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Atsushi Tanaka Hiroshi Tsukamoto Hiroki Mitoma Chikako Kiyohara Naoyasu Ueda Masahiro Ayano Shun-ichiro Ohta Yasushi Inoue Yojirou Arinobu Hiroaki Niiro Takahiko Horiuchi Koichi Akashi 《Arthritis research & therapy》2012,14(6):1-9
Introduction
Progranulin (PGRN) is the precursor of granulin (GRN), a soluble cofactor for toll-like receptor 9 (TLR9) signaling evoked by oligonucleotide (CpG)-DNA. Because TLR9 signaling plays an important role in systemic lupus erythematosus (SLE), we investigated whether PGRN is involved in the pathogenesis of SLE.Methods
We measured concentrations of serum PGRN and interleukin-6 (IL-6) with enzyme-linked immunosorbent assay (ELISA) in patients with SLE (n = 68) and in healthy controls (n = 60). We assessed the correlation between the serum PGRN levels and established disease-activity indexes. The sera from the patients with high PGRN titers (>80 ng/ml) at the initial evaluation were reevaluated after the disease was ameliorated by treatment. We also measured the IL-6 concentration secreted by peripheral blood mononuclear cells (PBMCs) incubated with (a) oligonucleotide (CpG-B) in the presence or absence of recombinant human PGRN (rhPGRN); and (b) lupus sera in the presence or absence of a neutralizing anti-PGRN antibody.Results
Serum PGRN levels were significantly higher in SLE patients than healthy controls. Their levels were significantly associated with activity of clinical symptoms. They also significantly correlated with values of clinical parameters, including the SLE Disease Activity Index and anti-double-stranded DNA antibody titers, and inversely with CH50, C3, and C4 levels. Moreover, serum PGRN levels significantly decreased after successful treatment of SLE. The rhPGRN significantly upregulated the production of IL-6 by PBMCs stimulated with CpG-B. Patients' sera stimulated production of IL-6 from PBMCs, which was significantly impaired by neutralization of PGRN. The serum PGRN levels significantly correlated with the serum IL-6 levels.Conclusions
Serum PGRN could be a useful biomarker for disease activity of SLE. PGRN may be involved in the pathogenesis of SLE partly by enhancing the TLR9 signaling. 相似文献2.
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Patients with systemic lupus erythematosus have abnormally elevated Epstein-Barr virus load in blood
Moon UY Park SJ Oh ST Kim WU Park SH Lee SH Cho CS Kim HY Lee WK Lee SK 《Arthritis research & therapy》2004,6(4):R295-R302
Various genetic and environmental factors appear to be involved in systemic lupus erythematosus (SLE). Epstein-Barr virus (EBV) is among the environmental factors that are suspected of predisposing to SLE, based on the characteristics of EBV itself and on sequence homologies between autoantigens and EBV antigens. In addition, higher titers of anti-EBV antibodies and increased EBV seroconversion rates have been observed in SLE patients as compared with healthy control individuals. Serologic responses do not directly reflect EBV status within the body. Clarification of the precise status of EBV infection in SLE patients would help to improve our understanding of the role played by EBV in this disease. In the present study we determined EBV types in SLE patients (n = 66) and normal control individual (n = 63) by direct PCR analysis of mouthwash samples. We also compared EBV load in blood between SLE patients (n = 24) and healthy control individuals (n = 29) using semiquantitative PCR assay. The number of infections and EBV type distribution were similar between adult SLE patients and healthy control individuals (98.5% versus 94%). Interestingly, the EBV burden in peripheral blood mononuclear cells (PBMCs) was over 15-fold greater in SLE patients than in healthy control individuals (mean +/- standard deviation: 463 +/- 570 EBV genome copies/3 microg PBMC DNA versus 30 +/- 29 EBV genome copies/3 microg PBMC DNA; P = 0.001), suggesting that EBV infection is abnormally regulated in SLE. The abnormally increased proportion of EBV-infected B cells in the SLE patients may contribute to enhanced autoantibody production in this disease. 相似文献
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Wu T Xie C Han J Ye Y Weiel J Li Q Blanco I Ahn C Olsen N Putterman C Saxena R Mohan C 《PloS one》2012,7(6):e37210
