Role In Pathogenesis Of Systemic Lupus Erythematosus Research Articles

Defensins in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease, resulting in inflammation and tissue damage. The precise etiology for SLE is so far unknown. It has been shown that the innate immunity plays a role in SLE pathogenesis. The innate immune system confers broad protection against pathogens by the secretion of broad-spectrum antibacterial and immunomodulatory substances named defensins. Recently, alpha-defensin, the products of neutrophils have been found to be upregulated at the mRNA and protein levels in SLE patients. In addition, increased antidefensin antibodies were found in sera of patients with SLE, but these levels decreased after therapy with corticosteroids. These recent findings suggest a role for defensins in the pathogenesis of SLE. Thus, activation and degranulation of neutrophils leads to alpha-defensin secretion in SLE patients. Given their immunomodulatory role, alpha-defensin secretion might activate the adaptive immune system leading to the stimulation of the immune system, as is manifested in SLE.

High serum IFN-α activity is a heritable risk factor for systemic lupus erythematosus

Interferon alpha (IFN-alpha) levels are elevated in many patients with systemic lupus erythematosus (SLE); however it is not known whether high serum IFN-alpha activity is a cause or a result of the disease. We studied 266 SLE patients and 405 of their healthy relatives, and frequently found high serum IFN-alpha activity in both patients and healthy relatives as compared to healthy unrelated individuals. High IFN-alpha activity was clustered in specific families in both SLE patients and their healthy first-degree relatives, suggesting a heritable trait. Heritability was also supported by quantitative familial correlation of IFN-alpha activity, concordance in affected sib pairs and frequent transmission of the high IFN-alpha activity trait from parents to offspring. Autoantibodies to RNA-binding proteins and double-stranded DNA were associated with high IFN-alpha activity in SLE patients; however these autoantibodies were very uncommon in healthy family members and did not explain the observed familial correlations. The frequency of high IFN-alpha activity was similar across all studied ethnic backgrounds. These data suggest that high serum IFN-alpha activity is a complex heritable trait, which plays a primary role in SLE pathogenesis.

Immature myeloid and plasmacytoid dendritic cells infiltrate renal tubulointerstitium in patients with lupus nephritis

Systemic lupus erythematosus (SLE) is an autoimmune disease involving several organs. SLE patients developing lupus nephritis (LN) frequently have the worst outcome. Recent data have shown that dendritic cells (DCs) may have a central role in SLE pathogenesis directing the immune response against auto-antigens. In this study we describe a reduction in circulating BDCA1+and BDCA3+ myeloid DCs, and BDCA2+ plasmacytoid DCs in patients with active LN compared to those in the remission state. Analysis of LN biopsies revealed a strong tubulo-interstitial infiltrate of BDCA1+, BDCA3+ and BDCA4+ DCs which were negative for DC-LAMP, a specific marker of mature DCs. The extent of the DCs infiltrate was higher in class III/IV LN than in normal kidney. These results show for the first time that three DCs subsets, decreased at circulating levels, are recruited within the kidney, indicating that DCs might play a pathogenic role in SLE patients with nephritis.

Systemic lupus erythematosus and nucleosome

The property of nucleosome in systemic lupus erythematosus (SLE) is reviewed. Nucleosome, complex of histone and DNA, is thought to have a pivotal role in pathogenesis of SLE. It is formed during apoptosis that is increased in peripheral lymphocytes of SLE. The concentration of nucleosome is elevated in SLE, probably related with disease activity. Nucleosome is speculated that the clearance from peripheral blood is decreased and that is modified by viral infection to become more immunogenic. Anti-nucleosome antibody is highly positive in majority of SLE, and is very specific for SLE except scleroderma and mixed connective tissue disease. This antibody is thought as a diagnostic marker and probably an activity marker for SLE. Anti-nucleosome antibody forms immune complex with nucleosome. As histone has strong positive charge, it is demonstrated that this nucleosome/anti-nucleosome complex is bound to negatively charged heparan sulfate of glomerular basement membrane in kidney. Then, complements bind to this antibody to generate lupus glomerulonephritis. Although main site of apoptosis in SLE is considered as lymphocytes, we experienced a case with SLE who had liver dysfunction with elevated soluble Fas ligand (sFasL) and apoptosis in her hepatocytes in the active stage of SLE. We measured serum sFasL, and found the relation of sFasL and liver involvement in active SLE. As major source of nucleosome should be apoptosis of lymphocytes in SLE, hepatocytes could be another candidate of apoptosis in some SLE.

Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains

Systemic lupus erythematosus (SLE) is an autoimmune disorder of a largely unknown etiology. Anti-double-stranded (ds) DNA antibodies are a classic hallmark of the disease, although the mechanism underlying their induction remains unclear. We demonstrate here that, in both lupus-prone and normal mouse strains, strong anti-dsDNA antibody responses can be induced by dendritic cells (DC) that have ingested syngeneic necrotic (DC/nec), but not apoptotic (DC/apo), cells. Clinical manifestations of lupus were evident, however, only in susceptible mouse strains, which correlate with the ability of DC/nec to release IFN-gamma and to induce the pathogenic IgG2a anti-dsDNA antibodies. Injection of DC/nec not only accelerated disease progression in the MRL/MpJ-lpr/lpr lupus-prone mice but also induced a lupus-like disease in the MRL/MpJ-+/+ wild-type control strain. Immune complex deposition was readily detectable in the kidneys, and the mice developed proteinuria. Strikingly, female MRL/MpJ-+/+ mice that had received DC/nec, but not DC/apo, developed a 'butterfly' facial lesion resembling a cardinal feature of human SLE. Our study therefore demonstrates that DC/nec inducing a Th1 type of responses, which are otherwise tightly regulated in a normal immune system, may play a pivotal role in SLE pathogenesis.

Expression and clinical significance of inducible co-stimulator on peripheral blood T lymphocyte subsets in patients with systemic lupus erythematosus

To investigate the expression of inducible co-stimulator (ICOS) and other immunological molecules on peripheral blood T lymphocyte subsets in patients with systemic lupus erythematosus (SLE) and to find out the relationship with disease-activity, disease-stage and the contents of anti-dsDNA antibody and immunoglobulin in serum so as to pave the way for further studying the possibly immunologically pathological role of ICOS in SLE. Peripheral blood samples were collected from 51 patients with SLE, 3 males and 22 females. Three-color flow cytometry was used to detect the levels of ICOS, CD45RO, CD45RA, and HLA-DR expression on the peripheral blood T lymphocytes subsets. The results were analyzed along with the disease-activity, disease-stage, contents of anti-dsDNA antibody and immunoglobulin in serum. Thirty healthy subjects were used as controls. Compared with the healthy subjects the level of ICOS expression on the peripheral blood CD4+ and CD8+ T cells in the patients with SLE during active- and stable-stages were significantly increased (all P < 0.05), but there was no significant difference between the last two group patients (P > or = 0.05); In the same patients, the level of ICOS expression on the peripheral blood CD4+, CD8+, CD45RO+, CD4+CD45RO+ and CD8+CD45RO+ cells in active-stage were significantly increased compared with those in stable-stage (P <0.05); The level of ICOS expression on the peripheral blood CD45RO+ cells in the untreated primary patients was higher than those with disease-relapse (P <0.05); The levels of ICOS expression on the peripheral blood CD45RO+ and CD4+CD45RO+ cells were significantly increased in the patients with serum anti-dsDNA antibody(+) and the patients with aberrantly high content of immunoglobulin compared with those of the patients with serum anti-dsDNA antibody(-) and the patients with normal content of immunoglobulin, respectively (all P < 0.05). ICOS is aberrantly highly expressed on certain peripheral blood T lymphocyte subsets in patients with SLE, which is related to disease-activity, disease-stage and the contents of serum anti-dsDNA antibody and immunoglobulin, thus ICOS may play a role in SLE pathogenesis.

Anti-DNA antibodies: a diagnostic and prognostic tool for systemic lupus erythematosus?

The clinical impact of anti-DNA antibodies lies on their diagnostic power for systemic lupus erythematosus (SLE), being a formal classification criterion. In spite of such a disease association, low-avidity anti-DNA antibodies might also be part of the natural autoantibody repertoire. Their switch to pathogenic high-avidity autoantibodies is the result of the autoimmune process leading to SLE.Anti-DNA antibodies were shown to play a role in SLE pathogenesis and particularly in kidney damage. Accordingly, antibody titres might fluctuate in relation to disease activity, but their prognostic value for flares is still debated.Several methods for anti-DNA detection were described and there is evidence that the assays identify different antibodies with different prognostic value. The results of a multicenter study on four different routine tests for anti-dsDNA antibody detection showed that: (i) Farr assay displays the best diagnostic specificity/sensitivity for SLE, followed by Crithidia luciliae method (CLIFT), (ii) the new generation of solid phase assay (EliA) shows an increased sensibility versus the classical enzyme linked immune assay (ELISA) but a decreased specificity. Antibody titre detected by EliA and Farr assay correlated with disease activity. These findings would suggest that more than one assay should be useful for SLE diagnosis and monitoring.

Type I Interferon Modulation of Cellular Responses to Cytokines and Infectious Pathogens: Potential Role in SLE Pathogenesis

Type I interferons (IFNs) are pleiotropic cytokines that have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). A key aspect of type I IFN biology is that previous exposure to type I IFNs alters subsequent cellular responses to extracellular stimuli. Type I IFNs may either prime cells for stronger responses to viruses, bacterial pathogens and cytokines such as IL-6 and IFNγ, or may suppress cellular responses to LPS and TNFα. Herein, we review type I IFN signal transduction via the Jak-STAT pathway, and mechanisms by which type I IFNs prime or suppress responses to environmental factors. We develop a hypothesis that type I IFN-dependent priming/enhancement of cellular responses to pro-inflammatory cytokines such as IFNγ and IL-6 contributes to pathogenesis of SLE. In addition, cross-regulation between type I IFNs and TNFα and its potential role in SLE pathogenesis is discussed.

