Emerging strategies for treating autoimmune disease with genetically modified dendritic cells.

Gene editing of living cells has become a crucial tool in medical research, enabling scientists to address fundamental biological questions and develop novel strategies for disease treatment. This technology has particularly revolutionized adoptive transfer cell therapy products, leading to significant advancements in tumor treatment and offering promising outcomes in managing transplant rejection, autoimmune disorders, and inflammatory diseases. While recent clinical trials have demonstrated the safety of tolerogenic dendritic cell (TolDC) immunotherapy, concerns remain regarding its effectiveness. This review aims to discuss the application of gene editing techniques to enhance the tolerance function of dendritic cells (DCs), with a particular focus on preclinical strategies that are currently being investigated to optimize the tolerogenic phenotype and function of DCs. We explore potential approaches for in vitro generation of TolDCs and provide an overview of emerging strategies for modifying DCs. Additionally, we highlight the primary challenges hindering the clinical adoption of TolDC therapeutics and propose future research directions in this field.

One gene to rule them all - clinical perspectives of a potent suppressor of cytokine signaling - SOCS1.

The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.

Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization.

As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC.

Genetic association and causal relationship between multiple modifiable risk factors and autoimmune liver disease: a two-sample mendelian randomization study.

BACKGROUND: The intricate etiology of autoimmune liver disease (AILD) involves genetic, environmental, and other factors that yet to be completely elucidated. This study comprehensively assessed the causal association between genetically predicted modifiable risk factors and AILD by employing Mendelian randomization. METHODS: Genetic variants associated with 29 exposure factors were obtained from genome-wide association studies (GWAS). Genetic association data with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) were also obtained from publicly available GWAS. Univariate and multivariate Mendelian randomization analyses were performed to identify potential risk factors for AILD. RESULTS: Genetically predicted rheumatoid arthritis (RA) (OR = 1.620, 95%CI 1.423-1.843, P = 2.506 × 10- 13) was significantly associated with an increased risk of AIH. Genetically predicted smoking initiation (OR = 1.637, 95%CI 1.055-2.540, P = 0.028), lower coffee intake (OR = 0.359, 95%CI 0.131-0.985, P = 0.047), cholelithiasis (OR = 1.134, 95%CI 1.023-1.257, P = 0.017) and higher C-reactive protein (CRP) (OR = 1.397, 95%CI 1.094-1.784, P = 0.007) were suggestively associated with an increased risk of AIH. Genetically predicted inflammatory bowel disease (IBD) (OR = 1.212, 95%CI 1.127-1.303, P = 2.015 × 10- 7) and RA (OR = 1.417, 95%CI 1.193-1.683, P = 7.193 × 10- 5) were significantly associated with increased risk of PBC. Genetically predicted smoking initiation (OR = 1.167, 95%CI 1.005-1.355, P = 0.043), systemic lupus erythematosus (SLE) (OR = 1.086, 95%CI 1.017-1.160, P = 0.014) and higher CRP (OR = 1.199, 95%CI 1.019-1.410, P = 0.028) were suggestively associated with an increased risk of PBC. Higher vitamin D3 (OR = 0.741, 95%CI 0.560-0.980, P = 0.036) and calcium (OR = 0.834, 95%CI 0.699-0.995, P = 0.044) levels were suggestive protective factors for PBC. Genetically predicted smoking initiation (OR = 0.630, 95%CI 0.462-0.860, P = 0.004) was suggestively associated with a decreased risk of PSC. Genetically predicted IBD (OR = 1.252, 95%CI 1.164-1.346, P = 1.394 × 10- 9), RA (OR = 1.543, 95%CI 1.279-1.861, P = 5.728 × 10- 6) and lower glycosylated hemoglobin (HbA1c) (OR = 0.268, 95%CI 0.141-0.510, P = 6.172 × 10- 5) were positively associated with an increased risk of PSC. CONCLUSIONS: Evidence on the causal relationship between 29 genetically predicted modifiable risk factors and the risk of AIH, PBC, and PSC is provided by this study. These findings provide fresh perspectives on the management and prevention strategies for AILD.

Unlocking the genetic tapestry of autoimmune diseases: Unveiling common genes across multiple conditions.

OBJECTIVES: This study aimed to unravel the complexities of autoimmune diseases by conducting a comprehensive analysis of gene expression data across 10 conditions, including systemic lupus erythematosus (SLE), psoriasis, Sjögren's syndrome, sclerosis, immune-associated diseases, osteoarthritis, cystic fibrosis, inflammatory bowel disease (IBD), type 1 diabetes, and Guillain-Barré syndrome. METHODS: Gene expression profiles were rigorously examined to identify both upregulated and downregulated genes specific to each autoimmune disease. The study employed visual representation techniques such as heatmaps, volcano plots, and contour-MA plots to provide an intuitive understanding of the complex gene expression patterns in these conditions. RESULTS: Distinct gene expression profiles for each autoimmune condition were uncovered, with psoriasis and osteoarthritis standing out due to a multitude of both upregulated and downregulated genes, indicating intricate molecular interplays in these disorders. Notably, common upregulated and downregulated genes were identified across various autoimmune conditions, with genes like SELENBP1, MMP9, BNC1, and COL1A1 emerging as pivotal players. CONCLUSION: This research contributes valuable insights into the molecular signatures of autoimmune diseases, highlighting the unique gene expression patterns characterizing each condition. The identification of common genes shared among different autoimmune conditions, and their potential role in mitigating the risk of rare diseases in patients with more prevalent conditions, underscores the growing significance of genetics in healthcare and the promising future of personalized medicine.

Causal association between autoimmune liver disease and Sjögren's syndrome: A Mendelian randomization study.

BACKGROUND: Observational studies have found an association between autoimmune liver disease (AILD) and Sjögren's syndrome (SS). However, the causal relationship between the two remains unknown. Clinical guidelines indicate that the coexistence of AILD with other autoimmune diseases may impact prognosis and quality of life; hence, early recognition and management of extrahepatic autoimmune diseases is particularly crucial. Against this backdrop, this study aimed to utilize Mendelian randomization (MR) methods to investigate the potential causal relationship between AILD and SS. METHODS: We extracted summary statistics on AILD and SS from publicly available genome-wide association studies (GWAS) databases to identify appropriate instrumental variables (IVs). The inverse-variance weighted (IVW) method was utilized as the primary approach, with the weighted median (WM) method and MR-Egger method employed as supplementary methods to evaluate the potential causal relationship between the two conditions. Sensitivity analyses, including Cochran's Q test, MR-polynomial residuals and outliers (MR-PRESSO), MR-Egger intercept test, and the leave-one-out test, were performed to assess the stability of the results. RESULTS: The MR study results indicate a significant causal relationship between PBC and PSC with the risk of SS in the European population (IVW: odds ratio [OR] = 1.155, 95% confidence interval [CI]: 1.092-1.222, p < .001; IVW: OR = 1.162, 95% CI: 1.051-1.284, p = .003). A series of sensitivity analyses have confirmed the reliability of the results. CONCLUSIONS: Our study indicates that the presence of both PBC and PSC increases the susceptibility to SS. However, no reliable causal relationship was found between SS and the risk of PBC or PSC. These findings contribute to elucidating the potential pathogenic mechanisms of the disease and are of significant importance for the management of patients with PBC and PSC.

Shared genetic architecture between autoimmune disorders and B-cell acute lymphoblastic leukemia: insights from large-scale genome-wide cross-trait analysis.

BACKGROUND: To study the shared genetic structure between autoimmune diseases and B-cell acute lymphoblastic leukemia (B-ALL) and identify the shared risk loci and genes and genetic mechanisms involved. METHODS: Based on large-scale genome-wide association study (GWAS) summary-level data sets, we observed genetic overlaps between autoimmune diseases and B-ALL, and cross-trait pleiotropic analysis was performed to detect shared pleiotropic loci and genes. A series of functional annotation and tissue-specific analysis were performed to determine the influence of pleiotropic genes. The heritability enrichment analysis was used to detect crucial immune cells and tissues. Finally, bidirectional Mendelian randomization (MR) methods were utilized to investigate the casual associations. RESULTS: Our research highlighted shared genetic mechanisms between seven autoimmune disorders and B-ALL. A total of 73 pleiotropic loci were identified at the genome-wide significance level (P < 5 × 10-8), 16 of which had strong evidence of colocalization. We demonstrated that several loci have been previously reported (e.g., 17q21) and discovered some novel loci (e.g., 10p12, 5p13). Further gene-level identified 194 unique pleiotropic genes, for example IKZF1, GATA3, IKZF3, GSDMB, and ORMDL3. Pathway analysis determined the key role of cellular response to cytokine stimulus, B cell activation, and JAK-STAT signaling pathways. SNP-level and gene-level tissue enrichment suggested that crucial role pleiotropic mechanisms involved in the spleen, whole blood, and EBV-transformed lymphocytes. Also, hyprcoloc and stratified LD score regression analyses revealed that B cells at different developmental stages may be involved in mechanisms shared between two different diseases. Finally, two-sample MR analysis determined causal effects of asthma and rheumatoid arthritis on B-ALL. CONCLUSIONS: Our research proved shared genetic architecture between autoimmune disorders and B-ALL and shed light on the potential mechanism that might involve in.

LncRNAs involvement in pathogenesis of immune-related disease via regulation of T regulatory cells, an updated review.

The pathophysiology of several illnesses, including cancer and autoimmune diseasesdepends on human regulatory T cells (Tregs), and abnormalities in these cells may function as triggers for these conditions. Cancer and autoimmune, and gynecological diseases are associated with the differentiation of the proinflammatory T cell subset TH17 and its balance with the production of Treg. Recently, long non-coding RNAs (lncRNAs) have become important regulatory molecules in a wide range of illnesses. During epigenetic regulation, they can control the expression of important genes at several levels by affecting transcription, post-transcriptional actions, translation, and protein modification. They might connect with different molecules, such as proteins, DNA and RNA, and their structural composition is intricate. Because lncRNAs regulatebiological processes, including cell division, death, and growth, they are linked to severaldiseases. A notable instance of this is the lncRNA NEAT1, which has been the subject of several investigations to ascertain its function in immune cell development. In the context of immune cell development, several additional lncRNAs have been connected to Treg cell differentiation. In this work, we summarize current findings about the diverse functions of lncRNAs in Treg cell differentiation and control of the Th17/Treg homeostasis in autoimmune disorders, cancers, as well as several gynecological diseases where Tregs are key players.

Autoimmune diseases and their genetic link to bronchiectasis: insights from a genetic correlation and Mendelian randomization study.

Background: Previous studies have demonstrated that autoimmune diseases are closely associated with bronchiectasis (BE). However, the causal effects between autoimmune diseases and BE remain elusive. Methods: All summary-level data were obtained from large-scale Genome-Wide Association Studies (GWAS). The univariate Mendelian randomization (UVMR) was utilized to investigate the genetic causal correlation (rg) of 12 autoimmune diseases and bronchiectasis, The Multivariable Mendelian Randomization (MVMR) method was used to explore the effects of the confounding factors. Further investigation was conducted to identify potential intermediate factors using mediation analysis. Finally, the linkage disequilibrium score regression (LDSC) method was used to identify genetic correlations among complex traits. A series of sensitivity analyses was performed to validate the robustness of the results. Results: The LDSC analysis revealed significant genetic correlations between BE and Crohn's disease (CD) (rg = 0.220, P = 0.037), rheumatoid arthritis (RA) (rg = 0.210, P = 0.021), and ulcerative colitis (UC) (rg = 0.247, P = 0.023). However, no genetic correlation was found with other autoimmune diseases (P > 0.05). The results of the primary IVW analysis suggested that for every SD increase in RA, there was a 10.3% increase in the incidence of BE (odds ratio [OR] = 1.103, 95% confidence interval [CI] 1.055-1.154, P = 1.75×10-5, FDR = 5.25×10-5). Furthermore, for every standard deviation (SD) increase in celiac disease (CeD), the incidence of BE reduced by 5.1% (OR = 0.949, 95% CI 0.902-0.999, P = 0.044, FDR = 0.044). We also observed suggestive evidence corresponding to a 3% increase in BE incidence with T1DM (OR = 1.033, 95% CI 1.001-1.066, P = 0.042, FDR = 0.063). Furthermore, MVMR analysis showed that RA was an independent risk factor for BE, whereas mediator MR analysis did not identify any mediating factors. The sensitivity analyses corroborated the robustness of these findings. Conclusion: LDSC analysis revealed significant genetic correlations between several autoimmune diseases and BE, and further MVMR analysis showed that RA is an independent risk factor for BE.

Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis.

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.

The casual relationship between autoimmune diseases and multiple myeloma: a Mendelian randomization study.

Observational studies showed possible associations between systemic lupus erythematosus and multiple myeloma. However, whether there is a casual relationship between different types of autoimmune diseases (type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, primary sclerosing cholangitis, primary biliary cirrhosis, and juvenile idiopathic arthritis) and multiple myeloma (MM) is not well known. We performed a two-sample Mendelian randomization (MR) study to estimate the casual relationship. Summary-level data of autoimmune diseases were gained from published genome-wide association studies while data of MM was obtained from UKBiobank. The Inverse-Variance Weighted (IVW) method was used as the primary analysis method to interpret the study results, with MR-Egger and weighted median as complementary methods of analysis. There is causal relationship between primary sclerosing cholangitis [OR = 1.00015, 95% CI 1.000048-1.000254, P = 0.004] and MM. Nevertheless, no similar causal relationship was found between the remaining seven autoimmune diseases and MM. Considering the important role of age at recruitment and body mass index (BMI) in MM, we excluded these relevant instrument variables, and similar results were obtained. The accuracy and robustness of these findings were confirmed by sensitivity tests. Overall, MR analysis suggests that genetic liability to primary sclerosing cholangitis could be causally related to the increasing risk of MM. This finding may serve as a guide for clinical attention to patients with autoimmune diseases and their early screening for MM.

Large-scale genome-wide association studies reveal the genetic causal etiology between air pollutants and autoimmune diseases.

BACKGROUND: Epidemiological evidence links a close correlation between long-term exposure to air pollutants and autoimmune diseases, while the causality remained unknown. METHODS: Two-sample Mendelian randomization (TSMR) was used to investigate the role of PM10, PM2.5, NO2, and NOX (N = 423,796-456,380) in 15 autoimmune diseases (N = 14,890-314,995) using data from large European GWASs including UKB, FINNGEN, IMSGC, and IPSCSG. Multivariable Mendelian randomization (MVMR) was conducted to investigate the direct effect of each air pollutant and the mediating role of common factors, including body mass index (BMI), alcohol consumption, smoking status, and household income. Transcriptome-wide association studies (TWAS), two-step MR, and colocalization analyses were performed to explore underlying mechanisms between air pollution and autoimmune diseases. RESULTS: In TSMR, after correction of multiple testing, hypothyroidism was causally associated with higher exposure to NO2 [odds ratio (OR): 1.37, p = 9.08 × 10-4] and NOX [OR: 1.34, p = 2.86 × 10-3], ulcerative colitis (UC) was causally associated with higher exposure to NOX [OR: 2.24, p = 1.23 × 10-2] and PM2.5 [OR: 2.60, p = 5.96 × 10-3], rheumatoid arthritis was causally associated with higher exposure to NOX [OR: 1.72, p = 1.50 × 10-2], systemic lupus erythematosus was causally associated with higher exposure to NOX [OR: 4.92, p = 6.89 × 10-3], celiac disease was causally associated with lower exposure to NOX [OR: 0.14, p = 6.74 × 10-4] and PM2.5 [OR: 0.17, p = 3.18 × 10-3]. The risky effects of PM2.5 on UC remained significant in MVMR analyses after adjusting for other air pollutants. MVMR revealed several common mediators between air pollutants and autoimmune diseases. Transcriptional analysis identified specific gene transcripts and pathways interconnecting air pollutants and autoimmune diseases. Two-step MR revealed that POR, HSPA1B, and BRD2 might mediate from air pollutants to autoimmune diseases. POR pQTL (rs59882870, PPH4=1.00) strongly colocalized with autoimmune diseases. CONCLUSION: This research underscores the necessity of rigorous air pollutant surveillance within public health studies to curb the prevalence of autoimmune diseases.

Autoimmune cytopenia and Kabuki syndrome in paediatrics: Insights in 11 patients.

Kabuki syndrome (KS) is now listed in the Human Inborn Errors of Immunity (IEI) Classification. It is a rare disease caused by KMT2D and KDM6A variants, dominated by intellectual disability and characteristic facial features. Recurrently, pathogenic variants are identified in those genes in patients examined for autoimmune cytopenia (AIC), but interpretation remains challenging. This study aims to describe the genetic diagnosis and the clinical management of patients with paediatric-onset AIC and KS. Among 11 patients with AIC and KS, all had chronic immune thrombocytopenic purpura, and seven had Evans syndrome. All had other associated immunopathological manifestations, mainly symptomatic hypogammaglobinaemia. They had a median of 8 (5-10) KS-associated manifestations. Pathogenic variants were detected in KMT2D gene without clustering, during the immunological work-up of AIC in three cases, and the clinical strategy to validate them is emphasized. Eight patients received second-line treatments, mainly rituximab and mycophenolate mofetil. With a median follow-up of 17 (2-31) years, 8/10 alive patients still needed treatment for AIC. First-line paediatricians should be able to recognize and confirm KS in children with ITP or multiple AIC, to provide early appropriate clinical management and specific long-term follow-up. The epigenetic immune dysregulation in KS opens exciting new perspectives.

The IFIH1-A946T risk variant promotes diabetes in a sex-dependent manner.

Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet ß-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 (IFIH1), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 (IFIH1A946T) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that the IFIH1A946T risk variant, (IFIH1R) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developed Ifih1R knock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis in Ifih1R compared to non-risk Ifih1 (Ifih1NR) mice and a significant acceleration of diabetes onset in Ifih1R females. Ifih1R mice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared to Ifih1NR, indicative of increased IFN I signaling. Ifih1R mice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8+ T cells. Our results indicate that IFIH1R may contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects of Ifih1R in NOD mice, which will be important to consider for the development of therapeutics for T1D.

Clonal hematopoiesis and autoimmunity.

Clonal hematopoiesis (CH) has been associated with aging, occurring in about 10% of individuals aged >70 years, and immune dysfunction. Aged hematopoietic stem and progenitor cells exhibit pathological changes in immune function and activation of inflammatory pathways. CH clones commonly harbor a loss of function mutation in DNMT3A or TET2, which causes increased expression of inflammatory signaling genes, a proposed mechanism connected to CH and the development of age-related diseases. Additionally, inflammation may stress the hematopoietic compartment, driving the expansion of mutant clones. While the epidemiologic overlap between CH, hematologic malignancies, and atherosclerotic cardiovascular diseases has been reported, the mechanisms linking these concepts are largely unknown and merit much further investigation. Here, we review studies highlighting the interplay between CH, inflamm-aging, the immune system, and the prevalence of CH in autoimmune diseases.

Causal relationship between several autoimmune diseases and renal malignancies: A two-sample mendelian randomization study.

OBJECTIVE: Observational studies have shown an association between systemic autoimmune disease (AD) and multiple malignancies. However, due to the difficulty indetermining the temporal nature of the order, their causal relationship remains elusive. Based on pooled data from a large population-wide genome-wide association study (GWAS), this study explores the genetic causality between systemic autoimmune disease and renal malignancy. METHODS: We took a series of quality control steps from a large-scale genome-wide association study to select single nucleotide polymorphisms (SNPs) associated with systemic autoimmune disease as instrumental variables(IVs) to analyze genetic causality with renal malignancies. Inverse variance weighting (IVW), MR- Egger, weighted median, simple model and weighted model were used for analysis. The results were mainly based on IVW (Random Effects), followed by sensitivity analysis. Inverse-Variance Weighted(IVW) and MR-Egger were used to test for heterogeneity. MR- Egger is also used for pleiotropic testing. A single SNP analysis was used to identify single nucleotide polymorphisms (SNPs) with potential impact. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate causality, and sensitivity analysis was performed to evaluate pleiotropy and instrumental validity. RESULTS: Acute and subacute iridocylitis (P = 0.006, OR = 1.077), Ankylosing spondylitis (P = 0.002, OR = 1.051), and spondyloarthritis (P = 0.009, OR = 1.073) were positively associated with an increased risk of renal malignancy. Coxarthrosis (P = 0.008, OR = 0.483), Juvenile rheumatism (P = 0.011, OR = 0.897), and Systemic lupus erythematosus (P = 0.014, OR = 0.869) were negatively associated with an increased risk of renal malignancy. The results of sensitivity analysis were consistent without heterogeneity or pleiotropy. CONCLUSION: Our study suggests a causal relationship between different systemic autoimmune diseases and renal malignancies. These findings prompt health care providers to take seriously the potential risk of systemic autoimmune disease and provide new insights into the genetics of kidney malignancies.

Applications of CRISPR Epigenome Editors in Tumor Immunology and Autoimmunity.

Over the past decade, CRISPR-Cas systems have become indispensable tools for genetic engineering and have been used in clinical trials for various diseases. Beyond genome editing, CRISPR-Cas systems can also be used for performing programmable epigenetic modifications. Recent efforts in enhancing CRISPR-based epigenome modifiers have yielded potent tools enabling targeted DNA methylation/demethylation capable of sustaining epigenetic memory through numerous cell divisions. Moreover, it has been understood that during chronic inflammatory states, including cancer, T cells encounter a state called T cell exhaustion that involves elevated inhibitory receptors (e.g., LAG-3, TIM3, PD-1, CD39) and reduced effector T cell-related protein levels (IFN-γ, granzyme B, and perforin). Importantly, epigenetic dysregulation has been identified as one of the key drivers of T cell exhaustion, and it remains one of the biggest obstacles in the field of immunotherapy and decreases the efficiency of chimeric antigen receptor T (CAR-T) cell therapy. Similarly, autoimmune diseases exhibit epigenetically dysfunctional regulatory T (Treg) cells. For instance, FOXP3 intronic regions, known as conserved noncoding sequences, display hypomethylation in healthy states but hypermethylation in pathological contexts. Therefore, the reversal of epigenetic dysregulation in cancer and autoimmune diseases using CRISPR-based epigenome modifiers has important therapeutic implications. In this review, we outline the progressive refinement of CRISPR-based epigenome modifiers and explore their potential therapeutic applications in tumor immunology and autoimmunity.

Role of microRNAs in Immune Regulation with Translational and Clinical Applications.

