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Significance: Epigenetic dysregulation plays an important role in the pathogenesis and development of autoimmune diseases. Oxidative stress is associated with autoimmunity and is also known to alter epigenetic mechanisms. Understanding the interplay between oxidative stress and epigenetics will provide insights into the role of environmental triggers in the development of autoimmunity in genetically susceptible individuals. Recent Advances: Abnormal DNA and histone methylation patterns in genes and pathways involved in interferon and tumor necrosis factor signaling, cellular survival, proliferation, metabolism, organ development, and autoantibody production have been described in autoimmunity. Inhibitors of DNA and histone methyltransferases showed potential therapeutic effects in animal models of autoimmune diseases. Oxidative stress can regulate epigenetic mechanisms via effects on DNA damage repair mechanisms, cellular metabolism and the local redox environment, and redox-sensitive transcription factors and pathways. Critical Issues: Studies looking into oxidative stress and epigenetics in autoimmunity are relatively limited. The number of available longitudinal studies to explore the role of DNA methylation in the development of autoimmune diseases is small. Future Directions: Exploring the relationship between oxidative stress and epigenetics in autoimmunity will provide clues for potential preventative measures and treatment strategies. Inception cohorts with longitudinal follow-up would help to evaluate epigenetic marks as potential biomarkers for disease development, progression, and treatment response in autoimmunity. Antioxid. Redox Signal . 36, 423-440.

Caffeine is a widely consumed pharmacologically active product. We focused on characterizing immunomodulatory effects of caffeine on peripheral blood mononuclear cells. Caffeine at high doses showed a robust downregulatory effect on cytokine activity and genes related to several autoimmune diseases including lupus and rheumatoid arthritis. Dose-dependent validation experiments showed downregulation at the mRNA levels of key inflammation-related genes including STAT1, TNF, IFNG, and PPARG. TNF and PPARG were suppressed even with the lowest caffeine dose tested, which corresponds to the serum concentration of caffeine after administration of one cup of coffee. Cytokine levels of IL-8, MIP-1β, IL-6, IFN-γ, GM-CSF, TNF, IL-2, IL-4, MCP-1, and IL-10 were decreased significantly with caffeine treatment. Upstream regulator analysis suggests that caffeine inhibits STAT1 signaling, which was confirmed by showing reduced phosphorylated STAT1 after caffeine treatment. Further studies exploring disease-modulating potential of caffeine in autoimmune diseases and further exploring the mechanisms involved are warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: We sought to define age-associated DNA methylation changes in naive CD4 + T cells., Materials & Methods: Naive CD4 + T cells were collected from 74 healthy individuals (age 19-66 years), and age-related DNA methylation changes were characterized., Results: We identified 11,431 age-associated CpG sites, 57% of which were hypermethylated with age. Hypermethylated sites were enriched in CpG islands and repressive transcription factor binding sites, while hypomethylated sites showed T cell specific enrichment in active enhancers marked by H3K27ac and H3K4me1. Our data emphasize cancer-related DNA methylation changes with age, and also reveal age-associated hypomethylation in immune-related pathways, such as T cell receptor signaling, FCγR-mediated phagocytosis, apoptosis and the mammalian target of rapamycin signaling pathway. The MAPK signaling pathway was hypermethylated with age, consistent with a defective MAPK signaling in aging T cells., Conclusion: Age-associated DNA methylation changes may alter regulatory mechanisms and signaling pathways that predispose to autoimmunity.

