Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, is a prominent inducer of proinflammatory cytokines in vitro and in vivo. We previously found that kidney cells display the TWEAK receptor Fn14, and that TWEAK stimulation of mesangial cells and podocytes induces a potent proinflammatory response. Several of the cytokines up-regulated in the kidney in response to TWEAK are instrumental in Lupus nephritis; we therefore hypothesized that TWEAK/Fn14 interactions may be important in the cascade(s) leading to renal damage in systemic Lupus erythematosus. In this study, we analyzed the effects of Fn14 deficiency in the chronic graft-vs-host model of SLE, and the benefits of treatment with an anti-TWEAK mAb in this mouse model. We found that anti-nuclear Ab titers were no different between C57BL/6 Fn14 wild-type and deficient mice injected with alloreactive bm12 splenocytes. However, kidney disease was significantly less severe in Fn14 knockout mice. Furthermore, kidney IgG deposition, IL-6, MCP-1, RANTES, and IP-10, as well as macrophage infiltration, were significantly decreased in Fn14-deficient mice with induced lupus. Similarly, mice with induced Lupus treated with an anti-TWEAK neutralizing mAb had significantly diminished kidney expression of IL-6, MCP-1, IL-10, as well as proteinuria, but similar autoantibody titers, as compared with control-treated mice. We conclude that TWEAK is an important mediator of kidney damage that acts by promoting local inflammatory events, but without impacting adaptive immunity in this experimental LN model. Thus, TWEAK blockade may be a novel therapeutic approach to reduce renal damage in SLE.
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PMID:TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus. 1802 43

Systemic lupus erythematosis is an autoimmune disease of unknown etiology. Lupus pathology is thought to reflect autoantibody-mediated damage due to a failure of B lymphocyte tolerance. Since excessive B cell-activating factor belonging to the TNF family (BAFF) expression correlates with human and murine lupus, and BAFF signals B cell survival through BAFF-R, it is believed that excessive BAFF-R signaling can subvert B cell tolerance and facilitate lupus development. Here we report the unexpected finding that BAFF-R-mutant A/WySnJ mice develop a lupus-like syndrome. These mice carry the B cell maturation defect-1 (Bcmd-1) mutant allele of the Baffr gene. Bcmd-1 causes premature B cell death and profound B cell deficiency. Despite having 90% fewer splenic B cells than normal mice, A/WySnJ mice had an 18-fold increased frequency of splenocytes secreting IgM antibodies to dsDNA, and increased amounts of circulating IgM and IgG to dsDNA by 9 months of age. By age 11 months, most A/WySnJ mice displayed renal pathology characteristic of lupus, including proteinuria as well as periodic acid-Schiff-positive deposits and glomerular capillary bed destruction. Importantly, we genetically linked this autoimmunity to Bcmd-1, since congenic AW.Baffr(+/+) mice carrying a wild-type allele developed none of these phenotypes. Our data provide the first evidence linking altered BAFF-R signaling to the development of B cell-mediated autoimmunity.
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PMID:Systemic autoimmunity in BAFF-R-mutant A/WySnJ strain mice. 1820 May 1

Lupus treatment has evolved considerably with spectacular advances that can be summarized in 10 points. Hydroxychloroquine and cyclophosphamide are still standard drugs, provided their use is optimized. Contraception and postmenopausal hormone replacement therapy have finally been tested in randomized studies with fairly reassuring results, although prudence remains essential in patients with severe lupus and above all in those with thrombotic complications (antiphospholipid syndrome). Mycophenolic acid has been shown to be useful in the treatment of lupus nephropathies, but its specific place in the therapeutic strategy remains to be defined. Other drugs (sirolimus, abatacept) are currently being evaluated. Anti-lymphocyte B therapies are growing in popularity. Rituximab and other drugs (anti-BAFF, TACI-Fc) are also being evaluated and their results appear very interesting. Interferon alpha (type I) inhibition is an attractive therapeutic approach in lupus but its use in humans is still premature. Peptide vaccination with fragments of autoantibodies or autoantigens is an elegant strategy, and preliminary results justify further studies. Anti-TNF molecules may be beneficial in lupus. Complement inhibition can be useful in lupus and antiphospholipid syndrome but drugs usable in humans (anti-C5) must be developed. Atheromatosis in lupus is the principal cause of morbidity and mortality and must be managed. Smoking cessation is essential, but other approaches (statins) should also be discussed. Many futuristic types of immune manipulation may be envisioned (proteasome inhibition, modulation of Fc gammaRIIB, and modulation of cell signaling (PI3kgamma)). Hence the perspectives are numerous. We will soon be able to optimize the treatment of our patients. Nevertheless, rigorous evaluation of the risk/benefit ratio of new drugs and of their most appropriate place in the therapeutic strategy against systemic lupus is indispensable.
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PMID:[Systemic lupus erythematosus: news and therapeutic perspectives]. 1824 45