MicroRNAs (miRNAs) are 19-23 nucleotide long, evolutionarily conserved noncoding RNA molecules that regulate gene expression at the post-transcriptional level. In this review, involvement of miRNAs is summarized in the differentiation and function of immune cells, in anti-infective immune responses, immunodeficiencies and autoimmune diseases. Roles of miRNAs in anticancer immunity and in the transplantation of solid organs and hematopoietic stem cells are also discussed. Major focus is put on the translational clinical applications of miRNAs, including the establishment of noninvasive biomarkers for differential diagnosis and prediction of prognosis. Patient selection and response prediction to biological therapy is one of the most promising fields of application. Replacement or inhibition of miRNAs has enormous therapeutic potential, with constantly expanding possibilities. Although important challenges still await solutions, evaluation of miRNA fingerprints may contribute to an increasingly personalized management of immune dysregulation with a remarkable reduction in toxicity and treatment side effects. More detailed knowledge of the molecular effects of physical exercise and nutrition on the immune system may facilitate self-tailored lifestyle recommendations and advances in prevention.

T-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms.

Endogenous retroviruses (ERVs) are an integral part of the mammalian genome. The role of immune control of ERVs in general is poorly defined as is their function as anti-cancer immune targets or drivers of autoimmune disease. Here, we generate mouse-strains where Moloney-Murine Leukemia Virus tagged with GFP (ERV-GFP) infected the mouse germline. This enables us to analyze the role of genetic, epigenetic and cell intrinsic restriction factors in ERV activation and control. We identify an autoreactive B cell response against the neo-self/ERV antigen GFP as a key mechanism of ERV control. Hallmarks of this response are spontaneous ERV-GFP+ germinal center formation, elevated serum IFN-γ levels and a dependency on Age-associated B cells (ABCs) a subclass of T-bet+ memory B cells. Impairment of IgM B cell receptor-signal in nucleic-acid sensing TLR-deficient mice contributes to defective ERV control. Although ERVs are a part of the genome they break immune tolerance, induce immune surveillance against ERV-derived self-antigens and shape the host immune response.

Marked intestinal trans-differentiation by autoimmune gastritis along with ectopic pancreatic and pulmonary trans-differentiation.

BACKGROUND: Autoimmune gastritis (AIG) is a prevalent chronic inflammatory disease with oncogenic potential that causes destruction of parietal cells and severe mucosal atrophy. We aimed to explore the distinctive gene expression profiles, activated signaling pathways, and their underlying mechanisms. METHODS: A comprehensive gene expression analysis was conducted using biopsy specimens from AIG, Helicobacter pylori-associated gastritis (HPG), and non-inflammatory normal stomachs. Gastric cancer cell lines were cultured under acidic (pH 6.5) conditions to evaluate changes in gene expression. RESULTS: Gastric mucosa with AIG had a unique gene expression profile compared with that with HPG and normal mucosa, such as extensively low expression of ATP4A and high expression of GAST and PAPPA2, which are involved in neuroendocrine tumorigenesis. Additionally, the mucosa with AIG and HPG showed the downregulation of stomach-specific genes and upregulation of small intestine-specific genes; however, intestinal trans-differentiation was much more prominent in AIG samples, likely in a CDX-dependent manner. Furthermore, AIG induced ectopic expression of pancreatic digestion-related genes, PNLIP, CEL, CTRB1, and CTRC; and a master regulator gene of the lung, NKX2-1/TTF1 with alveolar fluid secretion-related genes, SFTPB and SFTPC. Mechanistically, acidic conditions led to the downregulation of master regulator and stemness control genes of small intestine, suggesting that increased environmental pH may cause abnormal intestinal differentiation in the stomach. CONCLUSIONS: AIG induces diverse trans-differentiation in the gastric mucosa, characterized by the transactivation of genes specific to the small intestine, pancreas, and lung. Increased environmental pH owing to AIG may cause abnormal differentiation of the gastric mucosa.