This study aimed to investigate the association between the genetic burden of systemic lupus erythematosus (SLE) and the loss of tolerance to self-nuclear antigens in the preclinical stage.

We analysed genetic data from 349 Korean individuals who tested positive for autoantibodies in the preclinical stage, along with 33,596 healthy controls and 2057 patients with SLE. Genome-wide and pathway-specific polygenic risk scores (PRSs) of SLE were calculated based on 180 known non-human leukocyte antigen (non-HLA) SLE loci, HLA-DRB1 classical alleles, and predefined immune-related pathways to subsequently correlate with clinical phenotypes, particularly the presence of antinuclear antibodies (ANAs) at various titre thresholds.

Individuals with preclinical autoimmune conditions exhibited significantly higher SLE PRSs than healthy controls (P = 2.99 × 10-5), with a significantly upward trend between ANA titres and PRS (P = 1.12 × 10-3). Stratification analysis revealed that preclinical-stage individuals with PRSs exceeding the means of age- and sex-matched PRSs among patients with SLE were at a significantly higher risk of ANA development (odds ratio = 2.25; P = 8.12 × 10-3 at a dilution factor of 1:80). Pathway-specific PRS analysis identified the significant enrichment of SLE-risk effects in nine pathways, such as signalling related to reactive oxygen species production, T cell receptor, B cell receptor, and cytokines, in ANA-positive preclinical individuals (Padjusted < 0.05).

Our findings illustrate that the genetic burden of SLE may lead to a crucial transition from normal to preclinical autoimmune conditions prior to the pathogenic stage by increasing the susceptibility to and levels of ANAs.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with diverse clinical manifestations and unpredictable progression, posing significant challenges to accurate diagnosis and effective treatment. Traditional biomarkers and treatments often fail to address the disease's molecular and clinical heterogeneity. Recent advancements in CRISPR gene-editing technology and multiomics approaches offer transformative opportunities for personalized SLE care by unraveling its underlying molecular complexity and enabling precise therapeutic interventions. CRISPR technology allows targeted editing of SLE-associated genetic mutations, addressing disease drivers directly, while multiomics-including genomics, transcriptomics, and proteomics-provides insights into dysregulated immune networks, identifying biomarkers and therapeutic targets. Integrating these approaches can refine patient stratification and enhance the precision of treatments. Artificial intelligence (AI) complements these technologies by synthesizing high-dimensional data, enabling personalized treatment plans, predicting disease trajectories, and optimizing therapeutic strategies. However, the integration of CRISPR and multiomics in clinical settings raises challenges, including technical limitations, ethical concerns, and economic barriers. Emerging clinical trials and case studies demonstrate the potential of these innovations to personalize care and improve outcomes. Nonetheless, the transition from experimental research to routine clinical application requires robust regulatory frameworks and strategies to address these challenges. This review aims to explore the potential of CRISPR and multiomics technologies to revolutionize SLE diagnosis and therapy, emphasizing their integration with AI to advance personalized care. By addressing existing barriers, the review envisions a future where precision medicine transforms SLE management, paving the way for individualized, patient-centered autoimmune therapy.

Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs. Diversified types of medications have been shown effective for alleviating SLE syndromes, ranging from cytokines, antibodies, hormones, molecular inhibitors or antagonists, to cell transfusion. Drugs developed for treating other diseases may benefit SLE patients, and agents established as SLE therapeutics may be SLE-inductive. Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety. After introducing the research history of SLE and its epidemiology, we categorized primary determinants driving SLE pathogenesis by their mechanisms; combed through current knowledge on SLE diagnosis and grouped them by disease onset, activity and comorbidity; introduced the genetic, epigenetic, hormonal and environmental factors predisposing SLE; and comprehensively categorized preventive strategies and available SLE therapeutics according to their functioning mechanisms. In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management.

Noninfectious anterior uveitis shares genetic factors, including HLA-B27, with ankylosing spondylitis (AS). The aim of this study was to identify significant single nucleotide polymorphisms (SNPs) associated with noninfectious anterior uveitis in AS patients, which may help predict help predict the risk of developing this condition and provide deeper insights into its genetic basis.

A genome-wide association study (GWAS) was conducted using the genomic data of 468 AS patients, including 90 with noninfectious anterior uveitis and 378 without it, from the Taiwan Precision Medicine Initiative. This study identified relevant genes using SnpXplorer and developed a polygenic risk score (PRS) model to identify AS patients with an increased risk of noninfectious anterior uveitis. Biological pathways were analyzed via Enrichr-KG and various databases.

GWAS revealed two novel SNPs, rs1736952 and rs17354984, with p values <5 × 10 -8 , and 74 SNPs with p values <1 × 10 -4 . The associated genes were involved mainly in antigen presentation, interferon signaling, immune regulation pathways, ciliary movement, and neurodegeneration. An optimal PRS model was constructed using 19 SNPs, achieving an area under the curve (AUC) of 0.907.

Our results revealed that two novel and significant SNP loci, rs1736952 and rs17354984, are strongly associated with noninfectious anterior uveitis in patients with AS. However, their roles in uveitis and other immune disorders warrant further investigation.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder affecting multiple systems, characterized by the development of harmful autoantibodies and immune complexes that lead to damage in organs and tissues. Chinese medicine (CM) plays a role in mitigating complications, enhancing treatment effectiveness, and reducing toxicity of concurrent medications, and ensuring a safe pregnancy. However, CM mainly solves the disease comprehensively through multi-target and multi-channel regulation process, therefore, its treatment mechanism is often complicated, involving many molecular links. This review introduces the research progress of pathogenesis of SLE from the aspects of genetics, epigenetics, innate immunity and acquired immunity, and then discusses the molecular mechanism and target of single Chinese herbal medicine and prescription that are commonly used and effective in clinic to treat SLE.

Hyper-activations of monocytes/macrophages and dendritic cells (DCs) contribute to the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus (SLE). Fatty acid synthase (FASN) is essential for the de novo synthesis of long-chain fatty acids, which play a key role in controlling the activation, differentiation, and function of immune cells. However, the role of FASN in regulating the activations of monocytes/macrophages and DCs has not been studied. In this study, we investigated the involvement of the FASN in modulating the activations of macrophages and DCs, as well as the pathogenesis of SLE. Importantly, we observed a significant upregulation of FASN expression in monocytes and DCs from patients with SLE. This increase is strongly correlated with disease severity and activation status of the immune cells. Furthermore, overexpression of FASN significantly boosts the TLR4/7/9-mediated activation of macrophages and DCs, while knockdown of FASN markedly inhibits this activation. Notably, knockdown of FASN alleviates TLR7 agonist imiquimod (IMQ)-induced lupus in mice and the activation of macrophages and DCs. It makes more sense that pharmaceutical targeting of FASN by using TVB-2640 significantly alleviates IMQ-induced lupus in mice and the activation of macrophages and DCs, as well as in spontaneous lupus MRL/lpr mice. Thus, FASN contributes to the TLRs-mediated activation of macrophages and DCs, as well as the pathogenesis of SLE. More importantly, FASN inhibitor TVB-2640 is expected to be an effective drug in the treatment of SLE.

Although significant progress has been achieved in elucidating the genetic architecture of systemic lupus erythematosus (SLE), identifying genes underlying the pathogenesis has been challenging. The NZM2410-derived lupus susceptibility Sle3 locus is associated with T cell hyperactivity and activated myeloid cells. However, candidate genes associated with these phenotypes have not been identified. Here, we narrow the Sle3 locus to a smaller genomic segment (Sle3k) and show that mice carrying Sle3k and Sle1 loci developed lupus nephritis. We identify Klf13 as the primary candidate gene that is associated with genome-wide transcription changes resulting in higher levels of proinflammatory cytokines, enhanced T cell activation, and hyperresponsiveness of myeloid cells. Correspondingly, Klf13 -/- mice display repression of genes involved in mediating immune activation, including key proinflammatory cytokines/chemokines in T cells and dysregulation in cytokine signaling pathways in myeloid cells in response to toll receptor ligands. Klf13 upregulation is associated with increased production of RANTES, a key chemokine in lupus nephritis, in activated T cells and the kidneys of lupus-prone mice. In sum, our findings reveal Klf13 as a key gene in the Sle3 interval in mediating lupus pathogenesis that may have implications in the rational design of new therapies for SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs, yet its underlying mechanisms remain unclear, and precise biomarkers are lacking. In this study, we employed Mendelian randomization and HEIDI tools to comprehensively analyze large-scale Genome-Wide Association Study (GWAS) and expression Quantitative Trait Loci (eQTL) data, leading to the identification of seven novel potential functional genes associated with SLE, including BLK, ELF1, STIM1, B3GALT6, APOLD1, INPP5B, and FHL3. Subsequent investigations revealed a significant downregulation of ELF1 gene expression in CD4+ T cells of SLE patients compared to healthy controls. Moreover, within various SLE subgroups, such as those with decreased serum complement C3 levels, positive urinary protein, new-onset skin rashes, and SLE Disease Activity Index (SLEDAI) scores ≥ 5, ELF1 expression displayed a consistent decreasing trend. Notably, ROC curve analysis highlighted the diagnostic potential of ELF1 expression in SLE (AUC = 0.9493), as well as its value in assessing disease activity (AUC = 0.6852) and renal involvement (AUC = 0.7363). In conclusion, this study underscores the potential of ELF1 as a SLE biomarker for diagnosis and evaluation, offering insights into the underlying mechanisms of SLE and paving the way for future therapeutic research.

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a complex clinical course and diverse presentations. The immunopathogenesis of SLE has long intrigued physicians and researchers. Despite its extensive global prevalence, there is no specific treatment to prevent and treat SLE, and in the majority of SLE patients, the management involves controlling disease remissions and symptom reactivations or flares. SLE patients suffer from damage to different organs of the body, complicating disease management. They are predisposed to infectious diseases that could contribute to enhanced disease progression. Devising effective management strategies requires a comprehensive understanding of the effects of the disease and its influence on the immune system. SLE affects females more frequently than men. However, male SLE patients often suffer from more severe disease than females. Gender variations have also been noted in clinical manifestations in patients with SLE. In light of this, additional research is needed to understand these variations and promote the progress of gender-specific patient management and treatment strategies. This review aimed to compare the influence of gender on the clinical consequences, immunopathogenesis, and associated consequences between male and female SLE patients. An extensive literature search was conducted to collect relevant data. PubMed, MEDLINE, Embase, and Google Scholar were searched from inception to the present for articles that compared clinical outcomes and associated disorders in terms of gender among SLE patients. We also explored the immunopathogenesis, mechanisms underlying gender-based clinical effects of SLE, and infectious disease-related consequences. Additionally, we provide key updates regarding the treatment and management of SLE.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which multiple organs are damaged by the immune system. Although standard treatment options such as hydroxychloroquine (HCQ), glucocorticoids (GCs), and other immunosuppressive or immune-modulating agents can help to manage symptoms, they do not offer a cure. Hence, there is an urgent need for the development of novel drugs and therapies. In recent decades, cell therapies have been used for the treatment of SLE with encouraging results. Hematopoietic stem cell transplantation, mesenchymal stem cells, regulatory T (Treg) cell, natural killer cells, and chimeric antigen receptor T (CAR T) cells are advanced cell therapies which have been developed and evaluated in clinical trials in humans. In clinical application, each of these approaches has shown advantages and disadvantages. In addition, further studies are necessary to conclusively establish the safety and efficacy of these therapies. This review provides a summary of recent clinical trials investigating cell therapies for SLE treatment, along with a discussion on the potential of other cell-based therapies. The factors influencing the selection of common cell therapies for individual patients are also highlighted.