Introduction: Despite progress in our understanding of disease pathogenesis for systemic autoimmune rheumatic diseases (SARD), these diseases are still associated with high morbidity, disability, and mortality. Much of the strongest evidence to date implicating environmental factors in the development of autoimmunity has been based on well-established, large, longitudinal prospective cohort studies. Methods: Herein, we review the current state of knowledge on known environmental factors associated with the development of SARD and potential areas for future research. Results: The risk attributable to any particular environmental factor ranges from 10-200%, but exposures are likely synergistic in altering the immune system in a complex interplay of epigenetics, hormonal factors, and the microbiome leading to systemic inflammation and eventual organ damage. To reduce or forestall the progression of autoimmunity, a better understanding of disease pathogenesis is still needed. Conclusion: Owing to the complexity and multifactorial nature of autoimmune disease, machine learning, a type of artificial intelligence, is increasingly utilized as an approach to analyzing large datasets. Future studies that identify patients who are at high risk of developing autoimmune diseases for prevention trials are needed. [ABSTRACT FROM AUTHOR]

The author reflects on the association of autoimmunity with methyl-CpG-binding protein 2 (MeCP2) overexpression. He cites a study by Yang and colleagues which revealed a defect in T helper cell type 1 (TH1) response and interferon-gamma (IFN-Γ) production in children due to MECP2 duplication. He says that the results are supported by a study on a transgenic mouse which overexpresses MECP2.

Background: Type 1 diabetes (T1D) is preceded by a heterogenous pre-clinical phase, islet autoimmunity (IA). We aimed to identify pre vs. post-IA seroconversion (SV) changes in DNAm that differed across three IA progression phenotypes, those who lose autoantibodies (reverters), progress to clinical T1D (progressors), or maintain autoantibody levels (maintainers). Methods: This epigenome-wide association study (EWAS) included longitudinal DNAm measurements in blood (Illumina 450K and EPIC) from participants in Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, one or more islet autoantibodies on at least two consecutive visits. We compared reverters - individuals who sero-reverted, negative for all autoantibodies on at least two consecutive visits and did not develop T1D (n=41); maintainers - continued to test positive for autoantibodies but did not develop T1D (n=60); progressors - developed clinical T1D (n=42). DNAm data were measured before (pre-SV visit) and after IA (post-SV visit). Linear mixed models were used to test for differences in pre-vs post-SV changes in DNAm across the three groups. Linear mixed models were also used to test for group differences in average DNAm. Cell proportions, age, and sex were adjusted for in all models. Median follow-up across all participants was 15.5 yrs. (interquartile range (IQR): 10.8-18.7). Results: The median age at the pre-SV visit was 2.2 yrs. (IQR: 0.8-5.3) in progressors, compared to 6.0 yrs. (IQR: 1.3-8.4) in reverters, and 5.7 yrs. (IQR: 1.4-9.7) in maintainers. Median time between the visits was similar in reverters 1.4 yrs. (IQR: 1-1.9), maintainers 1.3 yrs. (IQR: 1.0-2.0), and progressors 1.8 yrs. (IQR: 1.0-2.0). Changes in DNAm, pre- vs post-SV, differed across the groups at one site (cg16066195) and 11 regions. Average DNAm (mean of pre- and post-SV) differed across 22 regions. Conclusion: Differentially changing DNAm regions were located in genomic areas related to beta cell function, immune cell differentiation, and immune cell function. [ABSTRACT FROM AUTHOR]

Objective: Pancreatic beta cell destruction is a hallmark of type 1 diabetes (T1D), a heterogeneous disorder with a wide range of potential causes. T cell activation molecules have been shown to play an important role in the development of T1D, according to the majority of studies. Some autoimmune diseases have been linked to SNPs in the 4q27 region, specifically in the KIAA1109-interleukin 2 (IL2)-IL21 block. The purpose of this research was to look into how certain polymorphic variants in the 4q27 region are linked to T1D. Methods: We investigated whether variants in the 4q27 region could be a causal factor in T1D susceptibility. Polymorphisms of ten single-nucleotide polymorphisms (SNPs) belonging to the KIAA1109/IL21/IL2 block were studied in 255 individuals from 59 families using the Sequenom MassARRAY platform. Results: The IL21/IL2 region was found to have a significant association with T1D in Tunisian cohorts. We found that the T allele of the rs2221903 marker is disproportionately passed down from parents to their children. In addition, haplotype analyses encompassing all of the SNPs under consideration show that the GACAGGA and the shortly TT haplotypes were significantly over-transmitted from parents to their children, suggesting they may be a T1D genetic susceptibility factor in our population. Conclusion: Several autoimmune disorders (ADs) have been linked to the IL2/IL21 genes, suggesting that there is a shared genetic background that confers a common genetic predisposition across ADs. More research into the genetic and functional aspects of the 4q27 region is needed to better explain the role it plays in the risk of ADs. [ABSTRACT FROM AUTHOR]

