The gene silencing of IRF5 and BLYSS effectively modulates the outcome of experimental lupus nephritis

Systemic lupus erythematosus is a highly complex and hetero- geneous autoimmune disease mostly mediated by B cells. It is characterized by circulating self-reactive antibodies that depo- sit and form immune complexes in kidney, leading to irrepa- rable tissue damage and resulting in lupus nephritis. In a New Zealand Black X New Zealand White F1 mouse model, we tested two different small interfering RNA (siRNA) silencing treatments against interferon regulatory factor 5 (IRF5) and B cell-activating factor (BLYSS) expression and their combination in a second set of animals. The administra- tion of these two siRNAs separately prevented the progression of proteinuria and albuminuria at similar levels to that in cyclo- phosphamide animals. These treatments effectively resulted in a reduction of serum anti-double-stranded DNA (dsDNA) an- tibodies and histopathological renal score compared with non- treated group. Treated groups showed macrophage, T cell, and B cell infiltrate reduction in renal tissue. Moreover, kidney gene expression analysis revealed that siRNA treatments modulated very few pathways in contrast to cyclophosphamide, despite showing similar therapeutic effects. Additionally, the com- bined therapy tested in a second set of animals, in which the disease appeared more virulent, exhibited better results than monotherapies in the disease progression, delaying the disease onset and ameliorating the disease outcome. Herein, we pro- vide the potential therapeutic effect of both selective IRF5 and BLYSS silencing as an effective and potential treatment, particularly in early phases of the disease

A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P<0.01 in the initial screen were then followed up in 344 additional Swedish patients and 1299 controls. SNPs in the IKBKE, TANK, STAT1, IL8 and TRAF6 genes gave nominal signals of association with SLE in this extended Swedish cohort. To replicate these findings we extracted data from a genomewide association study on SLE performed in a US cohort. Combined analysis of the Swedish and US data, comprising a total of 2136 cases and 9694 controls, implicates IKBKE and IL8 as SLE susceptibility loci (Pmeta=0.00010 and Pmeta=0.00040, respectively). STAT1 was also associated with SLE in this cohort (Pmeta=3.3 × 10−5), but this association signal appears to be dependent of that previously reported for the neighbouring STAT4 gene. Our study suggests additional genes from the type I interferon system in SLE, and highlights genes in this pathway for further functional analysis

An epigenome-wide association study of total serum immunoglobulin E concentration

Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever and allergic asthma. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations-with a meta-analysis false discovery rate less than 10(-4)-between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases

No association of primary Sjogren's syndrome with Fc gamma receptor gene variants

The genetic background of primary Sjögren's syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fcγ receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fcγ receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N=527) and controls (N=528) were genotyped for the Fcγ receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fcγ receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS

Utopies féministes et expérimentations urbaines

Les villes modernes sont en apparence des lieux de liberté, de mixité que chacun utilise à sa guise. Les projets de ville sont projets de vie meilleure, voire de société nouvelle, souvent d'égalité. Pourtant l'étude de leurs fondements historiques, de leurs évolutions, de leurs projets politiques montre que, tout en étant créatrices de pratiques nouvelle et porteuses d'innovation, les villes sont fondamentalement le reflet des normes sociales dominantes. Et dans les sociétés actuelles, femmes et hommes n'avancent pas du même pas alors même que le Droit les y engage. Comment ce dilemme s'est-il inscrit dans l'espace urbain? Comment changer la vie en changeant la ville? Comment rêver, projeter, réaliser des villes où règne l'égalité entre les habitants, citoyens et citoyennes? Quels rêves d'égalité, de mixité, de séparation, de dominations se sont inscrits dans l'espace des villes? Quels projets ont été assez prégnants pour connaître des formes de réalisation? Quelles utopies ont échoué sur la plage des chimères? Quels temps ont porté des conceptions féministes assez fortes pour modifier les rôles de sexe, pour donner aux femmes une place d'individues à part entière? C'est à partier de ces interrogations que nous avons porté attention aux dimensions féministes des expérimentations urbaines. Nous avons regardé les projets anciens et ceux qui sont expérimentés aujourd'hui pour comprendre comment les normes sociales de sexe s'affichent dans les villes, comment lieux et genres interagissent dans leur construction sociale simultanée, et pour saisir enfin la sexualité comme vecteur fondamental de l'utopie socio-urbaine. Utopies féministes et expérimentations urbaines réunit des réflexions et des analyses sur la place des femmes et des hommes dans la ville et sur les projets urbains égalitaires, utopistes ou réalisés, qui veulent changer les rapports entre les sexes

No association of primary Sjogren's syndrome with Fc gamma receptor gene variants

The genetic background of primary Sjögren's syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fcγ receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fcγ receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N=527) and controls (N=528) were genotyped for the Fcγ receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fcγ receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS