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Human SLE (human + sle)
Selected AbstractsSystemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strainsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2005Liang Ma Abstract 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-, 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. [source] Constitutive overexpression of BAFF in autoimmune-resistant mice drives only some aspects of systemic lupus erythematosus,like autoimmunityARTHRITIS & RHEUMATISM, Issue 8 2010William Stohl Objective To determine whether overexpression of BAFF can promote systemic lupus erythematosus (SLE),like autoimmunity in mice that are otherwise autoimmune-resistant. Methods We used class II major histocompatibility complex (MHC),deficient C57BL/6 (B6) mice as a model of resistance to SLE and Sles1 -bearing B6 mice as a model of resistance to the autoantibody-promoting capacity of the Sle1 region. We generated BAFF-transgenic (Tg) counterparts to these respective mice and evaluated lymphocyte phenotype, serologic autoimmunity, renal immunopathology, and clinical disease in the BAFF-Tg and non-Tg mouse sets. Results Although constitutive BAFF overexpression did not lead to B cell expansion in class II MHC,deficient B6 mice, it did lead to increased serum IgG autoantibody levels. Nevertheless, renal immunopathology was limited, and clinical disease did not develop. In B6 and B6.Sle1 mice, constitutive BAFF overexpression led to increased numbers of B cells and CD4+ memory cells, as well as increased serum IgG and IgA autoantibody levels. Renal immunopathology was modestly greater in BAFF-Tg mice than in their non-Tg counterparts, but again, clinical disease did not develop. Introduction of the Sles1 region into B6.Sle1.Baff mice abrogated the BAFF-driven increase in CD4+ memory cells and the Sle1 -driven, but not the BAFF-driven, increase in serum IgG antichromatin levels. Renal immunopathology was substantially ameliorated. Conclusion Although constitutive BAFF overexpression in otherwise autoimmune-resistant mice led to humoral autoimmunity, meaningful renal immunopathology and clinical disease did not develop. This raises the possibility that BAFF overexpression, even when present, may not necessarily drive disease in some SLE patients. This may help explain the heterogeneity of the clinical response to BAFF antagonists in human SLE. [source] Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-, activity in lupus patientsARTHRITIS & RHEUMATISM, Issue 2 2010Rafah Salloum Objective Interferon-, (IFN,) is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variation near IRF7 is implicated in SLE susceptibility. SLE-associated autoantibodies can stimulate IFN, production through the Toll-like receptor/IRF7 pathway. This study was undertaken to determine whether variants of IRF7 act as risk factors for SLE by increasing IFN, production and whether autoantibodies are important to this phenomenon. Methods We studied 492 patients with SLE (236 African American, 162 European American, and 94 Hispanic American subjects). Serum levels of IFN, were measured using a reporter cell assay, and single-nucleotide polymorphisms (SNPs) in the IRF7/PHRF1 locus were genotyped. Results In a joint analysis of European American and Hispanic American subjects, the rs702966 C allele was associated with the presence of anti,double-stranded DNA (anti-dsDNA) antibodies (odds ratio [OR] 1.83, P = 0.0069). The rs702966 CC genotype was only associated with higher serum levels of IFN, in European American and Hispanic American patients with anti-dsDNA antibodies (joint analysis P = 4.1 × 10,5 in anti-dsDNA,positive patients and P = 0.99 in anti-dsDNA,negative patients). In African American subjects, anti-Sm antibodies were associated with the rs4963128 SNP near IRF7 (OR 1.95, P = 0.0017). The rs4963128 CT and TT genotypes were associated with higher serum levels of IFN, only in African American patients with anti-Sm antibodies (P = 0.0012). In African American patients lacking anti-Sm antibodies, an effect of anti-dsDNA,rs702966 C allele interaction on serum levels of IFN, was observed, similar to the other patient groups (overall joint analysis P = 1.0 × 10,6). In European American and Hispanic American patients, the IRF5 SLE risk haplotype showed an additive effect with the rs702966 C allele on IFN, level in anti-dsDNA,positive patients. Conclusion Our findings indicate that IRF7/PHRF1 variants in combination with SLE-associated autoantibodies result in higher serum levels of IFN,, providing a biologic relevance for this locus at the protein level in human SLE in vivo. [source] Regression of systemic lupus erythematosus after development of an acquired Toll-like receptor signaling defect and antibody deficiencyARTHRITIS & RHEUMATISM, Issue 9 2009Marcella Visentini Toll-like receptor 9 (TLR-9) and TLR-7 may have a role in the production of anti-DNA and anti-RNA autoantibodies, respectively, but murine models do not clearly demonstrate their contribution to the development of systemic lupus erythematosus (SLE). Herein we describe a patient with SLE who had long-lasting remission of her autoimmune disease after development of an antibody deficiency resembling common variable immunodeficiency (CVID). After CVID had developed, anti,double-stranded