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.
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.
Objective
To determine the stage of B cell development at which a systemic lupus erythematosus (SLE)–associated DNA methylation signature originates in African American (AA) and European American ...(EA) subjects, and to assess whether epigenetic defects in B cell development patterns could be predictive of SLE status in individual and mixed immune cell populations.
Methods
B cells from AA patients (n = 31) and EA patients (n = 49) with or without SLE were sorted using fluorescence‐activated cell sorting into 5 B cell subsets. DNA methylation, measured at ~460,000 CpG sites, was interrogated in each subset. Enrichment analysis of transcription factor interaction at SLE‐associated methylation sites was performed. A random forests algorithm was used to identify an epigenetic signature of SLE in the B cell subsets, which was then validated in an independent cohort of AA and EA patients and healthy controls.
Results
Regression analysis across all B cell stages resulted in identification of 60 CpGs that reached genome‐wide significance for SLE‐associated methylation differences (P ≤ 1.07 × 10−7). Interrogation of ethnicity‐specific CpGs associated with SLE revealed a hypomethylated pattern that was enriched for interferon (IFN)–regulated genes and binding of EBF1 in AA patients (each P < 0.001). AA patients with SLE could be distinguished from healthy controls when the predictive model developed with the transitional B cell subset was applied to other B cell subsets (mean receiver operating characteristic ROC area under the curve AUC 0.98), and when applied to CD19+ pan–B cells (mean ROC AUC 0.95) and CD4+ pan–T cells (mean ROC AUC 0.97) from the independent validation cohort.
Conclusion
These results indicate that SLE‐specific methylation patterns are ethnicity dependent. A pattern of epigenetic changes near IFN‐regulated genes early in B cell development is a hallmark of SLE in AA female subjects. EBF1 binding sites are highly enriched for significant methylation changes, implying that this may be a potential regulator of SLE‐associated epigenetic changes.
Abstract
Motivation
Meiotic recombination facilitates the transmission of exchanged genetic material between homologous chromosomes and plays a crucial role in increasing the genetic variations in ...eukaryotic organisms. In humans, thousands of crossover events have been identified by genotyping related family members. However, most of these crossover regions span tens to hundreds of kb, which is not sufficient resolution to accurately identify the crossover breakpoints in a typical trio family.
Results
We have developed MRLR, a software using 10X linked reads to identify crossover events at a high resolution. By reconstructing the gamete genome, MRLR only requires a trio family dataset and can efficiently discover the crossover events. Using MRLR, we revealed a fine-scale pattern of crossover regions in six human families. From the two closest heterozygous alleles around the crossovers, we determined that MRLR achieved a median resolution 4.5 kb. This method can delineate a genome-wide landscape of crossover events at a precise scale, which is important for both functional and genomic features analysis of meiotic recombination.
Availability and implementation
MRLR is freely available at https://github.com/ChongLab/MRLR, implemented in Perl.
Supplementary information
Supplementary data are available at Bioinformatics online.
We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10
) regions, including 36 that are new. We ...define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4
effector T cells. Using chromatin-accessibility profiling of CD4
T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.
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.
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