To investigate the association between single nucleotide polymorphism (SNP) at the rs3918188, rs1799983 and rs1007311 loci of the endothelial nitric oxide synthase (eNOS) gene and genetic susceptibility to systemic lupus erythematosus (SLE) in northeastern China. The base distribution of eNOS gene rs3918188, rs1799983 and rs1007311 in 1712 human peripheral blood samples from Northeast China was detected by SNaPshot sequencing technology. The correlation between genotype, allele and gene model of these loci of the eNOS gene and the genetic susceptibility to SLE was investigated by logistic regression analysis. The results of the differences in the frequency distribution of their gene models were visualised using R 4.3.2 software. Finally, HaploView 4.2 software was used to analyse the relationship between the haplotypes of the three loci mentioned above and the genetic susceptibility to SLE. A multifactor dimensionality reduction (MDR) analysis was used to determine the best SNP-SNP interaction model. The CC genotype and C allele at the rs3918188 locus may be a risk factor for SLE (CC vs AA: OR = 1.827, P < 0.05; C vs A: OR = 1.558, P < 0.001), and this locus increased the risk of SLE in the dominant model and the recessive model (AC + CC vs AA: OR = 1.542, P < 0.05; CC vs AA + AC: OR = 1.707, P < 0.001), while the risk of SLE was reduced in the overdominant model (AC vs AA + CC: OR = 0.628, P < 0.001). The GT genotype and T allele at locus rs1799983 may be a protective factor for SLE (GT vs GG: OR = 0.328, P < 0.001; T vs G: OR = 0.438, P < 0.001) and this locus reduced the risk of SLE in the overdominant model (GT vs GG + TT: OR = 0.385, P < 0.001). There is a strong linkage disequilibrium between the rs1007311 and rs1799983 loci of the eNOS gene. Among them, the formed haplotype AG increased the risk of SLE compared to GG. AT and GT decreased the risk of SLE compared to GG. In this study, the eNOS gene rs3918188 and rs1799983 loci were found to be associated with susceptibility to SLE. This helps to deeply explore the mechanism of eNOS gene and genetic susceptibility to SLE. It provides a certain research basis for the subsequent exploration of the molecular mechanism of these loci and SLE, as well as the early diagnosis, treatment and prognosis of SLE.

Autoimmune diseases constitute a broad, heterogenous group with many diverse and often overlapping symptoms. Even so, they are traditionally classified as either systemic, rheumatic diseases or organ-directed diseases. Several theories exist about autoimmune diseases, including defective self-recognition, altered self, molecular mimicry, bystander activation and epitope spreading. While there is no consensus about these theories, it is generally accepted that genetic, pre-disposing factors in combination with environmental factors can result in autoimmune disease. The relative contribution of genetic and environmental factors varies between diseases, as does the significance of individual contributing factors within related diseases. Among the genetic factors, molecules involved in antigen (Ag) recognition, processing, and presentation stand out (e.g., MHC I and II) together with molecules involved in immune signaling and regulation of cellular interactions (i.e., immuno-phenotypes). Also, various immuno-deficiencies have been linked to development of autoimmune diseases. Among the environmental factors, infections (e.g., viruses) have attracted most attention, but factors modulating the immune system have also been the subject of much research (e.g., sunlight and vitamin D). Multiple sclerosis currently stands out due to a very strong and proven association with Epstein-Barr virus infection, notably in cases of late infection and in cases of EBV-associated mononucleosis. Thus, a common picture is emerging that both systemic and organ-directed autoimmune diseases may appropriately be described as auto-immuno-deficiency syndromes (AIdeSs), a concept that emphasizes and integrates existing knowledge on the role of immuno-deficiencies and chronic infections with development of overlapping disease syndromes with variable frequencies of autoantibodies and/or autoreactive T cells. This review integrates and exemplifies current knowledge on the interplay of genetically determined immuno-phenotypes and chronic infections in the development of AIdeSs.

Genome-wide association studies implicate multiple loci in risk for systemic lupus erythematosus (SLE), but few contain exonic variants, rendering systematic identification of non-coding variants essential to decoding SLE genetics. We utilized SNP-seq and bioinformatic enrichment to interrogate 2180 single-nucleotide polymorphisms (SNPs) from 87 SLE risk loci for potential binding of transcription factors and related proteins from B cells. 52 SNPs that passed initial screening were tested by electrophoretic mobility shift and luciferase reporter assays. To validate the approach, we studied rs2297550 in detail, finding that the risk allele enhanced binding to the transcription factor Ikaros (encoded by IKZF1), thereby modulating expression of IKBKE. Correspondingly, primary cells from genotyped healthy donors bearing the risk allele expressed higher levels of the interferon / NF-κB regulator IKKε. Together, these findings define a set of likely functional non-coding lupus risk variants and identify a regulatory pathway involving rs2297550, Ikaros, and IKKε implicated by human genetics in risk for SLE.

Systemic lupus erythematosus (SLE) is a common autoimmune disease with a polymorphic clinical presentation involving multisystem damages with significant differences in prevalence and disease severity among different ethnic groups. Although genetic, hormonal, and environmental factors have been demonstrated to contribute a lot to SLE, the pathogenesis of SLE is still unknown. Numerous evidence revealed that gene variants within the type I interferons (IFN) signaling pathway performed the great genetic associations with autoimmune diseases including SLE. To date, through genome-wide association studies (GWAS), genetic association studies showed that more than 100 susceptibility genes have been linked to the pathogenesis of SLE, among which TYK2, STAT1, STAT4, and IRF5 are important molecules directly connected to the type I interferon signaling system. The review summarized the genetic associations and the detailed risk loci of STAT4 and IRF5 with Asian SLE patients, explored the genotype distributions associated with the main clinical manifestations of SLE, and sorted out the potential reasons for the differences in susceptibility in Asia and Europe. Moreover, the therapies targeting STAT4 and IRF5 were also evaluated in order to propose more personalized and targeted treatment plans in SLE.

Patients with rheumatic diseases frequently operate with incomplete or incorrect information while planning for and experiencing pregnancy, often due to variability in provider care and knowledge. Risk assessment at each stage of pregnancy-pre-conception, during pregnancy, and postpartum-is focused on reducing maternal and neonatal complications. This review aims to compile updated, evidence-based guidance on how to minimize risk factors contributing to adverse pregnancy outcomes (APOs). Mitigation of known causes of infertility, appropriate testing and monitoring, achieving low disease activity on pregnancy-safe disease-modifying antirheumatic drugs (DMARDs) prior to conception, controlling hypertension (a frequent comorbidity among patients with certain rheumatic diseases), and the use of appropriate adjunctive medications (such as low-dose aspirin when preeclampsia risk is high) can optimize fertility and prevent adverse maternal and neonatal outcomes.

Mitochondrial dysfunction has been increasingly recognized as a trigger for systemic lupus erythematosus (SLE). Recent bioinformatics studies have suggested Fam210b as a significant candidate for the classification and therapeutic targeting of SLE. To experimentally prove the role of Fam210b in SLE, we constructed Fam210b knockout (Fam210b-/-) mice using the CRISPR-Cas9 method. We found that approximately 15.68% of Fam210b-/- mice spontaneously developed lupus-like autoimmunity, which was characterized by skin ulcerations, splenomegaly, and an increase in anti-double-stranded DNA (anti-dsDNA) IgG antibodies and anti-nuclear antibodies(ANA). Single-cell sequencing showed that Fam210b was mainly expressed in erythroid cells. Critically, the knockout of Fam210b resulted in abnormal erythrocyte differentiation and development in the spleens of mice. Concurrently, the spleens exhibited an increased number of CD71+ erythroid cells, along with elevated levels of reactive oxygen species (ROS) in the erythrocytes. The co-culture of CD71+ erythroid cells and lymphocytes resulted in lymphocyte activation and promoted dsDNA and IgG production. In summary, Fam210b knockout leads to a low probability of lupus-like symptoms in mice through the overproduction of ROS in CD71+ erythroid cells. Thus, Fam210b reduction may serve as a novel key marker that triggers the development of SLE.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder with varied clinical courses and prognoses, not only did the patients suffer from physical impairment, but also various physical and psychiatric comorbidities. Growing evidence have suggested that mental disorders in SLE patients, can lead to various adverse consequences.

To explored the features and influencing factors of mental health in patients with SLE and clarifying the correlations between mental health and personality characteristics and perceived social support. The results would provide a basis for psychological intervention in patients with SLE.

The clinical data of 168 patients with SLE admitted at the First Affiliated Hospital of Hainan Medical University between June 2020 and June 2022 were collected. Psychological assessment and correlation analysis were conducted using the Symptom Checklist-90 (SCL-90) and Perceived Social Support Scale, and the collected data were compared with the national norms in China. The relevant factors influencing mental health were identified by statistical analysis. A general information questionnaire, the Revised Life Orientation Test, and Short-Form 36-Item Health Survey were employed to assess optimism level and quality of life (QoL), respectively.

Patients with SLE obtained higher scores for the somatization, depression, anxiety, and phobic anxiety subscales than national norms (P < 0.05). A correlation was identified between total social support and total SCL-90 score or each subscale (P < 0.05). The factors significantly affecting patients' mental health were hormone dosage and disease activity index (DAI) (P < 0.05). The average optimism score of patients with SLE was 14.36 ± 4.42, and 30 cases were in the middle and lower levels. A positive correlation was found between optimism level and QoL scores.

Patients with SLE develop psychological disorders at varying degrees, which are significantly influenced by hormone dosage and DAI. Patients' mental health should be closely monitored during clinical diagnosis and treatment and provided adequate support in establishing positive, healthy thinking and behavior patterns and improving their optimism level and QoL.

An association has been observed between systemic lupus erythematosus (SLE) and primary biliary cholangitis (PBC) in observational studies, however, the exact causal link remains unclear. We aim to evaluate the causal relationships between SLE and PBC through bidirectional Mendelian randomization (MR). Single-nucleotide polymorphisms (SNPs) were selected as instrumental variables from publicly accessible genome-wide association studies (GWAS) in European populations. The PBC and SLE GWAS data were obtained from the MRC IEU Open GWAS database, consisting of 24,510 and 14,267 samples, respectively. After a series of quality control and outlier removal, inverse variance weighted was used as the primary approach to evaluate the causal association between SLE and PBC. The horizontal pleiotropy and heterogeneity were examined by the MR-Egger intercept test and Cochran Q value, respectively. Seven SNPs were included to examine the causal effect of SLE on PBC. Genetically predicted SLE may increase the risk of PBC development, with an odds ratio (OR) of 1.324 (95% confidence interval [CI] 1.220 ∼ 1.437, P ˂ .001). Twenty SNPs were included to explore the causal effect of PBC on SLE. Genetically predicted PBC may increase the risk of SLE development, with an OR of 1.414 (95% CI 1.323 ∼ 1.511, P ˂ .001). Horizontal pleiotropy and heterogeneity were absent (P > .05) among SNPs. The robustness of our results was further enhanced by using the leave-one-out method. Our research has provided new insights into SLE and PBC, indicating bidirectional causal associations between the 2 diseases. These findings offer valuable contributions to future clinical studies.