Sjögren’s syndrome (SjS) is a systemic, highly diverse, and chronic autoimmune disease with a significant global prevalence. It is a complex condition that requires careful management and monitoring. Recent research indicates that epigenetic mechanisms contribute to the pathophysiology of SjS by modulating gene expression and genome stability. DNA methylation, a form of epigenetic modification, is the fundamental mechanism that modifies the expression of various genes by modifying the transcriptional availability of regulatory regions within the genome. In general, adding a methyl group to DNA is linked with the inhibition of genes because it changes the chromatin structure. DNA methylation changes the fate of multiple immune cells, such as it leads to the transition of naïve lymphocytes to effector lymphocytes. A lack of central epigenetic enzymes frequently results in abnormal immune activation. Alterations in epigenetic modifications within immune cells or salivary gland epithelial cells are frequently detected during the pathogenesis of SjS, representing a robust association with autoimmune responses. The analysis of genome methylation is a beneficial tool for establishing connections between epigenetic changes within different cell types and their association with SjS. In various studies related to SjS, most differentially methylated regions are in the human leukocyte antigen (HLA) locus. Notably, the demethylation of various sites in the genome is often observed in SjS patients. The most strongly linked differentially methylated regions in SjS patients are found within genes regulated by type I interferon. This demethylation process is partly related to B-cell infiltration and disease progression. In addition, DNA demethylation of the runt-related transcription factor (RUNX1) gene, lymphotoxin-α (LTA), and myxovirus resistance protein A (MxA) is associated with SjS. It may assist the early diagnosis of SjS by serving as a potential biomarker. Therefore, this review offers a detailed insight into the function of DNA methylation in SjS and helps researchers to identify potential biomarkers in diagnosis, prognosis, and therapeutic targets. [ABSTRACT FROM AUTHOR]

The network of IL-17 cytokines is considered a key component of autoimmune and inflammatory processes. Blocking IL-17 showed great success in psoriasis as well as psoriatic arthritis, and in patients with axial spondyloarthritis. Secukinumab is one of the approved IL-17A inhibitors for these diseases and is now routinely used. In giant cell arteritis, a large vessel vasculitis, there is accumulating evidence for a pathogenic role of IL-17 and Th17 cells, which are part of the CD4+ T-cell subset. Giant cell arteritis occurs in individuals over 50 years of age and many have relative contraindications to glucocorticoid therapy, which today still represents the mainstay therapy. Despite the approval of tocilizumab, which targets the IL-6 receptor, a high demand for glucocorticoid-sparing agents remains that combine the effective suppression of the acute inflammation observed in giant cell arteritis with a safety profile that matches the needs of an older patient population. The first results from a phase II proof-of-principle study (TitAIN) support an optimistic outlook on a potential new treatment option with secukinumab in giant cell arteritis. [ABSTRACT FROM AUTHOR]

