The interplay of dendritic cell subsets in systemic lupus erythematosus

Dendritic cells (DC) control immunity and tolerance. Hence, we surmised that systemic lupus erythematosus (SLE), a systemic autoimmune disease with autoreactive T and B cells, might be due to DC alterations. Based on our findings, we are proposing a model of SLE where autoimmune responses are driven by unabated activation of myeloid DC through IFN-alpha produced by plasmacytoid DC. Thus, interplay between DC subsets might represent a key component of SLE pathogenesis.     

Role of resistin as a marker of inflammation in systemic lupus erythematosus

Introduction

Resistin is a cystein-rich secretory adipokine. It is proposed to have proinflammatory properties in humans. The aim of this study was to determine associations between serum levels of resistin and markers of inflammation and bone mineral density (BMD) in female patients with systemic lupus erythematosus (SLE).

Methods

One hundred sixty-three female patients with SLE (20 to 82 years old) were examined in a cross-sectional study. Venous blood samples were analyzed for resistin, erythrocyte sedimentation rate (ESR), C-reactive protein, creatinine, fasting lipids, complements, tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, sIL-6R (soluble IL-6 receptor), ICTP (C-terminal telopeptide of type I collagen), and PINP (N-terminal propeptide of type I procollagen). Simple and multiple regression analyses as well as logistic regression analyses were performed. Resistin in serum was compared with 42 healthy female controls with respect to age.

Results

Serum resistin levels in controls were similar to those of patients with SLE. Markers of inflammation and current dose of glucocorticosteroids correlated positively to resistin in serum. Markers of renal function, number of prevalent vertebral fractures, and BMD were also significantly associated with resistin. In a multiple regression model, ESR, creatinine, C3, current glucocorticosteroid dose, high-density lipoprotein, and BMD radius remained significantly associated with resistin. In logistic regression analyses with resistin as the independent variable, a significant association was found with ESR (normal or elevated) but not with S-creatinine or z score for hip and radius total.

Conclusion

Although resistin measurements did not differ between patients and controls, resistin was clearly associated with general inflammation, renal disease, treatment with glucocorticosteroids, and bone loss. We hypothesize that resistin has proinflammatory and disease-promoting properties in SLE. Further studies are needed to elucidate the mechanism behind these associations.     

The DWEYS peptide in systemic lupus erythematosus

Current therapies for treating systemic lupus erythematosus (SLE) mainly rely upon nonspecific and toxic immunosuppression by corticosteroids and cytotoxics. Although biologics hold promise, many agents have yet to prove clinical efficiency in controlled trials, with further limitations related to safety and cost. The primary self-specificity in SLE is double-stranded (ds) DNA. Studying anti-dsDNA antibodies in animal models of lupus and SLE patients identified a neurotoxic and nephrotoxic subset, including the nephritogenic mouse monoclonal anti-dsDNA antibody R4 that crossreacts with a sequence present in subunits of the N-methyl-d-aspartate receptor. In this review, anti-dsDNA antibodies as a pathogenic factor in SLE and recent efforts for the creation of highly specific, nontoxic therapeutics against an extremely pathogenic subset of such antibodies is discussed.     

Complement and systemic lupus erythematosus

Complement is implicated in the pathogenesis of systemic lupus erythematosus (SLE) in several ways and may act as both friend and foe. Homozygous deficiency of any of the proteins of the classical pathway is causally associated with susceptibility to the development of SLE, especially deficiency of the earliest proteins of the activation pathway. However, complement is also implicated in the effector inflammatory phase of the autoimmune response that characterizes the disease. Complement proteins are deposited in inflamed tissues and, in experimental models, inhibition of C5 ameliorates disease in a murine model. As a further twist to the associations between the complement system and SLE, autoantibodies to some complement proteins, especially to C1q, develop as part of the autoantibody response. The presence of anti-C1q autoantibodies is associated with severe illness, including glomerulonephritis. In this chapter the role of the complement system in SLE is reviewed and hypotheses are advanced to explain the complex relationships between complement and lupus.     

The epigenetic face of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an archetypical systemic, autoimmune inflammatory disease characterized by the production of autoantibodies to multiple nuclear Ags. Apoptotic defects and impaired removal of apoptotic cells contribute to an overload of autoantigens that become available to initiate an autoimmune response. Besides the well-recognized genetic susceptibility to SLE, epigenetic factors are important in the onset of the disease, as even monozygotic twins are usually discordant for the disease. Changes in DNA methylation and histone modifications, the major epigenetic marks, are a hallmark in genes that undergo epigenetic deregulation in disease. In SLE, global and gene-specific DNA methylation changes have been demonstrated to occur. Moreover, histone deacetylase inhibitors reverse the skewed expression of multiple genes involved in SLE. In the present study, we discuss the implications of epigenetic alterations in the development and progression of SLE and how epigenetic drugs constitute a promising source of therapy to treat this disease.     

系统性红斑狼疮合并隐球菌脑膜炎1例

1临床资料 患者女,42岁。因“反复关节痛、口腔溃疡4年,头痛10d”于2008年1月急诊入院,患者4a前因反复关节痛、口腔溃疡,当地医院查自身抗体：ANA（＋）,nRNP／Sm、SSA、组蛋白均阳性。血常规中白细胞2．4×10^9／L,红细胞3．42×10^12／L,血红蛋白73g/L。诊断为系统性红斑狼疮,给予强的松40mg／d口服1个月后病情好转,3a内逐渐将强的松减量为10mg／d维持已1a。     

Anti-elastin antibodies in systemic lupus erythematosus

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.     

Lipid peroxidation in systemic lupus erythematosus

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.     

Cytokine disturbances in systemic lupus erythematosus

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.     

Deoxyribonuclease-Inhibitory antibodies in systemic lupus erythematosus

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.