increased, which might be a compensatory response to low CS levels or a result of elevated levels of IL-6 in these patients but could nevertheless contribute to rheumatoid inflammation. A similar observation has been made in patients with ankylosing spondylitis.
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PMID:Perturbations of arginine vasopressin secretion during inflammatory stress. Pathophysiologic implications. 1126 12

Tumor necrosis factor-alpha is a major effector and regulatory cytokine, which seems to have an outstanding position in rheumatic and other inflammatory states. Because TNF-alpha has been detected in the inflamed gut and sacroiliac joints of patients with chronic inflammatory bowel diseases and spondyloarthritides, like ankylosing spondylitis, there was need for studies of the efficacy of the modern biologic anti-TNF agents infliximab and etanercept in these diseases. Infliximab is approved for the treatment of Crohn disease. In addition, there are now also positive data for infliximab in the treatment of ankylosing spondylitis and for etanercept and infliximab in the treatment of psoriatic arthritis.
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PMID:New treatment options in spondyloarthropathies: increasing evidence for significant efficacy of anti-tumor necrosis factor therapy. 1155 23

With the mapping of the human genome having been completed, our ability to investigate and ideally better understand the genetic basis of rheumatic diseases is advancing at a rapid pace. Substantial evidence strongly favors a direct role for HLA-B27 in genetic susceptibility to ankylosing spondylitis and related spondyloarthropathies, although the underlying molecular basis has yet to be identified. HLA-B27 contributes only 16 to 50% of the total genetic risk for the disease, clearly indicating that other genes must be involved. However, no other putative disease genes have yet been absolutely proven. Potential genes include MHC (HLA class II, low molecular weight proteasome [LMP], transporter associated with antigen processing (TAP), tumor necrosis factor [TNF]-alpha, and major histocompatibility complex class I chain-related gene A (MICA), as well as non-MHC genes (IL-1RA, IL-6, IL-10, and CYP2D6). Genome-wide screens have identified other chromosomal areas of interest: 1p, 2q, 6p, 9q, 10q, 16q, and 19q. However, different studies have given conflicting results. HLA-B27 itself is a serologic specificity, which encompasses 25 different alleles that encode 23 different products (proteins): HLA-B*2701 to B*2723. These alleles may have evolved from the most widespread subtype, B*2705, and two of them, B*2706 in Southeast Asia and B*2709 in Sardinia, seem not to be associated with ankylosing spondylitis. The distinction between the disease associated and nonassociated subtypes may provide clues to the actual role of B27 in disease pathogenesis.
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PMID:HLA-B27 and genetic predisposing factors in spondyloarthropathies. 1155 26

Spondyloarthritis represents one of the commonest groups of inflammatory arthritides with onset in the third and fourth decades and primarily affecting the axial skeleton. Current treatment is primarily symptomatic, non-steroidal anti-inflammatory drugs being used most commonly. No therapeutics have been shown to prevent structural damage. The development of validated and standardised outcome instruments and a composite criterion of response should encourage evaluation of new therapeutics. Anti-TNF- alpha -directed therapeutics have been shown to be dramatically effective in short-term (12 week) placebo-controlled trials in both ankylosing spondylitis and psoriatic arthritis whilst observational cohorts describe efficacy that is maintained for over one year. Treatment has been well-tolerated, with mycobacterial infections being the primary concern. Significant costs and the requirement for continuous therapy are likely to spur the development of orally bioavailable agents targeting TNF- alpha expression.
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PMID:Novel therapies in the treatment of spondyloarthritis. 1208 4


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