DNA antibodies disappeared, although antinuclear antibodies remained positive for >10 years. In vitro studies revealed that the patient's B cells proliferated poorly and failed to differentiate into plasmablasts after stimulation of either TLR-9 or TLR-7, providing evidence for an acquired defect of the signaling pathway downstream of these TLRs. These observations suggest, although indirectly, that signaling through TLR-9 and TLR-7 is important in the pathogenesis of human SLE, and indicate that investigation of potential treatment strategies with TLR antagonists is warranted. [source] Reduced CD4+,CD25, T cell sensitivity to the suppressive function of CD4+,CD25high,CD127,/low regulatory T cells in patients with active systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 7 2008Ram Kumar Chowdary Venigalla Objective CD4+,CD25high regulatory T (Treg) cells play a crucial role in the maintenance of self tolerance and prevention of organ-specific autoimmunity. The presence of many in vivo,preactivated CD4+,CD25++ T cells in patients with systemic lupus erythematosus (SLE) poses a difficulty in discriminating CD25++ activated T cells from CD25high Treg cells. To overcome this problem, we analyzed the phenotype and function of CD4+,CD25high,CD127,/low natural Treg (nTreg) cells isolated from the peripheral blood of patients with SLE. Methods CD4+,CD25high,CD127,/low nTreg cells and CD4+,CD25, responder T (Tresp) cells from patients with SLE and normal donors were separated by fluorescence-activated cell sorting. Cell proliferation was quantified by 3H-thymidine incorporation, and immunophenotyping of the cells was done using FACScan. Results Comparable percentages of CD4+,CD25high,FoxP3+ T cells were observed in patients with SLE and normal donors. Proliferation of SLE nTreg cells sorted into the subset CD4+,CD25high,CD127,/low was significantly decreased compared with that of SLE nTreg cells sorted into the subset CD4+,CD25high (mean ± SEM 2,223 ± 351 counts per minute versus 9,104 ± 1,720 cpm, respectively), while in normal donors, these values were 802 ± 177 cpm and 2,028 ± 548 cpm, respectively, confirming that effector cell contamination was reduced. Notably, the suppressive activity of nTreg cells was intact in all groups. However, CD4+,CD25, Tresp cells isolated from patients with active SLE were significantly less sensitive than those from patients with inactive SLE to the suppressive function of autologous or normal donor CD4+,CD25high,CD127,/low nTreg cells. Furthermore, a significant inverse correlation was observed between the extent of T cell regulation in suppressor assays and the level of lupus disease activity. Conclusion This study is the first to show that, in human SLE, impaired sensitivity of Tresp cells to the suppressive effects of a comparably functional, highly purified nTreg cell population leads to a defective suppression of T cell proliferation in active SLE. Studies aiming to define the mechanisms leading to Tresp cell resistance might help in the development of highly specific, alternative immunotherapeutic tools for the control of systemic autoimmune diseases such as SLE. [source] Deficiency of the type I interferon receptor protects mice from experimental lupus,ARTHRITIS & RHEUMATISM, Issue 11 2007Dina C. Nacionales Objective Systemic lupus erythematosus (SLE) is diagnosed according to a spectrum of clinical manifestations and autoantibodies associated with abnormal expression of type I interferon (IFN-I),stimulated genes (ISGs). The role of IFN-I in the pathogenesis of SLE remains uncertain, partly due to the lack of suitable animal models. The objective of this study was to examine the role of IFN-I signaling in the pathogenesis of murine lupus induced by 2,6,10,14-tetramethylpentadecane (TMPD). Methods IFN-I receptor,deficient (IFNAR,/,) 129Sv mice and wild-type (WT) 129Sv control mice were treated intraperitoneally with TMPD. The expression of ISGs was measured by real-time polymerase chain reaction. Autoantibody production was evaluated by immunofluorescence and enzyme-linked immunosorbent assay. Proteinuria and renal glomerular cellularity were measured and renal immune complexes were examined by immunofluorescence. Results Increased ISG expression was observed in the peripheral blood of TMPD-treated WT mice, but not in the peripheral blood of TMPD-treated IFNAR,/, mice. TMPD did not induce lupus-specific autoantibodies (anti-RNP, anti-Sm, anti,double-stranded DNA) in IFNAR,/, mice, whereas 129Sv controls developed these specificities. Although glomerular immune complexes were present in IFNAR,/, mice, proteinuria and glomerular hypercellularity did not develop, whereas these features of glomerulonephritis were found in the TMPD-treated WT controls. The clinical and serologic manifestations observed in TMPD-treated mice were strongly dependent on IFNAR signaling, which is consistent with the association of increased expression of ISGs with lupus-specific autoantibodies and nephritis in humans. Conclusion Similar to its proposed role in human SLE, signaling via the IFNAR is central to the pathogenesis of autoantibodies and glomerulonephritis in TMPD-induced lupus. This lupus model is the first animal model shown to recapitulate the "interferon signature" in peripheral blood. [source] | ||||||||||