The development of systemic lupus erythematosus (SLE) involves both genetic and environmental factors. Epstein-Barr virus (EBV) infection has been implicated in SLE pathogenesis, particularly through the activity of latent membrane protein 1 (LMP-1). This study aimed to explore the role of LMP-1 in regulating susceptibility gene expression in SLE. Peripheral blood mononuclear cells (PBMCs) from SLE patients and H9 T cells were used to investigate this mechanism both in vivo and in vitro. RNA-seq analysis revealed that LMP-1 and the SLE susceptibility gene AT-rich interactive domain 5B (ARID5B) were significantly upregulated in SLE. Overexpression of LMP-1 in H9 T cells further increased ARID5B expression. Histone H3K27 methylation, catalyzed by enhancer of zeste homolog 2 (EZH2), was significantly elevated, suggesting epigenetic modifications play a role in this regulation. H3K27 methylation was studied due to its known involvement in transcriptional repression and chromatin remodeling in autoimmune diseases. Furthermore, phosphorylated p65 (p-p65), a marker of nuclear factor-kappa-B (NF-κB) pathway activation, was increased. Blocking the NF-κB signaling pathway reduced ARID5B expression, indicating that LMP-1 may regulate susceptibility genes through NF-κB signaling and histone modifications. These findings suggest that EBV LMP-1 contributes to SLE pathogenesis by epigenetically modulating susceptibility gene expression and activating inflammatory pathways.

BTB domain and CNC homolog 2 (BACH2) is a transcription repressor from the basic region leucine zipper (bZIP) family. Although BACH2 is predominantly expressed in lymphoid cells, it plays pivotal roles throughout hematological development and differentiation, ranging from the regulation of hematopoietic stem and progenitor cell (HSPC) lineage commitment to the development of both innate and adaptive immune cells. Given its extensive regulation of immunity, it is not surprising that BACH2 has been implicated in cancer, particularly in hematological malignancies. While multiple findings indicate that BACH2 acts primarily as a tumor suppressor, other findings suggest that BACH2, whether within tumor cells or their surrounding microenvironment, may contribute to tumorigenesis and progression, highlighting the complexity of its roles and the diverse networks involved in different contexts. In this review, we provide a comprehensive overview of the evolving roles of BACH2 across various stages of hematopoiesis, with a particular focus on its associations with cancer and its therapeutic potential in a wide range of cancer types.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease marked by abnormal B-cell proliferation and increased autoantibodies. miRNAs play a crucial role in regulating B-cell dysfunction and SLE pathology. miRNAs influence DNA methylation, B-cell activation, and gene expression, contributing to SLE pathogenesis. miRNAs impact B cells through key processes like proliferation, differentiation, tolerance, and apoptosis. miRNAs also exacerbate inflammation and immune responses by modulating Interleukin 4 (IL-4), IL-6, and interferon cytokines. Autophagy, a key degradation mechanism, is also regulated by specific miRNAs that impact SLE pathology. This article explores the role of multiple miRNAs in regulating B-cell development, proliferation, survival, and immune responses, influencing SLE pathogenesis. miRNAs like miR-23a, the miR-17 ∼ 92 family, and miR-125b/miR-221 affect B-cell development by regulating transcription factors, signaling pathways, and cell cycle genes. miRNAs such as miR-181a-5p and miR-23a-5p are differentially regulated across developmental stages, emphasizing their complex regulatory roles in B-cell biology. This article synthesizes miRNA-B cell interactions to offer new strategies and directions for SLE diagnosis and treatment.

WD repeat- and FYVE domain-containing protein 4 (WDFY4), coded by a gene on 10q11.23, is a member of the BEACH (Beige and Chediak-Higashi) domain-containing family. Genome-wide association studies identified WDFY4 variants as a risk factor for SLE in Asian and European populations. WDFY4 variants are also associated with RA and primary biliary cholangitis, in different ancestry populations. The WDFY4 protein plays an essential role in the cross-presentation of classic dendritic cells, reactive oxygen species-induced apoptosis of CD8+ T cells, and non-canonical autophagic activity in B cells. A novel variant rs7919656 was identified in Japanese clinically amyopathic dermatomyositis patients, with a highly expressed truncated isoform augmenting the melanoma differentiation-associated gene 5 (MDA5) signalling pathway. The same variant was later found to be significantly associated with RP-ILD in Chinese MDA5+DM patients. Here, we briefly review the association of WDFY4 with autoimmune diseases and its known function in the immune response.

Functional genes within genomic loci associated with systemic lupus erythematosus (SLE), as identified by genome-wide association studies, exhibit cell-specific characteristics. This study delves into the impact of genetic variants within SLE loci on gene expression in different types of immune cells, unraveling the complex interplay between genetics and immunopathogenesis. Through the integration of genetic association and single-cell transcriptomic sequencing data, we identified potential cell-specific susceptibility genes for SLE across diverse immune cell subsets. The single-cell eQTL analysis revealed 30,409 associations involving 3583 SLE-associated SNPs. These SNPs exhibited associations with expression levels of 147 genes across 14 distinct cell types. The single-cell summary data-based Mendelian randomization (SMR) analysis identified 119 significant associations between the expression levels of 44 genes and SLE. Notably, myeloid cells exhibited associations solely within the MHC region, while T, B, and natural killer cells showed associations with both MHC and non-MHC genes in relation to SLE. Analysis of single-cell transcriptomic data from 33 children SLE cases and 11 match controls (227,303 cells), as well as 7 adult SLE cases and 5 match controls (78,414 cells) highlights differential expression of key genes. Notably, genetic variants within HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, IRF7, IRF5, BLK and HLA-DPA1 play a pivotal role in mediating immune dysregulation in specific immune cell types. Our study contributes to a comprehensive understanding of the intricate relationships between genetics, gene expression and SLE susceptibility. The findings shed light on the cell-specific impacts of genetic variants within SLE-associated genomic loci.