Etanercept is an anti-TNF drug with marked efficacy in inflammatory arthritis. This review addresses dermatological side effects that have been encountered in our 85 patients on the drug for rheumatoid arthritis, and reviews other reported cutaneous adverse events. Injection site reactions are common and usually self-limiting. We and others have encountered patients with recall site reactions where the four rotated injection sites simultaneously develop a hypersensitivity reaction. In all cases, the rash has responded to antihistamines and the etanercept was thereby continued. Other injection site reactions include discoid lupus and cutaneous vasculitis that respond to cessation of treatment and appropriate therapy. Skin reactions more distant from the injection site are also reviewed, with erythema nodosum, widespread lupus rashes, infections and skin tumours summarised. A patient who developed a purpuric rash at the site of last injection with a drug induced worsening of thrombocytopaenia is described. Although the therapeutic advantages of etanercept outweigh the side effects, clinicians need to be aware of the adverse reactions of these drugs with their increasing use.
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PMID:Adverse dermatological reactions in rheumatoid arthritis patients treated with etanercept, an anti-TNFalpha drug. 1869 Sep 36

Genetic differences are involved in the development of lupus erythematosus (LE). Skin lesions are influenced by environmental triggers such as ultraviolet light, temperature, and chemical stresses, and the patterns of skin lesion are variable in cutaneous LE such as systemic LE (SLE), chronic discoid LE (CDLE), subacute cutaneous LE (SCLE), and LE tumidus (LET). Although there are a few conflicting reports, many Japanese dermatologists feel there are photosensitivity differences in lupus erythematosus between Asian and Caucasian subjects with SCLE and LET. HLA studies in Japanese subjects revealed that HLA-DRB1*1501 association was with both CDLE and SLE. The association between HLA-Cw6 and CDLE was first reported in Japanese population, and a HLA-A33-B44-DRB1*1302 haplotype showed a positive association in CDLE. However, these results are not compatible with those from Caucasian subjects. There are no significant associations among HLA studies, photosensitivity, and anti-Ro/SS-A antibodies in Japanese CLE patients. Photosensitivity will be a key factor to dissolve multi-factorial complexes of LE etiopathogenesis. Our present understanding is that an axis of photosensitivity, anti-Ro/SS-A antibodies and apoptosis via TNF are the best (markers) to verify the contribution of genetics in SCLE, LET, and other CLEs. The incidence and photosensitivity of SCLE and LET are much lower in Japanese than in Caucasian subjects. However, this discrepancy may open the window for investigating CLE pathogenesis through global collaborations. For this purpose and goal, a new and more conventional method should be developed for the examination of so-called photosensitivity.
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PMID:Ethnic differences in immunogenetic features and photosensitivity of cutaneous lupus erythematosus. 1879 90

Anti-TNF agents are increasingly being used for a rapidly expanding number of rheumatic and systemic autoimmune diseases. As a result of this use, and of the longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. The clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy, were analyzed through a baseline Medline search of articles published between January 1990 and May 2008 (www.biogeas.org). A total of 379 cases of autoimmune diseases secondary to TNF-targeted therapies were identified. The anti-TNF agents were administered for rheumatoid arthritis in more than 80% of cases. The use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus and interstitial lung disease. Other autoimmune diseases associated with TNF-targeted therapies have been recently described, e.g. sarcoidosis, antiphospholipid syndrome-related features, and autoimmune hepatitis or uveitis. Large, prospective, postmarketing studies are required to evaluate the risk of developing autoimmune diseases in patients receiving TNF-targeted therapies.
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PMID:Autoimmune diseases induced by TNF-targeted therapies. 1902 67

