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Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus 总被引:7,自引:0,他引:7
Denny MF Chandaroy P Killen PD Caricchio R Lewis EE Richardson BC Lee KD Gavalchin J Kaplan MJ 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(4):2095-2104
Increased monocyte/macrophage (Mphi) apoptosis occurs in patients with systemic lupus erythematosus (SLE) and is mediated, at least in part, by an autoreactive CD4(+) T cell subset. Furthermore, autoreactive murine CD4(+) T cells that kill syngeneic Mphi in vitro induce a lupus-like disease in vivo. However, it is unclear whether increased Mphi apoptosis in SLE per se is sufficient to accelerate/promote autoimmunity. We have investigated whether increased Mphi apoptosis in vivo, induced by the administration of clodronate liposomes, can exacerbate the autoimmune phenotype in NZB x SWR (SNF(1)) lupus-prone mice, and induce autoantibody production in haplotype-matched BALB/c x DBA1 (DBF(1)) non-lupus-prone mice. Lupus-prone mice SNF(1) mice that were treated with clodronate liposomes, but not mice treated with vehicle, developed significant increases in autoantibodies to dsDNA, nucleosomes, and the idiotypically related family of nephritic Abs Id(LN)F(1), when compared with untreated SNF(1) mice. Furthermore, clodronate treatment hastened the onset of proteinuria and worsened SNF(1) lupus nephritis. When compared with vehicle-treated controls, clodronate-treated non-lupus-prone DBF(1) mice developed significantly higher levels of anti-nucleosome and Id(LN)F(1) Abs but did not develop lupus nephritis. We propose that Mphi apoptosis contributes to the pathogenesis of autoantibody formation and organ damage through both an increase in the apoptotic load and impairment in the clearance of apoptotic material. This study suggests that mechanisms that induce scavenger cell apoptosis, such as death induced by autoreactive cytotoxic T cells observed in SLE, could play a pathogenic role and contribute to the severity of the disease. 相似文献
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Anna Petrackova Andrea Smrzova Petr Gajdos Marketa Schubertova Petra Schneiderova Pavel Kromer Vaclav Snasel Martina Skacelova Frantisek Mrazek Josef Zadrazil Pavel Horak Eva Kriegova 《Clinical proteomics》2017,14(1):32
Background
Systemic lupus erythematosus (SLE) is a remarkably heterogeneous autoimmune disease. Despite tremendous efforts, our knowledge of serum protein patterns in severe SLE phenotypes is still limited. We investigated the serum protein pattern of SLE, with special emphasis on irreversible organ damage and active lupus nephritis (LN) as assessed by renal Systemic Lupus Erythematosus Disease Activity Index.Methods
We used proximity extension immunoassay (PEA, Proseek Multiplex, Olink) to assess the serum levels of ninety-two inflammation-related proteins in Czech patients with SLE (n = 75) and age-matched healthy control subjects (n = 23). Subgroup analysis was carried out on the basis of organ damage (with/without, 42/33) and biopsy-proven LN (with/without, 27/48; active LN, n = 13; inactive LN, n = 14).Results
Of thirty deregulated proteins between SLE and the healthy controls (P corr < 0.05), the top upregulated proteins in SLE were sirtuin 2, interleukin 18 (IL18), and caspase 8 (P corr < 0.0006). Of these, sirtuin 2 and caspase 8 had not yet been reported with SLE. Elevated levels of IL8, CCL2/MCP1, CCL11, and MMP10 (P corr < 0.05) were detected in patients with organ damage for which the serum levels of CCL11 and MMP10 were particularly informative in organ damage prediction. Comparing patients based on LN, elevated levels of CSF1, sIL15RA, sCD40, sCX3CL1, caspase 8, sIL18R1, bNGF, and GDNF (P corr < 0.05) were detected in active LN. Except GDNF, all LN-associated markers showed usefulness in prediction of active renal disease.Conclusions
This highly sensitive PEA analysis identified the serum pattern of SLE, organ damage, and active LN, with many novel candidate proteins detected. Their exact role and suitability as biomarkers in SLE deserve further investigation.4.