This study aimed to elucidate the functional genes associated with systemic lupus erythematosus (SLE) in various cell types through the utilization of RNAm-SNPs.

Utilizing large-scale genetic data, we identified associations between RNAm-SNPs and SLE. The association between RNAm-SNPs and bulk and single-cell mRNA expression (eQTL) and protein levels (pQTL) were examined. Mendelian randomization and differential expression analyses were conducted to explore the links between gene expression, protein levels, and SLE.

We identified 41 RNAm-SNPs that were significantly associated with SLE. The GWAS signals exhibited notable enrichment in m6A-SNPs and m7G-SNPs. These RNAm-SNPs showed both eQTL and pQTL effects. In our single-cell analysis, 16 RNAm-SNPs exhibited associations with gene expression levels across 13 distinct cell types, including HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, HLA-DRB1 and IRF7. We identified 58 noteworthy associations between the expression levels of 20 genes and SLE across 12 distinct immune cell types. Notably, HLA-DQB1, HLA-DRB1 and IRF7 exhibited abnormalities in CD8+ T cells, IRF7 displayed abnormal expression in CD4+ T cells, while HLA-DRB1 and IRF7 were also distinctly perturbed in natural killer cells.

This study advances our understanding of the genetic basis of SLE by highlighting the significance of RNAm-SNPs and immune cell gene expression in SLE.

Sex-biased gene expression differs across human populations; however, the underlying genetic basis and molecular mechanisms remain largely unknown. Here, we explore the influence of ancestry on sex differences in the human transcriptome and its genetic effects on a Eurasian admixed population: Uyghurs living in Xinjiang (XJU), by analyzing whole-genome sequencing data and transcriptome data of 90 XJU and 40 unrelated Han Chinese individuals. We identified 302 sex-biased expressed genes and 174 sex-biased cis-expression quantitative loci (sb-cis-eQTLs) in XJU, which were enriched in innate immune-related functions, indicating sex differences in immunity. Notably, approximately one-quarter of the sb-cis-eQTLs showed a strong correlation with ancestry composition; i.e. populations of similar ancestry tended to show similar patterns of sex-biased gene expression. Our analysis further suggested that genetic admixture induced a moderate degree of sex-biased gene expression. Interestingly, analysis of chromosome interactions revealed that the X chromosome acted on autosomal immunity-associated genes, partially explaining the sex-biased phenotypic differences. Our work extends the knowledge of sex-biased gene expression from the perspective of genetic admixture and bridges the gap in the exploration of sex-biased phenotypes shaped by autosome and X-chromosome interactions. Notably, we demonstrated that sex chromosomes cannot fully explain sex differentiation in immune-related phenotypes.

T cells, as a major lymphocyte population involved in the adaptive immune response, play an important immunomodulatory role in the early stages of autoimmune diseases. Autophagy is a cellular catabolism mediated by lysosomes. Autophagy maintains cell homeostasis by recycling degraded cytoplasmic components and damaged organelles. Autophagy has a protective effect on cells and plays an important role in regulating T cell development, activation, proliferation and differentiation. Autophagy mediates the participation of T cells in the acquired immune response and plays a key role in antigen processing as well as in the maintenance of T cell homeostasis. In autoimmune diseases, dysregulated autophagy of T cells largely influences the pathological changes. Therefore, it is of great significance to study how T cells play a role in the immune mechanism of autoimmune diseases through autophagy pathway to guide the clinical treatment of diseases.

Giant cell arteritis (GCA) is an immune-mediated large-vessels vasculitis with complex etiology. Although the pathogenic mechanisms remain poorly understood, a central role for CD4+ T cells has been demonstrated. In this context, understanding the transcriptome dysregulation in GCA CD4+ T cells will yield new insights into its pathogenesis.

Transcriptome analysis was conducted on CD4+ T cells from 70 patients with GCA with different disease activity and treatment status (active patients before treatment and patients in remission with and without glucocorticoid treatment), and 28 healthy controls. The study also evaluated potential impacts of DNA methylation on gene expression alterations and assessed cross-talk with CD14+ monocytes.

This study has uncovered a substantial number of genes and pathways potentially contributing to the pathogenicity of CD4+ T cells in GCA. Specifically, CD4+ T cells from GCA patients with active disease exhibited altered expression levels of genes involved in multiple immune-related processes, including various interleukins (IL) signaling pathways. Notably, IL-2, a decisive interleukin for regulatory T cells homeostasis, was among the most significant. Additionally, impaired apoptotic pathways appear crucial in GCA development. Our findings also suggest that histone-related epigenetic pathways may be implicated in promoting an inflammatory phenotype in GCA active patients. Finally, our study observed altered signaling communication, such as the Jagged-Notch signaling, between CD4+ T cells and monocytes that could have pathogenic relevance in GCA.

Our study suggests the participation of novel cytokines and pathways and the occurrence of a disruption of monocyte-T cell crosstalk driving GCA pathogenesis.