The metabolic disturbances that underlie systemic lupus erythematosus are currently unknown. A metabolomic study was executed, comparing the sera of 20 SLE patients against that of healthy controls, using LC/MS and GC/MS platforms. Validation of key differences was performed using an independent cohort of 38 SLE patients and orthogonal assays. SLE sera showed evidence of profoundly dampened glycolysis, Krebs cycle, fatty acid β oxidation and amino acid metabolism, alluding to reduced energy biogenesis from all sources. Whereas long-chain fatty acids, including the n3 and n6 essential fatty acids, were significantly reduced, medium chain fatty acids and serum free fatty acids were elevated. The SLE metabolome exhibited profound lipid peroxidation, reflective of oxidative damage. Deficiencies were noted in the cellular anti-oxidant, glutathione, and all methyl group donors, including cysteine, methionine, and choline, as well as phosphocholines. The best discriminators of SLE included elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5-HETE. Importantly, similar elevations were not observed in another chronic inflammatory autoimmune disease, rheumatoid arthritis. To sum, comprehensive profiling of the SLE metabolome reveals evidence of heightened oxidative stress, inflammation, reduced energy generation, altered lipid profiles and a pro-thrombotic state. Resetting the SLE metabolome, either by targeting selected molecules or by supplementing the diet with essential fatty acids, vitamins and methyl group donors offers novel opportunities for disease modulation in this disabling systemic autoimmune ailment. 相似文献
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Ruiz-Narvaez EA Fraser PA Palmer JR Cupples LA Reich D Wang YA Rioux JD Rosenberg L 《Human genetics》2011,130(6):807-815
The major histocompatibility complex (MHC) on chromosome 6p21 is a key contributor to the genetic basis of systemic lupus
erythematosus (SLE). Although SLE affects African Americans disproportionately compared to European Americans, there has been
no comprehensive analysis of the MHC region in relationship to SLE in African Americans. We conducted a screening of the MHC
region for 1,536 single nucleotide polymorphisms (SNPs) and the deletion of the C4A gene in a SLE case–control study (380 cases, 765 age-matched controls) nested within the prospective Black Women’s Health
Study. We also genotyped 1,509 ancestral informative markers throughout the genome to estimate European ancestry to control
for population stratification due to population admixture. The most strongly associated SNP with SLE was the rs9271366 (odds
ratio, OR = 1.70, p = 5.6 × 10−5) near the HLA-DRB1 gene. Conditional haplotype analysis revealed three other SNPs, rs204890 (OR = 1.86, p = 1.2 × 10−4), rs2071349 (OR = 1.53, p = 1.0 × 10−3), and rs2844580 (OR = 1.43, p = 1.3 × 10−3), to be associated with SLE independent of the rs9271366 SNP. In univariate analysis, the OR for the C4A deletion was 1.38, p = 0.075, but after simultaneous adjustment for the other four SNPs the odds ratio was 1.01, p = 0.98. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk
alleles (OR = 1.67 per high-risk allele, p < 0.0001). Our strongest signal, the rs9271366 SNP, was also associated with higher risk of SLE in a previous Chinese genome-wide
association study (GWAS). In addition, two SNPs found in a GWAS of European ancestry women were confirmed in our study, indicating
that African Americans share some genetic risk factors for SLE with European and Chinese subjects. In summary, we found four
independent signals in the MHC region associated with risk of SLE in African American women. 相似文献
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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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Lipid peroxidation is an important process in oxygen toxicity. Free radicals inflict this damage by attacking polyunsaturated fatty acids, thus setting off a deleterious chain reaction that ultimately results in their disintegration into malondialdehye, 4 hydroxy-2-nonenal and other harmful by-products. Peroxidation of lipids has been implicated in several diseases including systemic lupus erythematosus (SLE). SLE is an autoimmune disorder with unknown aetiology, characterized by the presence of autoantibodies to self-antigens. There is a significant increase in the production of free radicals like superoxide and hydroxyl radicals in SLE. Indices of lipid peroxidation, like conjugated dienes, malondialdehyde, 8-isoprostaglandin F2 alpha are significantly elevated in SLE. Increased ceruloplasmin levels and decreased transferrin levels in the sera of SLE patients have also been described. The activities of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase and the amounts of the antioxidant reduced glutathione are also significantly altered in this disease. In addition, there are significant changes in the essential fatty acid profile in the sera of those affected with the disease. In animal models of the disease, immunization of mice with peptides derived from autoantigens induces SLE like disease. Immunization with an oxidatively modified autoantigen led to the rapid development of autoimmunity compared to immunization with the unmodified autoantigen. Thus, oxidative damage appears to play an important role in SLE pathogenesis. 相似文献
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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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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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