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.

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.

Association of autoimmune and allergic diseases with senile cataract: a bidirectional two-sample Mendelian randomization study.

Background: Many observational studies have been reported that patients with autoimmune or allergic diseases seem to have a higher risk of developing senile cataract, but the views are not consistent. In order to minimize the influence of reverse causality and potential confounding factors, we performed Mendelian Randomization (MR) analysis to investigate the genetic causal associations between autoimmune, allergic diseases and senile cataract. Methods: Single nucleotide polymorphisms associated with ten common autoimmune and allergic diseases were obtained from the IEU Open genome-wide association studies (GWAS) database. Summary-level GWAS statistics for clinically diagnosed senile cataract were obtained from the FinnGen research project GWAS, which consisted of 59,522 individuals with senile cataracts and 312,864 control individuals. MR analysis was conducted using mainly inverse variance weighted (IVW) method and further sensitivity analysis was performed to test robustness. Results: As for ten diseases, IVW results confirmed that type 1 diabetes (OR = 1.06; 95% CI = 1.05-1.08; p = 2.24×10-12), rheumatoid arthritis (OR = 1.05; 95% CI = 1.02-1.08; p = 1.83×10-4), hypothyroidism (OR = 2.4; 95% CI = 1.42-4.06; p = 1.12×10-3), systemic lupus erythematosus (OR = 1.02; 95% CI = 1.01-1.03; p = 2.27×10-3), asthma (OR = 1.02; 95% CI = 1.01-1.03; p = 1.2×10-3) and allergic rhinitis (OR = 1.07; 95% CI = 1.02-1.11; p = 2.15×10-3) were correlated with the risk of senile cataract. Celiac disease (OR = 1.04; 95% CI = 1.01-1.08; P = 0.0437) and atopic dermatitis (OR = 1.05; 95% CI = 1.01-1.10; P = 0.0426) exhibited a suggestive connection with senile cataract after Bonferroni correction. These associations are consistent across weighted median and MR Egger methods, with similar causal estimates in direction and magnitude. Sensitivity analysis further proved that these associations were reliable. Conclusions: The results of the MR analysis showed that there were causal relationships between type 1 diabetes, rheumatoid arthritis, hypothyroidism, systemic lupus erythematosus, asthma, allergic rhinitis and senile cataract. To clarify the possible role of autoimmune and allergy in the pathophysiology of senile cataract, further studies are needed.

Causal association between air pollution and autoimmune diseases: a two-sample Mendelian randomization study.

Background: In recent years, an increasing number of observational studies have reported the impact of air pollution on autoimmune diseases (ADs). However, no Mendelian randomization (MR) studies have been conducted to investigate the causal relationships. To enhance our understanding of causality, we examined the causal relationships between particulate matter (PM) and nitrogen oxides (NOx) and ADs. Methods: We utilized genome-wide association study (GWAS) data on PM and NOx from the UK Biobank in European and East Asian populations. We also extracted integrated GWAS data from the Finnish consortium and the Japanese Biobank for two-sample MR analysis. We employed inverse variance weighted (IVW) analysis to assess the causal relationship between PM and NOx exposure and ADs. Additionally, we conducted supplementary analyses using four methods, including IVW (fixed effects), weighted median, weighted mode, and simple mode, to further investigate this relationship. Results: In the European population, the results of MR analysis suggested a statistically significant association between PM2.5 and psoriasis only (OR = 3.86; 95% CI: 1.89-7.88; PIVW < 0.00625), while a potential association exists between PM2.5-10 and vitiligo (OR = 7.42; 95% CI: 1.02-53.94; PIVW < 0.05), as well as between PM2.5 and systemic lupus erythematosus (OR = 68.17; 95% CI: 2.17-2.1e+03; PIVW < 0.05). In East Asian populations, no causal relationship was found between air pollutants and the risk of systemic lupus erythematosus and rheumatoid arthritis (PIVW > 0.025). There was no pleiotropy in the results. Conclusion: Our results suggest a causal association between PM2.5 and psoriasis in European populations. With the help of air pollution prevention and control, the harmful progression of psoriasis may be slowed.

Effects of genetically predicted posttraumatic stress disorder on autoimmune phenotypes.

Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.

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.

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.

Analysis of Nanoparticles' Potential to Induce Autoimmunity.

Autoimmune responses are characterized by the presence of antibodies and lymphocytes specific to self or so-called autoantigens. Among such autoantigens is DNA; therefore, screening for antibodies recognizing single- and/or double-stranded DNA is commonly used to detect and classify autoimmune diseases. While autoimmunity affects both sexes, females are generally more affected than males, which is recapitulated in some animal models. A variety of factors, including genetic predisposition and the environment, contribute to the development of autoimmune disorders. Since certain drug products may also contribute to the development of autoimmunity, understanding a drug's potential to trigger an autoimmune response is of interest to immunotoxicology. However, models to study autoimmunity are limited, and it is generally agreed that no model can accurately predict autoimmunity in humans. Herein, we present an in vivo protocol utilizing the SJL/J mouse model to study nanoparticles' effects on the development of autoimmune responses. The protocol is adapted from the literature describing the use of this model to study chemically induced lupus.