An in-depth literature review of up to 2023 reveals 330 risk loci found by genetic association at p ≤ 5 × 10-8, with systemic lupus erythematosus (SLE) in at least one study of 160 pertinent publications. There are 225 loci found in East Asian (EAS), 106 in European (EU), 11 in African-American (AA), 18 Mixed American (MA), and 1 in Egyptian ancestries. Unexpectedly, most of these associations are found to date at p ≤ 5 × 10-8 in a single ancestry. However, the EAS and EU share 40 risk loci that are independently established. The great majority of the identified loci [250 (75.8%) of 330] do not contain a variant that changes an amino acid sequence. Meanwhile, most overlap with known regulatory elements in the genome [266 (80.6%) of 330], suggesting a major role for gene regulation in the genetic mechanisms of SLE. To evaluate the pathways altered by SLE-associated variants, we generated gene sets potentially regulated by SLE loci that consist of the nearest genes, published attributions, and genes predicted by computational tools. The most useful insights, at present, suggest that SLE genetic mechanisms involve (1) the regulation of both adaptive and innate immune responses including immune cell activation and differentiation; (2) the regulation of production and response to cytokines, including type I interferon; (3) apoptosis; (4) the sensing and removal of immune complexes and apoptotic particles; and (5) immune response to infections, including Epstein-Barr Virus, and symbiont microorganisms. These mechanisms affected by SLE genes involve multiple cell types, including B cells/plasma cells, T cells, dendritic cells, monocytes/macrophages, natural killer cells, neutrophils, and endothelial cells. The genetics of SLE from GWAS data reveal an incredibly complex profusion of interrelated molecular processes and interacting cells participating in SLE pathogenesis, mostly unified in the molecular regulation of inflammatory responses. These genetic associations in lupus and affected molecular pathways not only give us an understanding of the disease pathogenesis but may also help in drug discoveries for SLE treatment.

This study, conducted by searching keywords such as "maternal lupus", "neonatal lupus", and "congenital heart block" in databases including PubMed and Scopus, provides a detailed narrative review on fetal and neonatal lupus. Autoantibodies like anti-Ro/SSA and anti-La/SSB may cross the placenta and cause complications in neonates, such as congenital heart block (CHB). Management options involve hydroxychloroquine, which is able to counteract some of the adverse events, although the drug needs to be used carefully because of its impact on the QTc interval. Advanced pacing strategies for neonates with CHB, especially in severe forms like hydrops, are also assessed. This review emphasizes the need for interdisciplinary care by rheumatologists, obstetricians, and pediatricians in order to achieve the best maternal and neonatal health in lupus pregnancies. This multidisciplinary approach seeks to improve the outcomes and management of the disease, decreasing the burden on mothers and their infants.

Epidemiological studies have consistently demonstrated a high prevalence of concurrent autoimmune diseases in individuals with Graves' disease (GD).

The objective of this study is to establish a causal association between GD and autoimmune diseases.

We employed a two-sample Mendelian randomization (MR) to infer a causal association between GD and five autoimmune diseases, namely rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease (CD), ulcerative colitis (UC), and amyotrophic lateral sclerosis (ALS), in the East Asian and European population. Genetic correlations were explored through linkage disequilibrium score regression analysis (LDSC). Finally, colocalization analyses were performed to investigate possible genetic foundations.

Bidirectional MR analysis indicated that genetically predicted GD increased the risk of RA (Odds Ratio (OR): 1.34, 95 % Confidence Interval (CI): 1.21 to 1.47, P < 0.001) and SLE (OR: 1.21, 95%CI: 1.08 to 1.35, P < 0.001) in the East Asian population. In contrast, we found that genetically predicted RA (OR: 1.14, 95%CI: 1.05 to 1.24, P = 0.002) and SLE (OR: 1.10, 95%CI: 1.03 to 1.17, P = 0.003) were associated with a higher risk of GD. The results have been partially validated in European cohorts. Colocalization analysis suggested the potential existence of shared causal variants between GD and other autoimmune diseases. In particular, gene ARID5B may play an important role in the incidence of autoimmune diseases.

This study has confirmed that GD was associated with RA and SLE and found a possible key gene ARID5B. It may be necessary to strengthen detection to prevent the occurrence of comorbidities in clinical practice.

Systemic Lupus Erythematosus (SLE) is a multifactorial autoimmune disease that arises from a dynamic interplay between genetics and environmental triggers. The advent of sophisticated genomics technology has catalyzed a shift in our understanding of disease etiology, spotlighting the pivotal role of non-coding DNA variants in SLE pathogenesis. In this review, we present a comprehensive examination of the non-coding variants associated with SLE, shedding light on their role in influencing disease risk and progression. We discuss the latest methodological advancements that have been instrumental in the identification and functional characterization of these genomic elements, with a special focus on the transformative power of CRISPR-based gene-editing technologies. Additionally, the review probes into the therapeutic opportunities that arise from modulating non-coding regions associated with SLE. Through an exploration of the complex network of non-coding DNA, this review aspires to decode the genetic puzzle of SLE and set the stage for groundbreaking gene-based therapeutic interventions and the advancement of precision medicine strategies tailored to SLE management.