The identification of rare genetic variants associated to Systemic Lupus Erythematosus (SLE) could also help to understand the pathogenic mechanisms at the basis of the disease. In this study we have analyzed a cohort of 200 Italian SLE patients in order to explore the rare protein-coding variants in five genes (TNFAIP3, STAT4, IL10, TRAF3IP2, and HCP5) already investigated for commons variants found associated in our previous studies. Genomic DNA of 200 SLE patients was sequenced by whole exome sequencing. The identified variants were filtered by frequency and evaluated by in silico predictions. Allelic association analysis was performed with standard Fisher's exact test. Introducing a cutoff at MAF < 0.01, a total of 19 rare variants were identified. Seven of these variants were ultra-rare (MAF < 0.001) and six were absent in the GnomAD database. For TNFAIP3 gene, the variant c.A1939C was observed in 4 SLE patients and it is located in a region enriched in phosphorylation sites and affects the predict affinity of specific kinases. In TRAF3IP2 gene, we observed 5 different rare variants, including the novel variant c.G410A, located in the region that mediates interaction with TRAF6, and therefore a possible risk factor for SLE development. In STAT4 gene, we identified 6 different rare variants. Among these, three missense variants decrease the stability of this protein. Moreover, 3 novel rare variants were detected in 3 SLE patients. In particular, c.A767T variant was predicted as damaging by six prediction tools. Concluding, we have observed that even in genes whose common variability is associated with SLE susceptibility, it is possible to identify rare variants that could have a strong effect in the disease development and could therefore allow a better understanding of the functional domain involved.

To report the prevalences of other non-thyroid autoimmune diseases and identify factors associated with their presence in ocular myasthenia gravis (OMG) subjects.

A total of 208 subjects with OMG diagnosis were included. Demographic data, clinical characteristics, the ice-pack test, the acetylcholine receptor (AChR) antibody test, electrophysiology tests (single-fiber electromyography and repetitive nerve stimulation), the presence of thymoma, generalized myasthenia gravis conversion, and the presence of other non-thyroid autoimmune diseases (defined as the presence of at least one other non-thyroid autoimmune disease) were retrospectively reviewed. Factors associated with the presence of other non-thyroid autoimmune diseases were analyzed by univariate and multivariate logistic regression.

Of the total 208 subjects, 21 (10.10%) exhibited the presence of other non-thyroid autoimmune diseases (19 subjects (9.14%) and 2 subjects (0.96%) had one and two other non-thyroid autoimmune diseases, respectively), and systemic lupus erythematosus (SLE) was diagnosed in 9 subjects, followed by Sjogren's syndrome (7 subjects), rheumatoid arthritis (6 subjects), and ankylosing spondylitis (1 subject). Therefore, the prevalences of SLE, Sjogren's syndrome, rheumatoid arthritis, and ankylosing spondylitis in OMG subjects were estimated to be 4.33% (95% confidence interval (CI): 2.29-8.02%), 3.37% (95% CI: 1.64-6.79%), 2.88% (95% CI: 1.33-6.14%), and 0.48% (95% CI: 0.08-2.67%), respectively. Positivity of the AChR antibody was the only significant factor associated with the presence of other non-thyroid autoimmune diseases (odds ratio 4.10, 95% CI: 1.11-15.21, p = 0.035).

The presence of other non-thyroid autoimmune diseases was found in approximately 10% of OMG patients, with SLE displaying the highest prevalence. We recommend screening and monitoring for other non-thyroid autoimmune diseases in OMG patients, particularly those with positivity of the AChR antibody.

Waardenburg syndrome type 2 (WS2) has been reported to be a rare hereditary disorder, which is distinguished by vivid blue eyes, varying degrees of hearing impairment, and abnormal pigment deposition in the skin and hair. Variants in the sex-determining region Y-box containing gene 10 (SOXl0) gene may cause congenital deafness and have been demonstrated to be important during the development of WS2.

Complete clinical data of the proband and her family members (her parents and 2 sisters) was collected and physical examinations were performed in the hospital. The laboratory examination including hemoglobin, Coomb's test, urine protein, ENA, autoimmune hepatitis-related autoantibodies and ultrasonography were all conducted. We obtained the peripheral blood samples from all the participants and performed whole exome sequencing and sanger sequencing validation.

The present study identified a family of 5 members, and only the proband exhibited typical WS2. Beyond the characteristics of WS2, the proband also manifested absence of puberty. The proband and her younger sister manifested systemic lupus erythematosus (SLE). Whole exome sequencing revealed a de novo variant in the SOX10 gene. The variant c.175 C > T was located in exon 2 of the SOX10 gene, which is anticipated to result in early termination of protein translation.

The present study is the first to report a case of both WS2 and SLE, and the present findings may provide a new insight into WS2.

This study aimed to develop a predictive model using polygenic risk score (PRS) to forecast renal outcomes for adult systemic lupus erythematosus (SLE) in a Taiwanese population.

Patients with SLE (n=2782) and matched non-SLE controls (n=11 128) were genotyped using Genome-Wide TWB 2.0 single-nucleotide polymorphism (SNP) array. PRS models (C+T, LDpred2, Lassosum, PRSice-2, PRS-continuous shrinkage (CS)) were constructed for predicting SLE susceptibility. Logistic regression was assessed for C+T-based PRS association with renal involvement in patients with SLE.