COVID-19 vaccination and the risk of autoimmune diseases: a Mendelian randomization study.

Background: In recent times, reports have emerged suggesting that a variety of autoimmune disorders may arise after the coronavirus disease 2019 (COVID-19) vaccination. However, causality and underlying mechanisms remain unclear. Methods: We collected summary statistics of COVID-19 vaccination and 31 autoimmune diseases from genome-wide association studies (GWAS) as exposure and outcome, respectively. Random-effects inverse variance weighting (IVW), MR Egger, weighted median, simple mode, and weighted mode were used as analytical methods through Mendelian randomization (MR), and heterogeneity and sensitivity analysis were performed. Results: We selected 72 instrumental variables for exposure (p < 5 × 10-6; r2 < 0.001, genetic distance = 10,000 kb), and MR analyses showed that COVID-19 vaccination was causally associated with an increased risk of multiple sclerosis (MS) (IVW, OR: 1.53, 95% CI: 1.065-2.197, p = 0.026) and ulcerative colitis (UC) (IVW, OR: 1.00, 95% CI: 1.000-1.003, p = 0.039). If exposure was refined (p < 5 × 10-8; r2 < 0.001, genetic distance = 10,000 kb), the associations became negative. No causality was found for the remaining outcomes. These results were robust to sensitivity and heterogeneity analyses. Conclusion: Our study provided potential evidence for the impact of COVID-19 vaccination on the risk of MS and UC occurrence, but it lacks sufficient robustness, which could provide a new idea for public health policy.

Understanding the pathogenic significance of altered calcium-calmodulin signaling in T cells in autoimmune diseases.

Calcium/calmodulin-dependent protein kinase IV (CaMK4) serves as a pivotal mediator in the regulation of gene expression, influencing the activity of transcription factors within a variety of immune cells, including T cells. Altered CaMK4 signaling is implicated in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, which are characterized by dysregulated immune responses and clinical complexity. These conditions share common disturbances in immune cell functionality, cytokine production, and autoantibody generation, all of which are associated with disrupted calcium-calmodulin signaling. This review underscores the consequences of dysregulated CaMK4 signaling across these diseases, with an emphasis on its impact on Th17 differentiation and T cell metabolism-processes central to maintaining immune homeostasis. A comprehensive understanding of roles of CaMK4 in gene regulation across various autoimmune disorders holds promise for the development of targeted therapies, particularly for diseases driven by Th17 cell dysregulation.

Innovate therapeutic targets for autoimmune diseases: insights from proteome-wide mendelian randomization and Bayesian colocalization.

BACKGROUND: Despite growing knowledge regarding the pathogenesis of autoimmune diseases (ADs) onset, the current treatment remains unsatisfactory. This study aimed to identify innovative therapeutic targets for ADs through various analytical approaches. RESEARCH DESIGN AND METHODS: Utilizing Mendelian randomization, Bayesian co-localization, phenotype scanning, and protein-protein interaction network, we explored potential therapeutic targets for 14 ADs and externally validated our preliminary findings. RESULTS: This study identified 12 circulating proteins as potential therapeutic targets for six ADs. Specifically, IL12B was judged to be a risk factor for ankylosing spondylitis (p = 1.61E - 07). TYMP (p = 6.28E - 06) was identified as a protective factor for ulcerative colitis. For Crohn's disease, ERAP2 (p = 4.47E - 14), HP (p = 2.08E - 05), and RSPO3 (p = 6.52E - 07), were identified as facilitators, whereas FLRT3 (p = 3.42E - 07) had a protective effect. In rheumatoid arthritis, SWAP70 (p = 3.26E - 10), SIGLEC6 (p = 2.47E - 05), ISG15 (p = 3.69E - 05), and FCRL3 (p = 1.10E - 10) were identified as risk factors. B4GALT1 (p = 6.59E - 05) was associated with a lower risk of Type 1 diabetes (T1D). Interestingly, CTSH was identified as a protective factor for narcolepsy (p = 1.58E - 09) but a risk factor for T1D (p = 7.36E - 11), respectively. External validation supported the associations of eight of these proteins with three ADs. CONCLUSIONS: Our integrated study identified 12 potential therapeutic targets for ADs and provided novel insights into future drug development for ADs.

Gene Signature of Regulatory T Cells Isolated from Children with Selective IgA Deficiency and Common Variable Immunodeficiency.

Selective IgA deficiency (SIgAD) is the most common form and common variable immunodeficiency (CVID) is the most symptomatic form of predominant antibody deficiency. Despite differences in the clinical picture, a similar genetic background is suggested. A common feature of both disorders is the occurrence of autoimmune conditions. Regulatory T cells (Tregs) are the major immune cell type that maintains autoimmune tolerance. As the different types of abnormalities of Treg cells have been associated with autoimmune disorders in primary immunodeficiency (PID) patients, in our study we aimed to analyze the gene expression profiles of Treg cells in CVID and SIgAD patients compared to age-matched healthy controls. The transcriptome-wide gene profiling was performed by microarray technology. As a result, we analyzed and visualized gene expression patterns of isolated population of Treg cells. We showed the differences at the gene level between patients with and without autoimmunizations. Our findings suggest that the gene signatures of Treg cells isolated from SIgAD and CVID patients differ from age-matched healthy controls and from each other, presenting transcriptional profiles enriched in innate immune or Th response, respectively. The occurrence of autoimmunity in both types of PID is associated with down-regulation of class I IFNs signaling pathways. In summary, our findings improve our understanding of Treg dysfunctions in patients with common PIDs and associated autoimmunity.

