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Patients with systemic lupus erythematosus have up to a 50-fold increased risk of developing atherosclerotic cardiovascular
disease. Recent advances in the etiology of vascular damage in this disease stress the interplay of lupus-specific inflammatory
factors with traditional cardiac risk factors, leading to increased endothelial damage. This review analyzes the putative
role that immune dysregulation and lupus-specific factors may play in the pathogenesis of premature vascular damage in this
disease. The potential role of various cytokines, in particular type I interferons, in the development of accelerated atherosclerosis
is examined. Potential therapeutic targets are discussed. 相似文献
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Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a recently identified proinflammatory cytokine of the
TNF superfamily. Through activation of the fibroblast growth factor-inducible 14 (Fn14) receptor, TWEAK regulates cell proliferation,
cell death and inflammation. The available evidences have indicated that TWEAK might be a target for therapeutic intervention
in renal, vascular injury and neuropathy. Since renal, vascular and neuropsychiatric complications are frequently encountered
in systemic lupus erythematosus (SLE)—a systemic autoimmune disease, TWEAK-Fn14 pathway may be implicated in the pathogenesis
of SLE. In this review, we will discuss the TWEAK-Fn14 pathway and the therapeutic potential of modulating this pathway in
SLE. 相似文献
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Sköldberg F Rönnblom L Thornemo M Lindahl A Bird PI Rorsman F Kämpe O Landgren E 《Biochemical and biophysical research communications》2002,291(4):951-958
To identify candidate autoantigens associated with arthritis, a rat chondrocyte cDNA library was immunoscreened with serum from a patient with rheumatoid arthritis. One isolated cDNA encoded part of AHNAK, a 700-kDa phosphoprotein with DNA binding properties, that appears to be involved in several signal transduction pathways. Immunoreactivity against an in vitro translated human AHNAK fragment was detected in 4.6% (5/109) of patients with rheumatoid arthritis, 29.5% (18/61) of patients with systemic lupus erythematosus (SLE), and 1.2% (2/172) of blood donors. Anti-AHNAK antibodies reacted with a recombinant human AHNAK fragment and with native AHNAK from C32 cell lysates. In vitro translated AHNAK fragment could be cleaved by granzyme B and caspase-3. Anti-AHNAK positive SLE patients had a higher frequency of homogeneous antinuclear antibody staining patterns and a lower frequency of recent mucosal ulcerations. This is the first report that AHNAK can be targeted by the immune system in autoimmune disease. 相似文献
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Dreyfus DH 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(6):3460; author reply 3461
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Hai-Feng Pan Ning Zhang Wen-Xian Li Jin-Hui Tao Dong-Qing Ye 《Molecular biology reports》2010,37(1):395-398
T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) was the first surface molecule that specifically identifies
Th1 cells in both mice and human. Recently, identification of Galectin-9 as a ligand for TIM-3 has established the TIM-3–Galectin-9
pathway as an important regulator of Th1 immunity and tolerance induction. Many previous studies have demonstrated that TIM-3
influences chronic autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis. In addition, association of TIM-3
polymorphisms with susceptibility to several autoimmune diseases has been identified. Recent work has explored the role of
TIM-3 in systemic lupus erythematosus (SLE), and their results indicate that TIM-3 may represent a novel target for the treatment
of SLE. In this review, we will discuss the TIM-3 pathway and the therapeutic potential of modulating the pathway in SLE. 相似文献
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Interleukin-21(IL-21) is the most recently discovered member of the type-I cytokine family. Structurally, IL-21 shows homology
to IL-2, 4, and 15 proteins. It has a variety of effects on the immune system, including B cell activation, plasma cell differentiation,
and immunoglobulin production. Many previous studies have identified that IL-21 was associated with different autoimmune and
inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. In addition, recent
work has explored the role of IL-21 in systemic lupus erythematosus (SLE). Elevated expression of IL-21 was found in the sera
of patients and mice with SLE. Moreover, association of IL-21 and IL-21R polymorphisms with susceptibility to SLE have been
reported. All these findings suggest that IL-21 may have promise as a potential therapeutic target for SLE. In this review,
we will discuss the biological features of IL-21, the IL-21 signaling and its potential role in SLE. 相似文献
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Epigenetic alternations in genomic DNA encompass cytosine methylation in cytosine and guanine (CpG) dinucleotide islands, which are usually extended in the promoter and first exon of genes. The DNA methylation is carried out by DNA methyltransferases (DNMT) and it serves as an epigenetic method of gene expression modulation. The epigenetic alternations in genomic DNA have been implicated in the development of malignant and autoimmune diseases. The epigenetic aberration in regulatory DNA sequences may also be responsible for the emergence of changes in the immune system in patients with systemic lupus erythematosus (SLE). The agents 5-azacytidine (azacitidine) and 5-aza-2'-deoxycytidine (decitabine) belong to inhibitors of methyltransferase. These compounds affect the methylation level of promoter sequences and cause phenotypic changes in peripheral blood mononuclear cells (PBMC), which are similar to those observed in PBMC of SLE patients. The lack of methylcytosine in CpG dinucleotides may be responsible for the antigenic properties of microbial DNA. The presence of low-apoptotic methylated DNA fragments has been identified in plasma of SLE patients. These DNA fragments exhibit antigenic properties and may elicit the humoral response responsible for the flare of SLE. The low methylation of CpG residues in the regulatory sequences may also contribute to the elevated expression of human endogenous retroviruses (HERVs) in PBMC of SLE patients. The HERV components exhibit a profound similarity with nuclear antigens and may be responsible for the enhancement of the production of anti-antinuclear antibodies (ANA). Recent advances in the investigation of epigenetic DNA changes have formed the basis of improved understanding of etiopathogenesis of SLE, which may thereby facilitate improvement in therapeutic principles of this disease. 相似文献
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Zahava Vadasz Tharwat Haj Katalin Halasz Itzhak Rosner Gleb Slobodin Dina Attias Aharon Kessel Ofra Kessler Gera Neufeld Elias Toubi 《Arthritis research & therapy》2012,14(3):R146
Introduction
Semaphorin 3A (sema3A) and neuropilin-1 (NP-1) play a regulatory role in immune responses and have a demonstrated effect on the course of collagen induced arthritis. This study was undertaken to evaluate the role of sema3A and NP-1 in the pathogenesis of systemic lupus erythematosus (SLE) and the specific effect of sema3A on the auto-reactive properties of B cells in SLE patients.Methods
Thirty two SLE and 24 rheumatoid arthritis (RA) patients were assessed and compared with 40 normal individuals. Sema3A serum levels were measured and correlated with SLE disease activity. The in vitro effect of sema3A in reducing Toll-like receptor 9 (TLR-9) expression in B cells of SLE patients was evaluated.Results
Sema3A serum levels in SLE patients were found to be significantly lower than in RA patients (55.04 ± 16.30 ng/ml versus 65.54 ± 14.82 ng/ml, P = 0.018) and lower yet than in normal individuals (55.04 ± 16.30 ng/ml versus 74.41 ± 17.60 ng/ml, P < 0.0001). Altered serum sema3A levels were found to be in inverse correlation with SLE disease activity, mainly with renal damage. The expression of both sema3A and NP-1 on B cells from SLE patients was significantly different in comparison with normal healthy individuals. Finally, when sema3A was co-cultured with cytosine-phosphodiester-guanine oligodeoxynucleotides (CpG-ODN)-stimulated B cells of SLE patients, their TLR-9 expression was significantly reduced, by almost 50% (P = 0.001).Conclusions
This is the first study in which a reduced serum level of sema3A was found in association with SLE disease activity. It also raises the possibility that sema3A may have a regulatory function in SLE. 相似文献13.