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《Biomarkers》2013,18(8):758-763
Objective: Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of systemic inflammation. We aimed to characterize plasma suPAR levels in SLE patients.Methods: We measured plasma suPAR, C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in 89 SLE patients and 29 healthy controls.Results: suPAR and ESR values were higher in SLE than in controls, while CRP levels were comparable. ROC analysis of suPAR levels indicated a cut-off value of 5.70?ng/mL to distinguish patients with high disease activity (SLEDAI >8).Conclusion: suPAR might be an objective marker for identifying SLE patients with active disease. 相似文献
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Free radicals and damage caused by these molecular species are implicated in the pathogenesis of a variety of diseases, including autoimmune. Here we have examined oxidative damage, SOD activity and autoantibodies against SOD in systemic lupus erythematosus (SLE), a multifactorial disease with autoantibody production as an universal feature. We found significantly increased amounts of conjugated dienes in the SLE patients compared to normals (mean value of 0.917 vs 0.627, p = 0.0001) and MDA formation (6.96 vs 4.17 nmoles/microl, p = 0.0006) as well as decreased SOD activity. In addition, we found autoantibodies binding SOD by both ELISA and immunoblot. The presence of anti-SOD antibodies was associated with increased free radical damage in SLE patients. Heat inactivated anti-SOD autoantibodies were able to inhibit the activity of the enzyme. We propose that the inhibition of SOD by autoantibodies is, in part, responsible for the increased free radical damage seen in the disease. 相似文献
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Anders A Bengtsson ?sa Pettersson Stina Wichert Birgitta Gullstrand Markus Hansson Thomas Hellmark ?sa CM Johansson 《Arthritis research & therapy》2014,16(3):R120
Introduction
Polymorphonuclear leukocytes (PMN) are main effector cells in the acute immune response. While the specific role of PMN in systemic lupus erythematosus (SLE) and autoimmunity is still unclear, their importance in chronic inflammation is gaining more attention. Here we investigate aspects of function, bone marrow release and activation of PMN in patients with SLE.Methods
The following PMN functions and subsets were evaluated using flow cytometry; (a) production of reactive oxygen species (ROS) after ex vivo stimulation with phorbol 12-myristate 13-acetate (PMA) or Escherichia coli (E. coli); (b) capacity to phagocytose antibody-coated necrotic cell material; (c) PMN recently released from bone marrow, defined as percentage of CD10−D16low in peripheral blood, and (d) PMN activation markers; CD11b, CD62L and C5aR.Results
SLE patients (n = 92) showed lower ROS production compared with healthy controls (n = 38) after activation ex vivo. The ROS production was not associated with corticosteroid dose or other immunotherapies. PMA induced ROS production was significantly reduced in patients with severe disease. In contrast, neither ROS levels after E. coli activation, nor the capacity to phagocytose were associated with disease severity. This suggests that decreased ROS production after PMA activation is a sign of changed PMN behaviour rather than generally impaired functions. The CD10−CD16low phenotype constitute 2% of PMN in peripheral blood of SLE patients compared with 6.4% in controls, indicating a decreased release of PMN from the bone marrow in SLE. A decreased expression of C5aR on PMN was observed in SLE patients, pointing towards in vivo activation.Conclusions
Our results indicate that PMN from SLE patients have altered function, are partly activated and are released abnormally from bone marrow. The association between low ROS formation in PMN and disease severity is consistent with findings in other autoimmune diseases and might be considered as a risk factor. 相似文献8.
Yanfang Wu Feifei Zhang Jianyang Ma Xiaoyan Zhang Lingling Wu Bo Qu Shiwei Xia Shunle Chen Yuanjia Tang Nan Shen 《Arthritis research & therapy》2015,17(1)
IntroductionDespite growing evidence that large intergenic noncoding RNAs (lincRNAs) can regulate gene expression and widely take part in normal physiological and disease conditions, our knowledge of systemic lupus erythematosus (SLE)-related lincRNAs remains limited. The aim of this study was to detect the levels of four lincRNAs (ENST00000500949: linc0949, ENST00000500597: linc0597, ENST00000501992: linc1992, and ENST00000523995: linc3995) involved in innate immunity in the peripheral blood mononuclear cells (PBMCs) of patients with SLE and correlate these lincRNA levels with disease activity, organ damage, clinical features and medical therapies.MethodsPBMCs were obtained from 102 patients with SLE, 54 patients with rheumatoid arthritis (RA) and 76 healthy donors. lincRNA expression levels were measured by real-time quantitative polymerase chain reaction. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, and organ damage was evaluated with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index.Resultslinc0949 and linc0597 were significantly decreased in patients with SLE compared with patients with RA and healthy control subjects. linc0949 was correlated with SLEDAI-2K score (r = −0.329, P = 0.0007), as well as with complement component C3 level (r = 0.348, P = 0.0003). The level of linc0949 was also reduced in patients with SLE who had the presence of cumulative organ damage. In addition, decreasing expression of linc0949 was associated with lupus nephritis. linc0949 expression significantly increased after treatment, whereas neither disease activity nor organ damage correlated with linc0597 expression.ConclusionsOur results provide novel empirical evidence that linc0949 could be a potential biomarker for diagnosis, disease activity and therapeutic response in SLE.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0632-3) contains supplementary material, which is available to authorized users. 相似文献9.