Ovine footrot is an infectious disease with important contributions from Dichelobacter nodosus and Fusobacterium necrophorum. Footrot is characterized by separation of the hoof from underlying tissue, and this causes severe lameness that negatively impacts animal wellbeing, growth, and profitability. Large economic losses result from lost production as well as treatment costs, and improved genetic tools to address footrot are a valuable long-term goal. Prior genetic studies had examined European wool sheep, but hair sheep breeds such as Katahdin and Blackbelly have been reported to have increased resistance to footrot, as well as to intestinal parasites. Thus, footrot condition scores were collected from 251 U.S. sheep including Katahdin, Blackbelly, and European-influenced crossbred sheep with direct and imputed genotypes at OvineHD array (>500,000 single nucleotide polymorphism) density. Genome-wide association was performed with a mixed model accounting for farm and principal components derived from animal genotypes, as well as a random term for the genomic relationship matrix. We identified three genome-wide significant associations, including SNPs in or near GBP6 and TCHH. We also identified 33 additional associated SNPs with genome-wide suggestive evidence, including a cluster of 6 SNPs in a peak near the genome-wide significance threshold located near the glutamine transporter gene SLC38A1. These findings suggest genetic susceptibility to footrot may be influenced by genes involved in divergent biological processes such as immune responses, nutrient availability, and hoof growth and integrity. This is the first genome-wide study to investigate susceptibility to footrot by including hair sheep and also the first study of any kind to identify multiple genome-wide significant associations with ovine footrot. These results provide a foundation for developing genetic tests for marker-assisted selection to improve resistance to ovine footrot once additional steps like fine mapping and validation are complete.

The AT-rich interaction domain (ARID) family of DNA-binding proteins is a group of transcription factors and chromatin regulators with a highly conserved ARID domain that recognizes specific AT-rich DNA sequences. Dysfunction of ARID family members has been implicated in various human diseases including cancers and intellectual disability. Among them, ARID3a has gained increasing attention due to its potential involvement in autoimmunity. In this article we provide an overview of the ARID family, focusing on the structure and biological functions of ARID3a. It explores the role of ARID3a in autoreactive B cells and its contribution to autoimmune diseases such as systemic lupus erythematosus and primary biliary cholangitis. Furthermore, we also discuss the potential for drug discovery targeting ARID3a and present a plan for future research in this field.

Autoimmune diseases arise from atypical immune responses that attack self-tissue epitopes, and their development is intricately connected to the disruption of the JAK-STAT signaling pathway, where SOCS proteins play crucial roles. Conditions such as autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis exhibit immune system dysfunctions associated with JAK-STAT signaling dysregulation. Emerging therapeutic strategies utilize JAK-STAT inhibitors and SOCS mimetics to modulate immune responses and alleviate autoimmune manifestations. Although more research and clinical studies are required to assess their effectiveness, safety profiles, and potential for personalized therapeutic approaches in autoimmune conditions, JAK-STAT inhibitors and SOCS mimetics show promise as potential treatment options. This review explores the action, effectiveness, safety profiles, and future prospects of JAK inhibitors and SOCS mimetics as therapeutic agents for psoriasis, autoimmune uveitis, systemic lupus erythematosus, and autoimmune encephalitis. The findings underscore the importance of investigating these targeted therapies to advance treatment options for individuals suffering from autoimmune diseases.

The past few years have provided important insights into the genetic architecture of systemic autoimmunity through aggregation of findings from genome-wide association studies (GWAS) and whole-exome or whole-genome sequencing studies. In the prototypic systemic autoimmune disease systemic lupus erythematosus (SLE), monogenic disease accounts for a small fraction of cases but has been instrumental in the elucidation of disease mechanisms. Defects in the clearance or digestion of extracellular or intracellular DNA or RNA lead to increased sensing of nucleic acids, which can break B cell tolerance and induce the production of type I interferons leading to tissue damage. Current data suggest that multiple GWAS SLE risk alleles act in concert with rare functional variants to promote SLE development. Moreover, introduction of orthologous variant alleles into mice has revealed that pathogenic X-linked dominant and recessive SLE can be caused by novel variants in TLR7 and SAT1, respectively. Such bespoke models of disease help to unravel pathogenic pathways and can be used to test targeted therapies. Cell type-specific expression data revealed that most GWAS SLE risk genes are highly expressed in age-associated B cells (ABCs), which supports the view that ABCs produce lupus autoantibodies and contribute to end-organ damage by persisting in inflamed tissues, including the kidneys. ABCs have thus emerged as key targets of promising precision therapeutics.

Autophagy, a highly conserved cellular self-degradation pathway, has emerged with novel roles in the realms of immunity and inflammation. Genome-wide association studies have unveiled a correlation between genetic variations in autophagy-related genes and heightened susceptibility to autoimmune and inflammatory diseases. Subsequently, substantial progress has been made in unraveling the intricate involvement of autophagy in immunity and inflammation through functional studies. The autophagy pathway plays a crucial role in both innate and adaptive immunity, encompassing various key functions such as pathogen clearance, antigen processing and presentation, cytokine production, and lymphocyte differentiation and survival. Recent research has identified novel approaches in which the autophagy pathway and its associated proteins modulate the immune response, including noncanonical autophagy. This review provides an overview of the latest advancements in understanding the regulation of immunity and inflammation through autophagy. It summarizes the genetic associations between variants in autophagy-related genes and a range of autoimmune and inflammatory diseases, while also examining studies utilizing transgenic animal models to uncover the in vivo functions of autophagy. Furthermore, the review delves into the mechanisms by which autophagy dysregulation contributes to the development of three common autoimmune and inflammatory diseases and highlights the potential for autophagy-targeted therapies.

CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research and therapeutic development. While the exact role of CLEC16A in health and disease is still being elucidated, the gene plays a critical role in the regulation of autophagy, mitophagy, endocytosis, intracellular trafficking, immune function, and in biological processes such as insulin secretion and others that are important to cellular homeostasis. As shown in both human and animal modeling studies, CLEC16A hypofunction predisposes to both autoinflammatory phenotype and neurodegeneration. While the two are clearly related, further functional studies are needed to fully understand the mechanisms involved for optimized therapeutic interventions. Based on recent data, mitophagy-inducing drugs may be warranted, and such therapy should be tested in clinical trials as these drugs would tackle the underlying pathogenic mechanism (s) and could treat or prevent symptoms of autoimmunity and neurodegeneration in individuals with CLEC16A risk variants. Accordingly, interventions directed at reversing the dysregulated mitophagy and the consequences of loss of function of CLEC16A without activating other detrimental cellular pathways could present an effective therapy. This review presents the emerging role of CLEC16A in health and disease and provides an update on the disease processes that are attributed to variants located in the CLEC16A gene, which are responsible for autoimmune disorders and neurodegeneration with emphasis on how this information is being translated into practical and effective applications in the clinic.

Autophagy comprises a growing range of cellular pathways, which occupy central roles in response to energy deprivation, organelle turnover and proteostasis. Over the years, autophagy has been increasingly linked to governing several aspects of immunity, including host defence against various pathogens, unconventional secretion of cytokines and antigen presentation. While canonical autophagy-mediated antigen processing in thymic epithelial cells supports the generation of a self-tolerant CD4+ T cell repertoire, mounting evidence suggests that deregulated autophagy pathways contribute to or sustain autoimmune responses. In animal models of multiple sclerosis (MS), non-canonical autophagy pathways such as microtubule-associated protein 1 A/1 B-light chain 3 (LC3)-associated phagocytosis can contribute to major histocompatibility complex (MHC) class II presentation of autoantigen, thereby amplifying autoreactive CD4+ T cell responses. In systemic lupus erythematosus (SLE), increased type 1 interferon production is linked to excessive autophagy in plasmacytoid dendritic cells (DCs). In rheumatoid arthritis (RA), autophagy proteins contribute to pathological citrullination of autoantigen. Immunotherapies effective in autoimmune diseases modulate autophagy functions, and strategies harnessing autophagy pathways to restrain autoimmune responses have been developed. This review illustrates recent insights in how autophagy, distinct autophagy pathways and autophagy protein functions intersect with the evolution and progression of autoimmune diseases, focusing on MS, SLE and RA.

Systemic lupus erythematosus (SLE) is a severe multisystem autoimmune disease that predominantly affects women. Its etiology is complex and multifactorial, with several known genetic and environmental risk factors, but accurate risk prediction models are still lacking. We developed SLE risk prediction models, incorporating known genetic, lifestyle and environmental risk factors, and family history.

We performed a nested case-control study within the Nurses' Health Study cohorts (NHS). NHS began in 1976 and enrolled 121,700 registered female nurses ages 30-55 from 11 U.S. states; NHSII began in 1989 and enrolled 116,430 registered female nurses ages 25-42 from 14 U.S. states. Participants were asked about lifestyle, reproductive and environmental exposures, as well as medical information, on biennial questionnaires. Incident SLE cases were self-reported and validated by medical record review (Updated 1997 American College of Rheumatology classification criteria). Those with banked blood samples for genotyping (∼25% of each cohort), were selected and matched by age (± 4 years) and race/ethnicity to women who had donated a blood sample but did not develop SLE. Lifestyle and reproductive variables, including smoking, alcohol use, body mass index, sleep, socioeconomic status, U.S. region, menarche age, oral contraceptive use, menopausal status/postmenopausal hormone use, and family history of SLE or rheumatoid arthritis (RA) were assessed through the questionnaire prior to SLE diagnosis questionnaire cycle (or matched index date). Genome-wide genotyping results were used to calculate a SLE weighted genetic risk score (wGRS) using 86 published single nucleotide polymorphisms (SNPs) and 10 classical HLA alleles associated with SLE. We compared four sequential multivariable logistic regression models of SLE risk prediction, each calculating the area under the receiver operating characteristic curve (AUC): 1) SLE wGRS, 2) SLE/RA family history, 3) lifestyle, environmental and reproductive factors and 4) combining model 1-3 factors. Models were internally validated using a bootstrapped estimate of optimism of the AUC. We also examined similar sequential models to predict anti-dsDNA positive SLE risk.

We identified and matched 138 women who developed incident SLE to 1136 women who did not. Models 1-4 yielded AUCs 0.63 (95%CI 0.58-0.68), 0.64 (95%CI 0.59-0.68), 0.71(95% CI 0.66-0.75), and 0.76 (95% CI 0.72-0.81). Model 4 based on genetics, family history and eight lifestyle and environmental factors had best discrimination, with an optimism-corrected AUC 0.75. AUCs for similar models predicting anti-dsDNA positive SLE risk, were 0.60, 0.63, 0.81 and 0.82, with optimism corrected AUC of 0.79 for model 4.

A final model including SLE weighted genetic risk score, family history and eight lifestyle and environmental SLE risk factors accurately classified future SLE risk with optimism corrected AUC of 0.75. To our knowledge, this is the first SLE prediction model based on known risk factors. It might be feasibly employed in at-risk populations as genetic data are increasingly available and the risk factors easily assessed. The NHS cohorts include few non-White women and mean age at incident SLE was early 50s, calling for further research in younger and more diverse cohorts.