The archetypal systemic autoimmune disease systemic lupus erythematosus (SLE) has incompletely understood pathogenesis, although evidence suggests a strong genetic component. Unlike organ-specific autoimmune diseases such as type 1 diabetes, the genetics of lupus are not as dominated by the effect of a single locus. Undoubtedly, the major histocompatibility complex is the greatest and most consistent genetic risk factor in SLE susceptibility; however, recent candidate gene and whole genome association (WGA) studies have identified several other genes that are likely to advance our understanding of this complex disease. One of these, the TNF superfamily member OX40L, interacts with its unique receptor OX40, to maintain T cell memory by providing a late-stage co-stimulatory signal to sustain the survival of activated T cells. The precise immunological consequences are yet to be determined; however, signalling through OX40-OX40L is bidirectional and the reverse signalling pathway via OX40L may quantitatively enhance B cell proliferation to augment the B cell hyperactivity found in SLE. Like OX40L, several genes recently identified in WGA studies are components of B cell pathways. Collectively, these genes will help us to unravel the mechanisms by which aberrant B cell signalling results in lupus pathogenesis.
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PMID:Association of the co-stimulator OX40L with systemic lupus erythematosus. 1908 91

The role of tumour necrosis factor (TNF-alpha) signalling adapters in lupus nephritis (LN) is poorly understood. This study investigated renal expression of TNF-alpha and TNF signalling adapter proteins, including TNF receptor-associated death domain protein (TRADD), receptor-interacting protein (RIP) and TNF receptor-associated factor-2 (TRAF-2) in patients with LN. The renal expression of proliferating cell nuclear antigen (PCNA) and CD68 was also measured. The study showed that glomerular and tubular expression of TNF-alpha, TRADD, RIP and TRAF-2 was significantly up-regulated in class III and IV LN in which the intense staining was observed on the crescents, proximal and distal tubules and interstitial mononuclear cells. The number of PCNA-positive cells and CD68-positive cells (macrophages) was increased obviously in class III and IV LN. There was a correlation between the expression levels of TNF-alpha, TRADD, RIP, TRAF-2 and the number of PCNA-positive or CD68-positive cells and active index of renal pathology. These findings suggest that TNF-alpha and TNF-alpha adapters in patients with LN play a role in immunopathogenic injury via transmitting abnormal cell proliferating and proinflammatory signals. The findings have provided further insights into the role of TNF-alpha and its adapter proteins in the pathogenesis of LN and have important therapeutic implications.
Lupus 2009 Feb
PMID:Up-regulated renal expression of TNF-alpha signalling adapter proteins in lupus glomerulonephritis. 1915 Nov 12

The use of TNF alpha (TNFalpha) inhibitors has made a strong impact on the management of rheumatoid and psoriatic arthritis, ankylosing spondylitis and Crohn disease. Side effects of these agents include the development of autoantibodies and a lupus-like syndrome (drug-related lupus, DRL). Here, a case of a patient who developed DRL while receiving infliximab therapy which resolved spontaneously upon discontinuation of the agent and did not recur with subsequent institution of adalimumab is described. A discussion on the possible pathogenic mechanisms involved in the development of drug-related autoimmunity and differences between the agents is also included.
Lupus 2009 Feb
PMID:Is the development of drug-related lupus a contraindication for switching from one TNF alpha inhibitor to another? 1915 Nov 20

Systemic lupus erythematosus pathology reflects autoantibody-mediated damage due to a failure of B-lymphocyte tolerance. We previously reported that B-lymphopenic A/WySnJ mice develop a lupus-like syndrome and linked this syndrome to the B-cell maturation defect-1 (Bcmd-1) mutant allele of the B-cell-activating factor belonging to the TNF family-receptor (Baffr) gene. Here, we further evaluate the genetic basis for autoimmunity in A/WySnJ mice. We produced B6.Bcmd-1 and AW.Baffr(-/-) congenic mice (N5), and compared them with B6.Baffr(-/-) and A/WySnJ mice with respect to B-lymphocyte development. Bcmd-1-expressing mice had more B cells with greater maturity than Baffr(-/-) mice regardless of genetic background, indicating that Bcmd-1 encodes a partially functional BAFF-R. We also compared these mice for lupus phenotypes to determine whether Bcmd-1 is necessary and sufficient for disease, or whether the Baffr(-/-) (-) allele can also cause autoimmunity. The Baffr(-/-) allele did not lead to autoimmunity on either genetic background. In contrast, the Bcmd-1 allele was necessary and sufficient for development of low levels of IgM autoantibodies in B6.Bcmd-1 mice. However, Bcmd-1 plus unidentified A/WySnJ modifier genes were necessary for development of IgG autoantibodies and renal pathology. We propose that in A/WySnJ mice an excess of BAFF per B cell rescues self-reactive B cells through a partially functional BAFF-R in a B-lymphopenic environment.
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PMID:Altered BAFF-receptor signaling and additional modifier loci contribute to systemic autoimmunity in A/WySnJ mice. 1915 35


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