Circulating angiogenesis inhibitor endostatin and positive endothelial growth regulators in patients with systemic lupus erythematosus.

Serum concentrations of three angiogenic cytokines: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-18 (IL-18) and antiangiogenic factor endostatin in the serum of 52 patients with systemic lupus erythematosus (SLE) and 20 healthy subjects were investigated. The possible association between serum levels of these proteins and SLE activity as well as correlation between the concentrations of angiogenic cytokines and the level of endostatin was also analyzed. VEGF and IL-18 were detectable in all SLE patients and healthy control group. bFGF was measurable in 71.2% of patients with SLE and 65% of healthy persons. Endostatin was detectable in 94.2% of SLE patients and 95% of normal subjects. The serum levels of endostatin and bFGF were not significantly different in SLE and healthy control (P > 0.05). The median concentration of VEGF was higher in active SLE (238.4 pg/ml) than in inactive disease (118.1 pg/ml, P < 0.05) or in control group (133.5 pg/ml, P < 0.04). The median serum level of IL-18 was higher in the SLE patients (595.2 pg/ml) than in the control group (252.7 pg/ml) (P < 0.001). The correlations between the levels of angiogenic cytokines and endostatin with clinical features, laboratory abnormalities and also with the type of treatment were analysed. We found a positive correlation between VEGF serum concentration and SLE activity according to SLAM score (p = 0.275, P < 0.05). The significant positive correlation was also found between IL-18 and endostatin (p = 0.289, P < 0.04). In contrast, the correlation between bFGF and endostatin was significantly negative (p = - 0.299, P < 0.04). In conclusion, serum levels of the angiogenic and antiangiogenic factors may play an important role in SLE pathogenesis.

Dysregulation of p56lck Kinase in Patients with Systemic Lupus Erythematosus

In this study we investigated one of the possible mechanisms of p56lck down-regulation in peripheral blood lymphocytes (PBLs) from Systemic Lupus Erythematosus (SLE) patients and we correlated p56 dysregulation with accelerated apoptosis in SLE PBLs. PBLs from SLE patients and healthy donors were isolated. p56lck protein expression and Ick mRNA level were estimated by immunoblotting and RT-PCR, respectively. FACS analysis was used to evaluate the apoptosis and p56 levels in apoptotic and non-apoptotic PBLs. A non-radioactive Tyrosine Kinase Assay Kit was used to measure p56, ck activity. Our results demonstrated that PBLs from SLE patients displayed lower levels of Ick mRNA and p56lck protein as compared to healthy donors. The apoptosis of fresh or cultured PBLs was enhanced in SLE patients, especially in anti-DNA negative group. The expression of p56lck was inverse correlated with apoptosis of fresh and cultured SLE PBLs, especially in anti-DNA negative patients. Double staining FACS analysis showed that p56lck expression was lower in apoptotic than in non-apoptotic PBLs. p56ick specific activity was directly correlated to apoptosis in SLE PBLs. While the low expression of p56lck may be the result of lower degree of synthesis, the increased specific activity could directly correlated to the extent of apoptosis in SLE PBLs. Based on our observations, we assume that the p56lck dysregulation could play a role in SLE pathogenesis

Study on systemic lupus erythematosus activity and serum lymphocyte-associated immunoglobulin which is quantified with enzyme-linked immunosorbent assay

Lymphocyte-associated immunoglobulin (LAIg) levels in the sera from patients with systemic lupus erythematosus (SLE) were quantitatively measured by means of enzyme-linked immunosorbent assay (ELISA). The relation between LAIg and SLE activity was studied. The LAIgG levels in a group of sera from untreated patients were significantly higher than those in another from treated ones. As to LAIgM, however, there was no difference between the two groups. There was a significant correlation between the serum levels of complement (CH50) and LAIgG, but no correlation between the levels of CH50 and LAIgM. The levels of LAIgG significantly correlated with those of immune complex (IC) in non-inactivated sera. After inactivation of the sera, the correlation between the levels of LAIgG and those of IC disappeared, while a significant correlation between the levels of LAIgG and those of CH50 remained. There was no correlation between titers of cytotoxicity tests and the levels of LAIgG. LAIg detected by ELISA may contain different kinds of antilymphocyte antibodies from those detected by cytotoxicity test. The serum LAIgG may play some roles in pathogenesis of SLE, since its level correlates strongly with the serum level of complement, one of the representative indicators for the SLE activity.