In the training set, C+T-based SLE-PRS, only incorporating 27 SNPs, outperformed other models with area under the curve (AUC) values of 0.629, surpassing Lassosum (AUC=0.621), PRSice-2 (AUC=0.615), LDpred2 (AUC=0.609) and PRS-CS (AUC=0.602). Additionally, C+T-based SLE-PRS demonstrated consistent predictive capacity in the testing set (AUC=0.620). Individuals in the highest quartile exhibited earlier SLE onset (39.06 vs 44.22 years, p<0.01), higher Systemic Lupus Erythematosus Disease Activity Index scores (3.00 vs 2.37, p=0.04), elevated risks of renal involvement within the first year of SLE diagnosis, including WHO class III-IV lupus nephritis (OR 2.36, 95% CI 1.47 to 3.80, p<0.01), estimated glomerular filtration rate <60 mL/min/1.73m2 (OR 1.49, 95% CI 1.18 to 1.89, p<0.01) and urine protein-to-creatinine ratio >150 mg/day (OR 2.07, 95% CI 1.49 to 2.89, p<0.01), along with increased seropositivity risks, compared with those in the lowest quartile. Furthermore, among patients with SLE with onset before 50 years, the highest PRS quartile was significantly associated with more serious renal diseases within the first year of SLE diagnosis.

PRS of SLE is associated with earlier onset, renal involvement within the first year of SLE diagnosis and seropositivity in Taiwanese patients. Integrating PRS with clinical decision-making may enhance lupus nephritis screening and early treatment to improve renal outcomes in patients with SLE.

Genome-wide association studies implicate multiple loci in risk for systemic lupus erythematosus (SLE), but few contain exonic variants, rendering systematic identification of non-coding variants essential to decoding SLE genetics. We utilized SNP-seq and bioinformatic enrichment to interrogate 2180 single-nucleotide polymorphisms (SNPs) from 87 SLE risk loci for potential binding of transcription factors and related proteins from B cells. 52 SNPs that passed initial screening were tested by electrophoretic mobility shift and luciferase reporter assays. To validate the approach, we studied rs2297550 in detail, finding that the risk allele enhanced binding to the transcription factor Ikaros (IKZF1), thereby modulating expression of IKBKE. Correspondingly, primary cells from genotyped healthy donors bearing the risk allele expressed higher levels of the interferon / NF-κB regulator IKKϵ. Together, these findings define a set of likely functional non-coding lupus risk variants and identify a new regulatory pathway involving rs2297550, Ikaros, and IKKϵ implicated by human genetics in risk for SLE.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.

Early-onset systemic lupus erythematosus presents with a more severe disease and is associated with a greater genetic burden, especially in patients from Black, Asian or Hispanic ancestries. Next-generation sequencing techniques, notably whole exome sequencing, have been extensively used in genomic interrogation studies to identify causal disease variants that are increasingly implicated in the development of autoimmunity. This Review discusses the known casual variants of polygenic and monogenic systemic lupus erythematosus and its implications under certain genetic disparities while suggesting an age-based sequencing strategy to aid in clinical diagnostics and patient management for improved patient care.

Lupus nephritis is an important manifestation of systemic lupus erythematosus, which leads to chronic kidney disease, kidney failure, and can result in mortality. About 35%-60% of children with systemic lupus erythematosus develop kidney involvement. Over the past few decades, the outcome of patients with lupus nephritis has improved significantly with advances in immunosuppressive therapies and clinical management. Nonetheless, there is a paucity of high-level evidence to guide the management of childhood-onset lupus nephritis, because of the relatively small number of patients at each centre and also because children and adolescents are often excluded from clinical trials. Children and adults differ in more ways than just size, and there are remarkable differences between childhood- and adult-onset lupus nephritis in terms of disease severity, treatment efficacy, tolerance to medications and most importantly, psychosocial perspective. In this article, we review the 'art and science' of managing childhood-onset lupus nephritis, which has evolved in recent years, and highlight special considerations in this specific patient population.

This study investigated the impacts of CCR5 promoter region polymorphisms on the development of systemic lupus erythematosus (SLE) by comparing CCR5 genotypes and haplotypes from SLE patients with ethnically matched controls. A total of 382 SLE patients (289 European-derived and 93 African-derived) and 375 controls (243 European-derived and 132 African-derived) were genotyped for the CCR2-64I G > A (rs1799864), CCR5-59353 C > T (rs1799988), CCR5-59356 C > T (rs41469351), CCR5-59402 A > G (rs1800023) and CCR5-59653 C > T (rs1800024) polymorphisms through polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Previous data from CCR5Δ32 analysis was included in the study to infer the CCR5 haplotypes and as a possible confounding factor in the binary logistic regression. European-derived patients showed a higher frequency of CCR5 wild-type genotype (conversely, a reduced frequency of Δ32 allele) and a reduced frequency of the HHG*2 haplotype compared to controls; both factors significantly affecting disease risk [p = .003 (OR 3.5, 95%CI 1.6-7.5) and 2.0% vs. 7.2% (residual p = 2.9E - 5), respectively]. Additionally, the HHA/HHB, HHC and HHG*2 haplotype frequencies differed between African-derived patients and controls [10% vs. 20.5% (residual p = .003), 29.4% vs. 17.4% (residual p = .003) and 3.9% vs. 0.8% (residual p = .023), respectively]. Considering the clinical manifestations of the disease, the CCR5Δ32 presence was confirmed as a susceptibility factor to class IV nephritis in the African-derived group and when all patients were grouped for comparison [pcorrected  = .012 (OR 3.0; 95%CI 3.0-333.3) and pcorrected  = .0006 (OR 6.8; 95%CI 1.9-24.8), respectively]. In conclusion, this study indicates that CCR5 promoter polymorphisms are important disease modifiers in SLE. Present data reinforces the CCR5Δ32 polymorphism as a protective factor for the development of the disease in European-derived patients and as a susceptibility factor for class IV nephritis in African-derived patients. Furthermore, we also described a reduced frequency of HHA/HHB and an increased frequency of HHC and HHG*2 haplotypes in African-derived patients, which could modify the CCR5 protein expression in specific cell subsets.