Evans MD Cooke MS Akil M Samanta A Lunec J 《Biochemical and biophysical research communications》2000,273(3):894-898
Defective DNA damage processing has been reported in systemic lupus erythematosus (SLE). Vitamin C may modulate formation/removal of the oxidative DNA lesion 8-oxo-2'-deoxyguanosine (8-oxodG). Baseline levels of 8-oxodG measured in SLE serum, urine and PBMC DNA did not differ significantly from healthy subjects. In contrast to healthy subjects, no significant decrease in PBMC 8-oxodG or increase in urinary 8-oxodG was noted in vitamin C supplemented SLE patients. A significant, although attenuated, increase in serum 8-oxodG was detected in SLE patients, compared to healthy subjects. These data support putative abnormalities in the repair/processing of 8-oxodG in SLE. 相似文献
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The frequency of sister-chromatid exchanges (SCEs) was investigated in peripheral lymphocytes of lupus erythematosus patients and compared with values obtained for healthy controls. Irrespective of the kind of medical treatment, an increased level of spontaneously occurring SCEs could be demonstrated in lupus patients. In addition to spontaneously occurring SCEs, mitomycin C (MMC)-induced SCEs were evaluated. No difference between patients and controls was found with respect to MMC-induced SCEs. 相似文献
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Lian-Hong Li Wen-Xian Li Ou Wu Guo-Qing Zhang Hai-Feng Pan Xiang-Pei Li Jian-Hua Xu Hong Dai Dong-Qing Ye 《Molecular biology reports》2009,36(8):2047-2052
Systemic lupus erythematosus (SLE) is a common autoimmune disease with complex etiology. Recently, a possible role of apoptotic
cells in its pathogenesis has been suggested. This study is to evaluate the expression of Fas antigen on peripheral blood
lymphocytes (PBLs) in SLE, to determine whether membrane Fas (mFas) has a role in the organ damage in SLE and to explore its
relationship with the early apoptosis of the PBLs in SLE. Flow cytometry was used to evaluate the expression of mFas on PBLs
in 68 Chinese SLE patients and 37 healthy controls. Systemic lupus international collaborative clinics/american colleges of
rheumatology damage index (SDI) scores were calculated to further estimate the relationship of the expression of mFas with
disease severity. Results showed that mFas expression levels were significantly higher (P < 0.01) among SLE patients than those in healthy controls. Higher (P = 0.01) expressions of mFas were found in patients with SDI scores ≥ as compared to those with SDI scores <3. Patients with
neuropsychiatric or renal disease had a higher expression of mFas than those without neuropsychiatric (P = 0.03) or renal disease (P = 0.01). In addition, the expression levels had a positive (r = 0.381, P < 0.01) correlation with the early apoptosis rate of PBLs in SLE patients. Taken together, our study showed that Fas-expressing
PBLs were increased in SLE patients, especially in patients with higher SDI score, and the expression levels of mFas were
correlated to the organ damage and lymphocytes apoptosis. 相似文献
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Thirteen patients with systemic lupus erythematosus and depression (Depressed-SLE), 10 Depressed-Control subjects, and 25
Healthy Control subjects completed cognitive testing and self-report questionnaires of pain, depression, and fatigue. The
Depressed-SLE group scored higher on the American College of Rheumatology Neuropsychological Battery for systemic lupus erythematosus
cognitive impairment index compared to Depressed-Control and Healthy Control subjects (p < 0.05 and p < 0.02, respectively). No correlations between cognitive impairment and pain, fatigue, or perceived cognitive failures were
observed in the Depressed-SLE participants. Moderate agreement (86.4%) was found between a comprehensive neuropsychology battery
cognitive impairment index and the ACR-SLE impairment index in the Depressed-SLE patients. Overall, the magnitude and pattern
of cognitive impairment in Depressed-SLE patients cannot be explained by depression alone. 相似文献
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Diane L Kamen 《Arthritis research & therapy》2009,11(5):129-2
Infection is responsible for approximately 25% of all deaths in patients with systemic lupus erythematosus (SLE), making it
a leading cause of mortality among patients. Ruiz-Irastorza and colleagues, in a recent issue of Arthritis Research & Therapy, report the clinical predictors of major infections found in a prospective study of patients with SLE. Similar patterns of
infection and pathogens as reported in previous studies were seen; what is striking, however, was the protective effect seen
with anti-malarial use. Many infections in patients with SLE could be prevented with timely vaccinations, reducing exposure
to contagious contacts, screening for latent infections, minimizing exposure to corticosteroids, targeted prophylaxis for
high risk patients, and, unless contraindicated, anti-malarial therapy as standard of care. 相似文献
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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16.
G B Zamansky 《International journal of radiation biology and related studies in physics, chemistry, and medicine》1986,50(2):305-312
The repair of ultraviolet light-induced potentially lethal damage was investigated in density-inhibited skin fibroblast cell strains derived from patients with systemic lupus erythematosus. The effect of exposure to polychromatic ultraviolet light composed of environmentally relevant wavelengths or to the more commonly studied, short wavelength (254 nm) ultraviolet light was studied. Systemic lupus erythematosus cells, which are hypersensitive to ultraviolet light under growth promoting conditions, were able to repair potentially lethal damage as well as normal cells. 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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