Zahava Vadasz Tharwat Haj Katalin Halasz Itzhak Rosner Gleb Slobodin Dina Attias Aharon Kessel Ofra Kessler Gera Neufeld Elias Toubi 《Arthritis research & therapy》2012,14(3):1-8
Introduction
Higher levels of high density lipoprotein (HDL) subfractions HDL3-chol and particularly HDL2-chol protect against cardiovascular disease (CVD), but inflammation reduces the HDL level and may impair its anti-atherogenic effect. Changed HDL composition through the impact of inflammation on HDL subfractions may contribute to the excess risk of CVD in rheumatoid arthritis (RA). In this study, we investigated whether HDL2-chol and HDL3-chol concentrations differ between RA patients and healthy controls, and whether these levels are related to the level of RA disease activity.Methods
Non-fasting blood samples were collected from 45 RA patients and 45 healthy controls. None of the participants had a history of CVD, diabetes, or used lipid-lowering drugs. HDL2-chol and HDL3-chol concentrations were obtained by ultracentrifugation. Regression modeling was used to compare HDL subfraction levels between RA patients and healthy controls, and to analyze the effect of disease activity on HDL2-chol and HDL3-chol.Results
HDL2-chol and HDL3-chol were significantly lower in RA patients compared to healthy controls (P = 0.01, P = 0.005, respectively). The HDL2:HDL3 ratio was significantly lower in patients compared to controls (P = 0.04). Reduced HDL2-chol and HDL3-chol levels were primarily present in female RA patients and not in male RA patients. A modest effect of the disease activity score in 28 joins ( DAS28) on HDL2-chol concentrations was found, after correction for disease duration, glucocorticosteroid use and body mass index (BMI), with a 0.06 mmol/L decrease with every point increase in DAS28 (P = 0.05). DAS28 did not significantly affect HDL3-chol concentrations (P = 0.186).Conclusions
Both HDL subfractions but particularly HDL2-chol concentrations were decreased in RA, primarily in women. This seems to be associated with disease activity and is of clinical relevance. The reduction of the HDL subfraction concentrations, particularly the supposedly beneficial HDL2-chol, may negatively impact the cardiovascular risk profile of women with RA. 相似文献14.
Deoxyribonucleases (DNases) are key enzymes for digesting DNA. Abnormalities in the function of these enzymes may contribute to the development of anti-DNA antibodies in systemic lupus erythematosus (SLE). In this study, we used bovine DNase 1-coated ELISA plates to screen anti-DNase antibodies in SLE patients. About 62% of the sera of SLE patients (63/101) were positive for anti-DNase antibodies compared to only 8% of normal controls (8/98). A positive correlation was also found between the concentrations of anti-DNase and anti-DNA antibodies in sera of SLE patients. Affinity-purified anti-DNase immunoglobulin G (IgG) from pooled sera of SLE patients bound to bovine DNase as well as DNA. A synthetic peptide, corresponding to the catalytic site of DNase, was able to completely inhibit the binding of anti-DNase IgG to DNase. In addition to bovine DNase, the anti-DNase IgG also bound to and inhibited the enzymatic activities of DNase present in streptococcal supernatants and human urine. Immunization of lupus-prone NZB/NZW mice with bovine DNase enhanced the production of anti-DNase and DNA antibodies, and accelerated the occurrence of proteinuria. Taken together, these results suggest that DNase-inhibitory antibodies which recognize a conserved epitope near the catalytic site of DNase may act in the pathogenesis of SLE. 相似文献
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M Kale R Ramsey-Goldman S Bernatsky MB Urowitz D Gladman PR Fortin M Petri E Yelin S Manzi S Edworthy O Nived S-C Bae D Isenberg A Rahman JG Hanly C Gordon S Jacobsen E Ginzler DJ Wallace GS Alarcón MA Dooley L Gottesman K Steinsson A Zoma J-L Senécal S Barr G Sturfelt L Dreyer L Criswell J Sibley JL Lee AE Clarke 《Arthritis research & therapy》2012,14(Z3):A15
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The pathogenesis of systemic lupus erythematosus (SLE) is complex, and the resulting disease manifestations are heterogeneous.
Cytokine dysregulation is pervasive, and their protein and gene expression profiles may serve as markers of disease activity
and severity. Importantly, biologic agents that target specific cytokines may represent novel therapies for SLE. Four cytokines
(IL-6, TNFα, IFNα, and BLyS) are being evaluated as therapeutic targets in SLE. The present review will examine the roles
of each of these cytokines in murine and human SLE, and will summarize results from clinical trials of agents that target
these cytokines. 相似文献
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Anti-elastin antibodies in systemic lupus erythematosus 总被引:1,自引:0,他引:1
J Gmiński W Poborski A Kasprzak M Drózdz E Kardaszewicz M Machalski 《Polski tygodnik lekarski (Warsaw, Poland : 1960)》1990,45(25-26):513-515
Immunological response to elastin-derived peptides may cause tissue damage with subsequent degradation of the elastic fibres. Therefore, an incidence of anti-elastin antibodies in sera of patients with the systemic lupus erythematosus was studied. Sixty sera from 50 patients with systemic lupus erythematosus and 50 healthy subjects were assayed with dot-immunobinding technique. Titre 1:10 was considered diagnostically significant. Anti-elastin antibodies were diagnosed in 19 patients (31%) where as they were absent in the control group. In all cases anti-elastin antibodies were IgG. 相似文献
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