Insights into the immunopathogenesis of systemic lupus erythematosus (SLE) help to understand the complex disease patterns and to develop new treatment strategies. The disease manifestations essentially result from autoantibodies, immune complexes and cytokines. Particularly the propensity towards developing various autoantibodies is central to the disease itself; autoantibody specificities lead to highly variable organ manifestations. This review article delineates the clinically relevant state of knowledge on SLE pathogenesis, with the goal to establish a model useful for clinical practice, which also helps to classify the novel therapeutic approaches.

With the development of sequencing technologies, there is increasing evidence that long noncoding RNAs (lncRNAs) are involved in systemic lupus erythematosus (SLE). The level of NR_103776.1 expression in SLE and its clinical associations are still not well defined.

To identify differentially expressed lncRNAs and explore their functional roles in SLE.

Transcriptome sequencing was used to screen differentially expressed lncRNAs and mRNAs. Expression validation of clinical samples was performed by QRT-PCR. Bioinformatics was used to analyze its prognostic value and potential function.

Of the 231 significantly differentially expressed lncRNAs, NR_103776.1 could be used to distinguish not only SLE patients and rheumatoid arthritis patients but also active SLE patients, stable SLE patients, and healthy controls. NR_103776.1 was significantly and negatively correlated with inflammatory indexes (CRP and ESR). NR_103776.1 dysregulation might contribute to the metabolism of RNA and proteins in SLE patients.

This study not only provided a transcriptome profile of lncRNAs aberrantly expressed in individual nucleated cells of SLE patients but also suggested NR_103776.1 as a novel potential diagnostic biomarker.

Relationship between neuropeptide Y (NPY) serum levels, NPY genetic mutation with systemic lupus erythematosus (SLE) pathogenesis is yet to be clarified, and role of NPY in development of SLE needs elucidation.

This study included 460 SLE patients, 472 non-SLE cases, 500 healthy volunteers. Serum NPY, matrix metalloproteinase-1 (MMP-1) and MMP-8 levels were tested by ELISA. Genotyping 7 NPY single nucleotides polymorphisms (SNPs) (rs5573, rs5574, rs16129, rs16138, rs16140, rs16147, rs16478) was obtained by Kompetitive Allele-Specific PCR (KASP) method. Pristane-induced lupus mice were treated with NPY-Y1 receptor antagonist, and histological analysis, serological changes of the mice were evaluated.

NPY serum concentrations were significantly increased in SLE patients when compared to that in healthy volunteers, non-SLE cases. Rs5573 G allele, rs16129 T allele, rs16147 G allele frequencies were significantly different between SLE cases and healthy controls. Rs5574 TT + TC genotypes were related to levels of IgG, C3, C4 and erythrocyte sedimentation rate, and rs16138 GG + GC genotypes correlated with SLE cases with anti-double-stranded deoxyribonucleic acid antibody (anti-dsDNA) (+). Serum MMP-1, MMP-8 concentrations were higher in SLE patients, and NPY levels were significantly related to MMP-1, MMP-8 levels. After treatment of lupus mice with NPY-Y1 receptor antagonist, damage of liver, spleen and kidney was alleviated, production of autoantibodies (anti-nuclear antibody (ANA), total IgG, anti-dsDNA) and MMP-1, MMP-8 was down-regulated, and differentiation of CD3+, CD8+ T cells, B cells, monocytes, macrophages, T helper 1 (Th1), Th2, Th17 cells was reversed.

NPY may be a biomarker for lupus, which may promote occurrence and development of lupus.

Systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) share clinical as well as pathogenic similarities. Although previous studies suggest various abnormalities in different immune cell compartments, dedicated cell-type specific transcriptomic signatures are often masked by patient heterogeneity. Here, we performed transcriptional profiling of isolated CD4, CD8, CD16 and CD19 lymphocytes from pSS and SLE patients upon T cell stimulation, in addition to a steady-state condition directly after blood drawing, in total comprising 581 sequencing samples. T cell stimulation, which induced a pronounced inflammatory response in all four cell types, gave rise to substantial re-modulation of lymphocyte subsets in the two autoimmune diseases compared to healthy controls, far exceeding the transcriptomic differences detected at steady-state. In particular, we detected cell-type and disease-specific down-regulation of a range of pro-inflammatory cytokine and chemokine pathways. Such differences between SLE and pSS patients are instrumental for selective immune targeting by future therapies.

Previous studies have demonstrated an association between sex hormone-related traits and systemic lupus erythematosus (SLE). However, because of the difficulties in determining sequential temporality, the causal association remains elusive. In this study, we used two-sample Mendelian randomization (MR) to explore the genetic causal associations between sex hormone-related traits and SLE.

We used a two-sample MR to explore the causal association between sex hormone-related traits and SLE. The summarized data for sex hormone-related traits (including testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), and bioavailable testosterone (BT)) originated from large genome-wide association studies (GWASs) of European descent. Aggregated data for SLE were derived from the FinnGen consortium (835 cases and 300,162 controls). Random-effects inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, weighted mode, and fixed-effects IVW methods were used for the MR analysis. Random-effects IVW was the primary method used to analyze the genetic causal association between sex hormone-related traits and SLE. Heterogeneity of the MR results was detected using the IVW Cochran's Q estimates. The pleiotropy of MR results was detected using MR-Egger regression and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. Finally, leave-one-out analysis was performed to determine whether MR results were affected by a single single-nucleotide polymorphism (SNP).