Learning the Autoimmune Pathogenesis Through the Study of Aire.

One of the difficulties in studying the pathogenesis of autoimmune diseases is that the disease is multifactorial involving sex, age, MHC, environment, and some genetic factors. Because deficiency of Aire, a transcriptional regulator, is an autoimmune disease caused by a single gene abnormality, Aire is an ideal research target for approaching the enigma of autoimmunity, e.g., the mechanisms underlying Aire deficiency can be studied using genetically modified animals. Nevertheless, the exact mechanisms of the breakdown of self-tolerance due to Aire's dysfunction have not yet been fully clarified. This is due, at least in part, to the lack of information on the exact target genes controlled by Aire. State-of-the-art research infrastructures such as single-cell analysis are now in place to elucidate the essential function of Aire. The knowledge gained through the study of Aire-mediated tolerance should help our understanding of the pathogenesis of autoimmune disease in general.

Novel Insights into the Autoimmunity from the Genetic Approach of the Human Disease.

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic inborn error of autoimmunity that is caused by damaging germline variants in the AIRE gene and clinically manifests with multiple autoimmune diseases in patients. Studies on the function of the AIRE gene, discovered in 1997, have contributed to fundamental aspects of human immunology as they have been important in understanding the basic mechanism of immune balance between self and non-self. This chapter looks back to the discovery of the AIRE gene, reviews its main properties, and discusses the key findings of its function in the thymus. However, more recent autoantibody profilings in APECED patients have highlighted a gap in our knowledge of the disease pathology and point to the need to revisit the current paradigm of AIRE function. The chapter reviews these new findings in APECED patients, which potentially trigger new thoughts on the mechanism of immune tolerance.

Autoimmunity-associated allele of tyrosine phosphatase gene PTPN22 enhances anti-viral immunity.

The 1858C>T allele of the tyrosine phosphatase PTPN22 is present in 5-10% of the North American population and is strongly associated with numerous autoimmune diseases. Although research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its pro-autoimmune allele has in anti-viral immunity remains poorly defined. Here, we use single cell RNA-sequencing and functional studies to interrogate the impact of this pro-autoimmune allele on anti-viral immunity during Lymphocytic Choriomeningitis Virus clone 13 (LCMV-cl13) infection. Mice homozygous for this allele (PEP-619WW) clear the LCMV-cl13 virus whereas wildtype (PEP-WT) mice cannot. This is associated with enhanced anti-viral CD4 T cell responses and a more immunostimulatory CD8α- cDC phenotype. Adoptive transfer studies demonstrated that PEP-619WW enhanced anti-viral CD4 T cell function through virus-specific CD4 T cell intrinsic and extrinsic mechanisms. Taken together, our data show that the pro-autoimmune allele of Ptpn22 drives a beneficial anti-viral immune response thereby preventing what is normally a chronic virus infection.

IgLON5 deficiency produces behavioral alterations in a knockout mouse model.

Background: Anti-IgLON5 disease is a neurological disorder characterized by autoantibodies against IgLON5 and pathological evidence of neurodegeneration. IgLON5 is a cell adhesion molecule of unknown function that is highly expressed in the brain. Our aim was to investigate the impact of IgLON5 loss-of-function in evaluating brain morphology, social behavior, and the development of symptoms observed in an IgLON5 knockout (IgLON5-KO) mouse model. Methods: The IgLON5-KO mice were generated using CRISPR-Cas9 technology. Immunohistochemistry on fixed sagittal brain sections and Western blotting brain lysates were used to confirm IgLON5 silencing and to evaluate the presence of other cell surface proteins. Two- month-old IgLON5-KO and wild-type (WT) mice underwent a comprehensive battery of behavioral tests to assess 1) locomotion, 2) memory, 3) anxiety, 4) social interaction, and 5) depressive-like behavior. Brain sections were examined for the presence of anatomical abnormalities and deposits of hyperphosphorylated tau in young adult (2-month-old) and aged (22-month-old) mice. Results: Mice did not develop neurological symptoms reminiscent of those seen in patients with anti-IgLON5 disease. Behavioral testing revealed that 2-month-old IgLON5-KO mice showed subtle alterations in motor coordination and balance. IgLON5-KO females exhibited hyperactivity during night and day. Males were observed to have depressive-like behavior and excessive nest-building behavior. Neuropathological studies did not reveal brain morphological alterations or hyperphosphorylated tau deposits. Conclusion: IgLON5-KO mice showed subtle alterations in behavior and deficits in fine motor coordination but did not develop the clinical phenotype of anti-IgLON5 disease.

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.

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.

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.

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.