The functioning of the human immune system is highly dependent on the sex of the individual, which comes by virtue of sex chromosomes and hormonal differences. Epigenetic mechanisms such as X chromosome inactivation, mosaicism, skewing, and dimorphism in X chromosome genes and Y chromosome regulatory genes create a sex-based variance in the immune response between males and females. This leads to differential susceptibility in immune-related disorders like infections, autoimmunity, and malignancies. Various naturally available immunomodulators are also available which target immune pathways containing X chromosome genes. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that a complex and multifactorial interplay between genetic and environmental factors, such as viruses, play a crucial role in the development of the disease. Research over the past few decades has shown that there is not one single viral culprit, nor one single genetic pathway, causing the disease. Rather, viral infections, most notably enteroviruses (EV), appear to accelerate the autoimmune process leading to T1D and are often seen as a precipitator of clinical diagnosis. In support of this hypothesis, the use of antiviral drugs has recently shown efficacy in preserving beta cell function after onset of diabetes. In this review, we will discuss the various pathways that viral infections utilize to accelerate the development of T1D. There are three key mechanisms linking viral infections to beta-cell death: One is modulated by the direct infection of islets by viruses, resulting in their impaired function, another occurs in a more indirect fashion, by modulating the immune system, and the third is caused by heightened stress on the beta-cell by interferon-mediated increase of insulin resistance. The first two aspects are surprisingly difficult to study, in the case of the former, because there are still many questions about how viruses might persist for longer time periods. In the latter, indirect/immune case, viruses might impact immunity as a hit-andrun scenario, meaning that many or all direct viral footprints quickly vanish, while changes imprinted upon the immune system and the anti-islet autoimmune response persist. Given the fact that viruses are often associated with the precipitation of clinical autoimmunity, there are concerns regarding the impact of the recent global coronavirus-2019 (COVID-19) pandemic on the development of autoimmune disease. The long-term effects of COVID-19 infection on T1D will therefore be discussed, including the increased development of new cases of T1D. Understanding the interplay between viral infections and autoimmunity is crucial for advancing our knowledge in this field and developing targeted therapeutic interventions. In this review we will examine the intricate relationship between viral infections and autoimmunity and discuss potential considerations for prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Inborn errors of immunity may present with autoimmunity and autoinflammation as hallmark clinical manifestations. We aimed to identify the potential monogenic causes of autoimmune disorders in 26 patients from a pediatric reference hospital in Mexico through whole-exome sequencing. We specifically selected patients with a family history of autoimmune diseases, early-onset symptoms, and difficult-to-control autoimmune disorders or autoimmunity associated with infection predisposition. We identified the genetic variants that were compatible with the patients' phenotype in 54% of the patients. Autoimmune diseases are often caused by a combination of genetic factors, but cases that appear at a young age are resistant to treatment or occur in clusters, as well as the presence of autoimmune symptoms alongside infectious diseases should raise suspicion for an underlying inborn error of immunity. [ABSTRACT FROM AUTHOR]

An infection with severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) may have a significant impact on the human immune system. Interactions between the virus and defence mechanisms may promote the development of autoimmune processes which manifest as antinuclear antibody (ANA) synthesis. Since many different viruses are suspected to take part in the pathogenesis of different systemic autoimmune rheumatic diseases (SARDs), we examined whether coronavirus disease 2019 convalescents who suffer from mild to moderate disease have a higher risk of developing ANA and anti‐β2‐glicoprotein I IgG antibodies (β2 GPI). In a retrospective study, we examined 294 adults among volunteer blood donors divided into convalescents (N = 215) and healthy controls (N = 79). For ANA detection, we used line‐blotting, a type of indirect immunofluorescence assay (IF), to determine antigenic specificity and ELISA for β2 GPI. We found a lower incidence of ANA in convalescents than in healthy controls, with the majority of these antibodies directed to antigens with no known clinical significance. Additionally, no participants were positive for β2 GPI in either group. Our results show that COVID‐19 with mild to moderate symptoms in the generally healthy population does not induce the development of ANA or anti‐β2 GPI antibodies for at least 6 months following the disease. [ABSTRACT FROM AUTHOR]