Peripheral blood immune cells have different molecular characteristics at different stages of the whole lifespan. Knowledge of circulating immune cell types and states from children to centenarians remains incomplete. We profiled peripheral blood mononuclear cells (PBMCs) of multiple age groups with single-cell RNA sequencing (scRNA-seq), involving the age ranges of 1-12 (G1), 20-30(G2), 30-60(G3), 60-80(G4), and >110 years (G5). The proportion and states of myeloid cells change significantly from G1 to G2. We identified a novel CD8+CCR7+GZMB+ cytotoxic T cell subtype specific in G1, expressing naive and cytotoxic genes, and validated by flow cytometry. CD8+ T cells showed significant changes in the early stage (G1 to G2), while CD4+ T cells changed in the late stage (G4 to G5). Moreover, the intercellular crosstalk among PBMCs in G1 is very dynamic. Susceptibility genes for a variety of autoimmune diseases (AIDs) have different cell-specific expression localization, and the expression of susceptibility genes for AIDs changes with age. Notably, the CD3+ undefined T cells clearly expressed susceptibility genes for multiple AIDs, especially in G3. ETS1 and FLI1, susceptibility genes associated with systemic lupus erythematosus, were differentially expressed in CD4+ and CD8+ effector cells in G1 and G3. These results provided a valuable basis for future research on the unique immune system of the whole lifespan and AIDs.

WFS1-related disorders involve a wide range of clinical phenotypes, including diabetes mellitus and neurodegeneration. Inheritance patterns of pathogenic variants of this gene can be autosomal recessive or dominant, and differences in penetrance present challenges for accurate diagnosis and genetic counselling.

Three probands and one elder brother from three families were systematically evaluated and the clinical data of other family members were collected from the medical history. Whole-exome sequencing was performed on the probands, and RNA sequencing was performed on four patients, their parents with WFS1 variants, and four gender- and age-matched children with type 1 diabetes mellitus.

There were six patients with diabetes. Dilated cardiomyopathy, a rare manifestation of WFS1-related disease, was identified in one patient, along with MRI findings of brain atrophy at age 7 years and 3 months, the earliest age of discovery we know of. Whole-exome sequencing revealed five pathogenic or likely pathogenic variants in the WFS1 gene, including c.1348dupC (p.His450Profs*93), c.1381A>C (p.Thr461pro), c.1329C>G (p.Ser443Arg), c.2081delA (p.Glu694Glyfs*16), c.1350-1356delinsGCA (p.His450Glnfs*26), of which 3 variants (c.1348dupC, c.2081delA, c.1350-1356delinsGCA) were novel that have not been previously reported. The differentially expressed genes were mainly associated with immune-related pathways according to the Gene Ontology enrichment analysis of the RNA sequencing data. The exon 1 region of HLA-DRB1 in two patients was not transcribed, while the transcription of the region in their parents was normal.

This study emphasizes the clinical and genetic heterogeneity in patients, even in the same family with WFS1 variants. MRI evaluation of the brain should be considered when WFS1-related disorder is first diagnosed.

Lupus nephritis is a severe organ manifestation of systemic lupus erythematosus, and its pathogenesis involves complex etiology and mechanisms. Despite significant knowledge gains and extensive efforts put into understanding the development and relapsing disease activity, lupus nephritis remains a substantial cause of morbidity and mortality in lupus patients. Current therapies retain a significant unmet medical need regarding rates of complete response, preventing relapse of lupus nephritis, progression of chronic kidney disease to kidney failure, drug toxicity, and pill burden-related drug non-adherence. Connected to progression of chronic kidney disease are the associated risks for disabling or even lethal cardiovascular events, as well as chronic kidney disease-related secondary immunodeficiency and serious infections. In this regard, biomarkers are needed that can predict treatment response to specific drugs to enable personalized precision medicine. A series of clinical trials with innovative immunomodulatory drugs are ongoing and raise expectations for improvements in the management of lupus nephritis. Here, we review how new developments in pathogenesis connect with current and future perspectives for the management of lupus nephritis.

(1) Background: It is widely accepted that aberrant methylation patterns contribute to the development of systemic lupus erythematosus (SLE). Ten-eleven translocation (TET) methylcytosine dioxygenase is an essential enzyme of which there are three members, TET1, 2, and 3, involved in hydroxymethylation, a newly uncovered mechanism of active DNA methylation. The epigenomes of gene transcription are regulated by 5-hydroxymethylcytocine (5-hmC) and TETs, leading to dysregulation of the immune system in SLE. The purpose of this study was to investigate the global hydroxymethylation status in SLE peripheral blood mononuclear cells (PBMCs) and to explore the role of TETs in changing the patterns of methylation. (2) Methods: We collected PBMCs from 101 SLE patients and 100 healthy donors. TaqMan real-time polymerase chain-reaction assay was performed for the detection of 5-methylcytosine (5-mC), 5-hmC, and TET2 mRNA expression and single-nucleotide polymorphism genotyping. The methylation rates in different CpG sites of TET2 promoters were examined using next-generation sequencing-based deep bisulfite sequencing. Putative transcription factors were investigated using the UCSC Genome Browser on the Human Dec. 2013 (GRCh38/hg38) Assembly. (3) Results: 5-mC and 5-hmC were both decreased in SLE. The mRNA expression level of TET2 was notably high and found to be correlated with the levels of immunologic biomarkers that are indicative of SLE disease activity. The analysis of methylation rates in the TET2 promoter revealed that SLE patients had significantly higher and lower rates of methylation in TET2 105146072-154 and TET2 105146218-331, respectively. (4) Conclusions: TET2 may play an important role in 5-mC/5-hmC dynamics in the PBMCs of SLE patients. The epigenetic modification of TET2 promoters could contribute to the pathogenesis of SLE and the intensity of the immunologic reaction.