Random-effects IVW as the primary method showed that testosterone (odds ratio (OR), 0.87; 95% confidence interval (CI), 0.41-1.82; P = 0.705), E2 (OR, 0.95; 95% CI, 0.73-1.23; P = 0.693), SHBG (OR, 1.25; 95% CI, 0.74-2.13; P = 0.400), and BT (OR, 0.99; 95% CI, 0.67-1.47; P = 0.959) had no potential causal association with SLE. The MR-Egger, weighted median, simple mode, weighted mode, and fixed-effects IVW methods all indicated consistent results. The results of the MR-Egger regression showed that there was no pleiotropy in our MR analysis (P > 0.05). The IVW Cochran's Q estimates showed that the MR analysis results of E2, SHBG, and BT on SLE had no heterogeneity (P > 0.05), but testosterone and SLE had heterogeneity (P < 0.05). The leave-one-out analysis confirmed that a single SNP did not affect the MR results.

Our MR analysis demonstrated that genetically predicted testosterone, E2, SHBG, and BT levels were not associated with SLE risk, but the roles of other non-genetic pathways cannot be ruled out. Key Points • This is the first MR study to explore the causal association of sex hormone-related traits with SLE. • No evidence to support causal associations between sex hormone-related traits and SLE. • Our MR analysis may provide novel insights into the causal association between sex hormone-related traits and SLE risk.

Multiple reports on the co-existence of autoimmune diseases and myasthenia gravis (MG) have raised considerable concern. Therefore, we reviewed autoimmune diseases in MG to explore their clinical presentations and determine whether the presence of autoimmune diseases affects the disease severity and treatment strategies for MG. We reviewed all the major immune-mediated coexisting autoimmune conditions associated with MG. PubMed, Embase and Web of Science were searched for relevant studies from their inception to January 2023. There is a higher frequency of concomitant autoimmune diseases in patients with MG than in the general population with a marked risk in women. Most autoimmune comorbidities are linked to AChR-MG; however, there are few reports of MuSK-MG. Thyroid disorders, systemic lupus erythematosus, and vitiligo are the most common system autoimmune diseases associated with MG. In addition, MG can coexist with neurological autoimmune diseases, such as neuromyelitis optica (NMO), inflammatory myopathy (IM), multiple sclerosis (MS), and autoimmune encephalitis (AE), with NMO being the most common. Autoimmune diseases appear to develop more often in early-onset MG (EOMG). MS coexists more commonly with EOMG, while IM coexists with LOMG. In addition, MG complicated by autoimmune diseases tends to have mild clinical manifestations, and the coexistence of autoimmune diseases does not influence the clinical course of MG. The clinical course of neurological autoimmune diseases is typically severe. Autoimmune diseases occur most often after MG or as a combined abnormality; therefore, timely thymectomy followed by immunotherapy could be effective. In addition, thymoma-associated AChR MG is associated with an increased risk of AE and IM, whereas NMO and MS are associated with thymic hyperplasia. The co-occurrence of MG and autoimmune diseases could be attributed to similar immunological mechanisms with different targets and common genetic factor predisposition. This review provides evidence of the association between MG and several comorbid autoimmune diseases.

A 30-year-old female presented to their local emergency department with an active, unprovoked generalized tonic-clonic seizure in progress. Past medical and family history of the patient did not include inflammatory or autoimmune conditions nor epilepsy or seizure. The patient's toxicology screen was negative, along with neurological and infectious differentials assessed for rule-outs. This case report includes updated guidelines for the diagnosis and treatment of neuropsychiatric systemic lupus erythematosus for advanced practice providers.

Atherosclerosis and its main consequence, cardiovascular disease (CVD) are nowadays regarded as chronic inflammatory disease conditions, and CVD is the main cause of death in the world. Other examples of chronic inflammation are rheumatic and other autoimmune conditions, but also diabetes, obesity, and even osteoarthritis among others. In addition, infectious diseases can have traits in common with these conditions. Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, where atherosclerosis is increased and the risk of CVD is very high. This is a clinical problem but could also shed light on the role of the immune system in atherosclerosis and CVD. Underlying mechanisms are of major interest and these are only partially known. Phosphorylcholine (PC) is a small lipid-related antigen, which is both a danger associated molecular pattern (DAMP), and a pathogen associated molecular pattern (PAMP). Antibodies against PC are ubiquitous and 5-10% of circulating IgM is IgM anti-PC. Anti-PC, especially IgM and IgG1 anti-PC, has been associated with protection in the chronic inflammatory conditions mentioned above, and develops during the first years of life, while being present at very low levels at birth. Animal experiments with immunization to raise anti-PC ameliorate atherosclerosis and other chronic inflammatory conditions. Potential mechanisms include anti-inflammatory, immune modulatory, clearance of dead cells and protection against infectious agents. An intriguing possibility is to raise anti-PC levels through immunization, to prevent and/or ameliorate chronic inflammation.

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that attacks various organ systems with a variety of clinical implications, ranging from mild skin and mucosal manifestations to severe central nervous system manifestations and death. Cases of SLE have been documented nearly two centuries ago when scholars used the terms 'erythema centrifugum' and 'seborrhea congestiva' to describe the discoid skin lesions and the butterfly or malar rash in SLE. Since then, knowledge about this disease has developed rapidly, especially knowledge related to the underlying pathogenesis of SLE. To date, it is known that immune system dysregulation, supported by genetic and environmental predisposition, can trigger the occurrence of SLE in a group of susceptible individuals. Various inflammatory mediators, cytokines and chemokines, as well as intra- and intercellular signaling pathways, are involved in the pathogenesis of SLE. In this review, we will discuss the molecular and cellular aspects of SLE pathogenesis, with a focus on how the immune system, genetics and the environment interact and trigger the various clinical manifestations of SLE.