Antinuclear autoantibodies (ANA) are heterogeneous self-reactive antibodies that target the chromatin network, the speckled, the nucleoli, and other nuclear regions. The immunological aberration for ANA production remains partially understood, but ANA are known to be pathogenic, especially, in systemic lupus erythematosus (SLE). Most SLE patients exhibit a highly polygenic disease involving multiple organs, but in rare complement C1q, C1r, or C1s deficiencies, the disease can become largely monogenic. Increasing evidence point to intrinsic autoimmunogenicity of the nuclei. Necrotic cells release fragmented chromatins as nucleosomes and the alarmin HMGB1 is associated with the nucleosomes to activate TLRs and confer anti-chromatin autoimmunogenecity. In speckled regions, the major ANA targets Sm/RNP and SSA/Ro contain snRNAs that confer autoimmunogenecity to Sm/RNP and SSA/Ro antigens. Recently, three GAR/RGG-containing alarmins have been identified in the nucleolus that helps explain its high autoimmunogenicity. Interestingly, C1q binds to the nucleoli exposed by necrotic cells to cause protease C1r and C1s activation. C1s cleaves HMGB1 to inactive its alarmin activity. C1 proteases also degrade many nucleolar autoantigens including nucleolin, a major GAR/RGG-containing autoantigen and alarmin. It appears that the different nuclear regions are intrinsically autoimmunogenic by containing autoantigens and alarmins. However, the extracellular complement C1 complex function to dampen nuclear autoimmunogenecity by degrading these nuclear proteins. [ABSTRACT FROM AUTHOR]

The influence of environmental factors on the development of autoimmune disease is being broadly investigated to better understand the multifactorial nature of autoimmune pathogenesis and to identify potential areas of intervention. Areas of particular interest include the influence of lifestyle, nutrition, and vitamin deficiencies on autoimmunity and chronic inflammation. In this review, we discuss how particular lifestyles and dietary patterns may contribute to or modulate autoimmunity. We explored this concept through a spectrum of several autoimmune diseases including Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE) and Alopecia Areata (AA) affecting the central nervous system, whole body, and the hair follicles, respectively. A clear commonality between the autoimmune conditions of interest here is low Vitamin D, a well-researched hormone in the context of autoimmunity with pleiotropic immunomodulatory and anti-inflammatory effects. While low levels are often correlated with disease activity and progression in MS and AA, the relationship is less clear in SLE. Despite strong associations with autoimmunity, we lack conclusive evidence which elucidates its role in contributing to pathogenesis or simply as a result of chronic inflammation. In a similar vein, other vitamins impacting the development and course of these diseases are explored in this review, and overall diet and lifestyle. Recent work exploring the effects of dietary interventions on MS showed that a balanced diet was linked to improvement in clinical parameters, comorbid conditions, and overall quality of life for patients. In patients with MS, SLE and AA, certain diets and supplements are linked to lower incidence and improved symptoms. Conversely, obesity during adolescence was linked with higher incidence of MS while in SLE it was associated with organ damage. Autoimmunity is thought to emerge from the complex interplay between environmental factors and genetic background. Although the scope of this review focuses on environmental factors, it is imperative to elaborate the interaction between genetic susceptibility and environment due to the multifactorial origin of these disease. Here, we offer a comprehensive review about the influence of recent environmental and lifestyle factors on these autoimmune diseases and potential translation into therapeutic interventions. [ABSTRACT FROM AUTHOR]