Coronary artery disease (CAD) is a leading cause of death in patients with systemic lupus erythematosus (SLE). Despite clinical evidence supporting an association between SLE and CAD, pleiotropy-adjusted genetic association studies are limited and focus on only a few common risk loci. Here, we identify a net positive causal estimate of SLE-associated non-HLA SNPs on CAD by traditional Mendelian randomization (MR) approaches. Pathway analysis using SNP-to-gene mapping followed by unsupervised clustering based on protein-protein interactions (PPIs) identifies biological networks composed of positive and negative causal sets of genes. In addition, we confirm the casual effects of specific SNP-to-gene modules on CAD using only SNP mapping to each PPI-defined functional gene set as instrumental variables. This PPI-based MR approach elucidates various molecular pathways with causal implications between SLE and CAD and identifies biological pathways likely causative of both pathologies, revealing known and novel therapeutic interventions for managing CAD in SLE.

IRF5 plays a crucial role in the development of lupus. Genome-wide association studies have identified several systemic lupus erythematosus (SLE) risk single-nucleotide polymorphisms (SNPs) enriched in the IRF5 locus. However, no comprehensive genome editing-based functional analysis exists to establish a direct link between these variants and altered IRF5 expression, particularly for enhancer variants. This study was undertaken to dissect the regulatory function and mechanisms of SLE IRF5 enhancer risk variants and to explore the utilization of clustered regularly interspaced short palindromic repeat interference (CRISPRi) to regulate the expression of disease risk gene to intervene in the disease.

Epigenomic profiles and expression quantitative trait locus analysis were applied to prioritize putative functional variants in the IRF5 locus. CRISPR-mediated deletion, activation, and interference were performed to investigate the genetic function of rs4728142. Allele-specific chromatin immunoprecipitation-quantitative polymerase chain reaction and allele-specific formaldehyde-assisted isolation of regulatory element-quantitative polymerase chain reaction were used to decipher the mechanism of alleles differentially regulating IRF5 expression. The CRISPRi approach was used to evaluate the intervention effect in monocytes from SLE patients.

SLE risk SNP rs4728142 was located in an enhancer region, indicating a disease-related regulatory function, and risk allele rs4728142-A was closely associated with increased IRF5 expression. We demonstrated that an rs4728142-containing region could act as an enhancer to regulate the expression of IRF5. Moreover, rs4728142 affected the binding affinity of zinc finger and BTB domain-containing protein 3 (ZBTB3), a transcription factor involved in regulation. Furthermore, in monocytes from SLE patients, CRISPR-based interference with the regulation of this enhancer attenuated the production of disease-associated cytokines.

These results demonstrate that the rs4728142-A allele increases the SLE risk by affecting ZBTB3 binding, chromatin status, and regulating IRF5 expression, establishing a biologic link between genetic variation and lupus pathogenesis.

Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored.

To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers.

We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer.

Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.

There is growing evidence for the inherited basis of susceptibility to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified non-coding ALL risk variants at the ARID5B gene locus, but their exact functional effects and the molecular mechanism linking ARID5B to B-cell ALL leukemogenesis remain largely unknown.

We performed targeted sequencing of ARID5B in germline DNA of 5008 children with ALL. Variants were evaluated for association with ALL susceptibility using 3644 patients from the UK10K cohort as non-ALL controls, under an additive model. Cis-regulatory elements in ARID5B were systematically identified using dCas9-KRAB-mediated enhancer interference system enhancer screen in ALL cells. Disruption of transcription factor binding by ARID5B variant was predicted informatically and then confirmed using chromatin immunoprecipitation and coimmunoprecipitation. ARID5B variant association with hematological traits was examined using UK Biobank dataset. All statistical tests were 2-sided.

We identified 54 common variants in ARID5B statistically significantly associated with leukemia risk, all of which were noncoding. Six cis-regulatory elements at the ARID5B locus were discovered using CRISPR-based high-throughput enhancer screening. Strikingly, the top ALL risk variant (rs7090445, P = 5.57 × 10-45) is located precisely within the strongest enhancer element, which is also distally tethered to the ARID5B promoter. The variant allele disrupts the MEF2C binding motif sequence, resulting in reduced MEF2C affinity and decreased local chromosome accessibility. MEF2C influences ARID5B expression in ALL, likely via a transcription factor complex with RUNX1. Using the UK Biobank dataset (n = 349 861), we showed that rs7090445 was also associated with lymphocyte percentage and count in the general population (P = 8.6 × 10-22 and 2.1 × 10-18, respectively).

Our results indicate that ALL risk variants in ARID5B function by modulating cis-regulatory elements at this locus.

Systemic lupus erythematosus (SLE) is a complex disease involving many interactions at the molecular level, the details of which remain unclear. Here, we demonstrated an analytical paradigm of prioritizing genes and regulatory elements based on GWAS loci at the single-cell levels. Our initial step was to apply TWMR to identify causal genes and causal methylation sites in SLE. Based on the eQTL, LD and mQTL, we calculated the correlation between these genes and methylation sites. Next, we separately used gene expression and DNAm as exposure variables and outcome variables to analyze the regulatory mechanisms. We identified two mediating modes for SLE: 1) transcription mediation model and 2) epigenetic mediation model. Further, using single-cell RNA sequencing data, we revealed the cell subclusters associated with these mechanisms. Our identification of the mechanisms of SLE in different cell populations is of great significance for understanding the heterogeneity of disease in different cell populations.

