Systemic lupus erythematosus (SLE) is an autoimmune disease with known genetic, epigenetic, and environmental risk factors. To assess the role of DNA methylation in SLE, we collected CD4+ T-cells, ...CD19+ B-cells, and CD14+ monocytes from 49 SLE patients and 58 controls, and performed genome-wide DNA methylation analysis with Illumina Methylation 450 microarrays. We identified 166 CpGs in B-cells, 97 CpGs in monocytes, and 1,033 CpGs in T-cells with highly significant changes in DNA methylation levels (p < 1 × 10(-8)) among SLE patients. Common to all three cell-types were widespread and severe hypomethylation events near genes involved in interferon signaling (type I). These interferon-related changes were apparent in patients collected during active and quiescent stages of the disease, suggesting that epigenetically-mediated hypersensitivity to interferon persists beyond acute stages of the disease and is independent of circulating interferon levels. This interferon hypersensitivity was apparent in memory, naïve and regulatory T-cells, suggesting that this epigenetic state in lupus patients is established in progenitor cell populations. We also identified a widespread, but lower amplitude shift in methylation in CD4+ T-cells (> 16,000 CpGs at FDR < 1%) near genes involved in cell division and MAPK signaling. These cell type-specific effects are consistent with disease-specific changes in the composition of the CD4+ population and suggest that shifts in the proportion of CD4+ subtypes can be monitored at CpGs with subtype-specific DNA methylation patterns.
The Fc receptors (FcRs) and their interactions with immunoglobulin and innate immune opsonins, such as C-reactive protein, are key players in humoral and cellular immune responses. As the effector ...mechanism for some therapeutic monoclonal antibodies, and often a contributor to the pathogenesis and progression of autoimmunity, FcRs are promising targets for treating autoimmune diseases.
This review discusses the nature of different FcRs and the various mechanisms of their involvement in initiating and modulating immunocyte functions and their biological consequences. It describes a range of current strategies in targeting FcRs and manipulating their interaction with specific ligands, while presenting the pros and cons of these approaches. This review also discusses potential new strategies including regulation of FcR expression and receptor crosstalk.
FcRs are appealing targets in the treatment of inflammatory autoimmune diseases. However, there are still knowledge limitations and technical challenges, the most important being a better understanding of the individual roles of each of the FcRs and enhancement of the specificity in targeting particular cell types and specific FcRs.
Planets in young clusters are powerful probes of the evolution of planetary systems. Here we report the discovery of three planets transiting EPIC 247589423, a late-K dwarf in the Hyades ( 800 Myr) ...cluster, and robust detection limits for additional planets in the system. The planets were identified from their K2 light curves as part of our survey of young clusters and star-forming regions. The smallest planet has a radius comparable to Earth ( ), making it one of the few Earth-sized planets with a known, young age. The two larger planets are likely a mini-Neptune and a super-Earth, with radii of and , respectively. The predicted radial velocity signals from these planets are between 0.4 and 2 m s−1, achievable with modern precision RV spectrographs. Because the target star is bright (V = 11.2) and has relatively low-amplitude stellar variability for a young star (2-6 mmag), EPIC 247589423 hosts the best known planets in a young open cluster for precise radial velocity follow-up, enabling a robust test of earlier claims that young planets are less dense than their older counterparts.
Abstract
A common feature of autoimmune diseases, including systemic lupus erythematosus (SLE), is an increased prevalence in women. However, the molecular basis for sex disparity in SLE remains ...poorly understood. To examine the role of X-linked transcription in SLE adaptive immune cells, we performed RNA-seq in T cell and B cell subsets from either healthy donors or patients with SLE. Analyses of allelic expression (AE) profiles identified a pattern of increased allelic imbalance across the entire X chromosome in SLE lymphocytes. X-linked genes exhibiting AE in SLE had an extensive overlap with genes known to escape X chromosome inactivation (XCI). XIST RNA was overexpressed in SLE patients. Differential XIST expression correlated with AE profiles more positively at X-linked genes than the genome-wide background. Analysis of three independent RNA-seq data verified the XIST-associated skewed AE on X chromosome in SLE. Integrative analyses of DNA methylation profiles showed an increased variability of DNA methylation levels at these AE-related X-linked genes. In cultured lymphoblastic cells, knockdown of XIST specifically altered allelic imbalance patterns between X chromosomes. Our study provides genetic evidence that upregulation of XIST accompanied with more skewed allelic expression on X chromosome is associated with the pathogenesis of SLE and may provide mechanistic insights into the increased incidence of SLE in females.
Sarcoidosis is a systemic inflammatory disease characterized by the formation of granulomas in affected organs. Genome-wide association studies (GWASs) of this disease have been conducted only in ...European population. We present the first sarcoidosis GWAS in African Americans (AAs, 818 cases and 1,088 related controls) followed by replication in independent sets of AAs (455 cases and 557 controls) and European Americans (EAs, 442 cases and 2,284 controls). We evaluated >6 million SNPs either genotyped using the Illumina Omni1-Quad array or imputed from the 1000 Genomes Project data. We identified a novel sarcoidosis-associated locus, NOTCH4, that reached genome-wide significance in the combined AA samples (rs715299, P(AA-meta) = 6.51 × 10(-10)) and demonstrated the independence of this locus from others in the MHC region in the same sample. We replicated previous European GWAS associations within HLA-DRA, HLA-DRB5, HLA-DRB1, BTNL2, and ANXA11 in both our AA and EA datasets. We also confirmed significant associations to the previously reported HLA-C and HLA-B regions in the EA but not AA samples. We further identified suggestive associations with several other genes previously reported in lung or inflammatory diseases.
Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune ...dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.
In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune ...diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non-Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10(-06)) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non-MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.
Increased levels of B lymphocyte stimulator (BLyS) are associated with systemic autoimmunity in animal models of spontaneous autoimmune disease, and transgenic animals expressing BLyS develop typical ...autoimmune disease. Here, we demonstrate significant elevations of BLyS in the patients with systemic lupus erythematosus (SLE). The BLyS isolated from the sera of SLE patients had the same m.w. as the natural soluble form and was able to stimulate B cell activation in vitro. Increased BLyS in SLE patients was partially associated with higher levels of anti-dsDNA Ab of the IgG, IgM, and IgA classes, but not associated with the disease activity. Our results suggest that BLyS may be a useful marker for early activation of an autoimmune diathesis and likely plays a critical role in triggering activation of self-Ag-driven autoimmune B cells in human SLE. BLyS may provide an effective therapeutic target in systemic autoimmunity.
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