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Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post‐translational modifications and the regulation of chromatin accessibility by non‐coding RNAs, all of which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental‐driven nature, piloting myeloid and lymphoid cell fate decisions with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage‐specific transcription factors and maintenance of cell type‐specific epigenetic modifications, referred to as 'epigenetic memory', dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells. Moreover, metabolic and epigenetic reprogramming occurring during a primary innate immune response leads to enhanced responses to secondary challenges, a phenomenon known as 'trained immunity'. Here, we discuss how stable and dynamic epigenetic states control immune cell identity and plasticity in physiological and pathological conditions. Dissecting the regulatory circuits of cell fate determination and maintenance is of paramount importance for understanding the delicate balance between immune cell activation and tolerance, in healthy conditions and in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Epigenetics is the study of heritable, reversible gene expression patterns that do not originate from alterations in the DNA sequence. Epigenetic modifications influence gene expression patterns and include DNA methylation, histone modifications, and gene regulation via non-coding RNAs. While the study of epigenetics has been most broadly applied to neoplastic diseases, the role of the epigenome in a wide range of disease processes including autoimmune, allergic, and inflammatory processes is increasingly being recognized. Recent advances in the study of the epigenome have led to novel insights into the pathogenesis and potential therapeutic targets of various pathologic entities including inflammatory diseases. In this review, we examine the nature of epigenetic modifications in several well-studied autoimmune, allergic, and/or inflammatory disorders of the skin including systemic lupus erythematosus, vitiligo, systemic sclerosis, alopecia areata, pemphigus, psoriasis, atopic dermatitis, keloidal scarring, and hidradenitis suppurativa with the aim to determine how such epigenetic changes may be targeted for therapeutic benefit. [ABSTRACT FROM AUTHOR]

Women of reproductive age demonstrate an increased incidence of systemic lupus erythematosus, and reproductive hormones have been implicated in disease progression. Additionally, pregnancy can be associated with disease "flares", the reasons for which remain obscure. While apoptotic bodies are believed to provide an autoantigenic trigger in lupus, whether autoantigenic constituents vary with varying cellular insults, and whether such variations can be immunologically consequential in the context of pregnancy, remains unknown. As assessed by antigenicity and mass spectrometry, apoptotic bodies elicited by different drugs demonstrated the differential presence of lupus-associated autoantigens, and varied in the ability to elicit lupus-associated cytokines from lupus splenocytes and alter the phenotype of lupus B cells. Immunization of tamoxifen-induced apoptotic bodies in lupus-prone mice generated higher humoral autoreactive responses than did immunization with cisplatin-induced apoptotic bodies, and both apoptotic bodies were poorly immunogenic in healthy mice. Incubation of lupus splenocytes (but not healthy splenocytes) with the pregnancy hormone human chorionic gonadotropin (hCG) along with tamoxifen-induced apoptotic bodies (but not cisplatin-induced apoptotic bodies) induced increases in the secretion of lupus-associated cytokines and in the up-modulation of B cell phenotypic markers. In addition, levels of secreted autoantibodies (including of specificities linked to lupus pathogenesis) were enhanced. These events were associated with the heightened phosphorylation of several signaling intermediates. Observations suggest that hCG is a potential disease-promoting co-stimulant in a lupus-milieu; when combined with specific apoptotic bodies, it enhances the intensity of multiple lupus-associated events. These findings deepen mechanistic insight into the hormone's links with autoreactive responses in lupus-prone mice and humans. [ABSTRACT FROM AUTHOR]

In the normal immune system, T cell activation is tightly regulated and controlled at several levels to ensure that activation occurs in the right context to prevent the development of pathologic conditions such as autoimmunity or other harmful immune responses. CD4+FoxP3+ regulatory T cells (Treg) are crucial for the regulation of T cell responses in the peripheral lymphatic organs and thus for the prevention and control of autoimmunity. In systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease with complex etiology, a disbalance between Treg and pathogenic effector/memory CD4+ T cells develops during disease progression indicating that gradual loss of control over T cell activation is an important event in the immune pathogenesis. This progressive failure to adequately regulate the activation of autoreactive T cells facilitates chronic activation and effector/ memory differentiation of pathogenic T cells, which are considered to contribute significantly to the induction and perpetuation of autoimmune processes and tissue inflammation in SLE. However, in particular in humans, little is known about the factors which drive the escape from immune regulation and the chronicity of pathogenic T cell responses in an early stage of autoimmune disease when clinical symptoms are still unapparent. Here we briefly summarize important findings and discuss current views and models on the mechanisms related to the dysregulation of T cell responses which promotes chronicity and pathogenic memory differentiation with a focus on the early stage of disease in lupus-prone individuals. [ABSTRACT FROM AUTHOR]