Lupus nephritis (LN) is a crucial complication of systemic lupus erythematosus (SLE). IKZF2 was identified as a lupus susceptibility locus, while its exact molecular function in LN is unknown. We aimed to explore the relationship between IKZF2 and LN based on multi-omics data. In our study, we carried out a meta-analysis of publicly available data, including not only tubulointerstitium, but also glomerulus tissue samples from LN patients and controls. Based on the common differentially expressed genes (co-DEGs) and previous researches, we selected IKZF2 for further analysis. Then, we analyzed potential molecular mechanisms of co-DEGs and IKZF2 in LN. To explore the possible targets of IKZF2, protein-protein interaction network (PPI) network and ceRNA network of IKZF2 were also constructed. Moreover, we performed immune infiltration analysis and evaluated clinical value of IKZF2. A total of 26 co-DEGs were observed in the integration of the above DEGs coming from the four sets of data, of which IKZF2 was selected for further analysis. Functional enrichment analysis from IKZF2 and related PPI network confirmed the tight relationship between IKZF2 and the immune reaction. Moreover, immune filtration analysis revealed the significant correlation between IKZF2 and naïve B cell, NK cell activation, NK cell rest and other immune cells. Receiver operating characteristic (ROC) analysis showed that the areas under the ROC curves were 0.721, 0.80, 0.682, and 0.859 for IKZF2 in four datasets, which demonstrated the clinical value of IKZF2. Our study revealed that IKZF2 may play an essential role in the molecular function and development of LN, and might be a potential biomarker for distinguishing LN patients and healthy ones.

Genome-wide association studies have identified 2p13.1 as a prominent susceptibility locus for systemic lupus erythematosus (SLE)—a complex, multisystem autoimmune disease. However, the identity of underlying causal variant (s) and molecular mechanisms for increasing disease susceptibility are poorly understood. Using meta-analysis (cases = 10,252, controls = 21,604) followed by conditional analysis, bioinformatic annotation, and eQTL and 3D-chromatin interaction analyses, we computationally prioritized potential functional variants and subsequently experimentally validated their effects. Ethnicity-specific meta-analysis revealed striking allele frequency differences between Asian and European ancestries, but with similar odds ratios. We identified 20 genome-wide significant (p < 5 × 10−8) variants, and conditional analysis pinpointed two potential functional variants, rs6705628 and rs2272165, likely to explain the association. The two SNPs are near DGUOK, mitochondrial deoxyguanosine kinase, and its associated antisense RNA DGUOK-AS1. Using luciferase reporter gene assays, we found significant cell type- and allele-specific promoter activity at rs6705628 and enhancer activity at rs2272165. This is supported by ChIP-qPCR showing allele-specific binding with three histone marks (H3K27ac, H3K4me3, and H3K4me1), RNA polymerase II (Pol II), transcriptional coactivator p300, CCCTC-binding factor (CTCF), and transcription factor ARID3A. Transcriptome data across 28 immune cell types from Asians showed both SNPs are cell-type-specific but only in B-cells. Splicing QTLs showed strong regulation of DGUOK-AS1. Genotype-specific DGOUK protein levels are supported by Western blots. Promoter capture Hi-C data revealed long-range chromatin interactions between rs2272165 and several nearby promoters, including DGUOK. Taken together, we provide mechanistic insights into how two noncoding variants underlie SLE risk at the 2p13.1 locus.

Adaptive immune responses rely on the proliferation of T lymphocytes able to recognize and eliminate pathogens. The magnitude and duration of the expansion of activated T cell clones are finely regulated to minimize immunopathology and avoid autoimmunity. In patients with rheumatic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, activated lymphocytes survive and exert effector functions for prolonged periods, defying the mechanisms that normally curb their capacities during acute and chronic infections. Here, we review the molecular mechanisms that limit the duration of immune responses in health and discuss the factors that alter such regulation in the setting of systemic lupus erythematosus and rheumatoid arthritis. We highlight defects that could contribute to the development and progression of autoimmune disease and describe how chronic inflammation can alter the regulation of activated lymphocyte survival, promoting its perpetuation. These concepts might contribute to the understanding of the mechanisms that underlie the chronicity of inflammation in the context of autoimmunity.

During the past twenty years, a wide range of studies have established the existence of epigenetic alterations, particularly DNA methylation changes, in lupus. Epigenetic changes might have different contributions in children-onset versus adult-onset lupus. DNA methylation alterations have been identified and characterized in relation to disease activity and damage, different lupus subtypes and responses to drugs. However, to date there has been no practical application of these findings in the clinical milieu. In this article, we provide a review of key studies showing the relationship between DNA methylation and the many clinical aspects related to lupus. We also propose several options, in relation to the range of methodological developments and experimental design, that could optimize these findings and make them amenable for use in clinical practice.

Despite the existence of central tolerance mechanisms, including clonal deletion and receptor editing to eliminate self-reactive B cells, moderately self-reactive cells still survive in the periphery (about 20% of peripheral B cells). These cells normally exist in a functionally silenced state called anergy; thus, anergy has been thought to contribute to tolerance by active-silencing of potentially dangerous B cells. However, a positive rationale for the existence of these anergic B cells has recently been suggested by discoveries that broadly neutralizing antibodies for HIV and influenza virus possess poly- and/or auto-reactivity. Given the conundrum of generating inherent holes in the immune repertoire, retaining weakly self-reactive BCRs on anergic B cells could allow these antibodies to serve as an effective defense against pathogens, particularly in the case of pathogens that mimic forbidden self-epitopes to evade the host immune system. Thus, anergic B cells should be brought into a silenced or activated state, depending on their contexts. Here, we review recent progress in our understanding of how the anergic B cell state is controlled in B cell-intrinsic and B cell-extrinsic ways.