The immune response plays a crucial role in preventing diseases, such as infections. There are two types of immune responses, specific and innate immunity, each of which consists of two components: cellular immunity and humoral immunity. Dysfunction in any immune system component increases the risk of developing certain diseases. Systemic lupus erythematosus (SLE), an autoimmune disease in the human body, develops an immune response against its own components. In these patients, due to underlying immune system disorders and receipt of immunosuppressive drugs, the susceptibility to infections is higher than in the general population and is the single largest cause of mortality in this group. COVID-19 infection, which first appeared in late 2019, has caused several concerns in patients with SLE. However, there is no strong proof of additional risk of developing COVID-19 in patients with SLE, and in some cases, studies have shown less severity of the disease in these individuals. This review paper discusses the immune disorders in SLE and COVID-19. [ABSTRACT FROM AUTHOR]

Objectives: Lupus T cells demonstrate aberrant DNA methylation patterns dominated by hypomethylation of interferon-regulated genes. The objective of this study was to identify additional lupus-associated DNA methylation changes and determine the genetic contribution to epigenetic changes characteristic of lupus.Methods: Genome-wide DNA methylation was assessed in naïve CD4+ T cells from 74 patients with lupus and 74 age-matched, sex-matched and race-matched healthy controls. We applied a trend deviation analysis approach, comparing methylation data in our cohort with over 16 500 samples. Methylation quantitative trait loci (meQTL) analysis was performed by integrating methylation profiles with genome-wide genotyping data.Results: In addition to the previously reported epigenetic signature in interferon-regulated genes, we observed hypomethylation in the promoter region of the miR-17-92 cluster in patients with lupus. Members of this microRNA cluster play an important role in regulating T cell proliferation and differentiation. Expression of two microRNAs in this cluster, miR-19b1 and miR-18a, showed a significant positive correlation with lupus disease activity. Among miR-18a target genes, TNFAIP3, which encodes a negative regulator of nuclear factor kappa B, was downregulated in lupus CD4+ T cells. MeQTL identified in lupus patients showed overlap with genetic risk loci for lupus, including CFB and IRF7. The lupus risk allele in IRF7 (rs1131665) was associated with significant IRF7 hypomethylation. However, <1% of differentially methylated CpG sites in patients with lupus were associated with an meQTL, suggesting minimal genetic contribution to lupus-associated epigenotypes.Conclusion: The lupus defining epigenetic signature, characterised by robust hypomethylation of interferon-regulated genes, does not appear to be determined by genetic factors. Hypomethylation of the miR-17-92 cluster that plays an important role in T cell activation is a novel epigenetic locus for lupus. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is an infectious disease associated with the respiratory system caused by the SARS-CoV-2 virus. The aim of this review article is to establish an understanding about the relationship between autoimmune conditions and COVID-19 infections. Although majority of the population have been protected with vaccines against this virus, there is yet a successful curative medication for this disease. The use of autoimmune medications has been widely considered to control the infection, thus postulating possible relationships between COVID-19 and autoimmune diseases. Several studies have suggested the correlation between autoantibodies detected in patients and the severity of the COVID-19 disease. Studies have indicated that the SARS-CoV-2 virus can disrupt the self-tolerance mechanism of the immune system, thus triggering autoimmune conditions. This review discusses the current scenario and future prospects of promising therapeutic strategies that may be employed to regulate such autoimmune conditions. [ABSTRACT FROM AUTHOR]

A molecular mimicry between severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) and human proteins supports the possibility that autoimmunity takes place during coronavirus disease 2019 (COVID-19) contributing to tissue damage. For example, antiphospholipid antibodies (aPL) have been reported in COVID-19 as a result of such mimicry and thought to contribute to the immunothrombosis characteristic of the disease. Consistently, active immunization with the virus spike protein may elicit the production of cross-reactive autoantibodies, including aPL. We prospectively looked at the aPL production in healthcare workers vaccinated with RNA- (BNT162b2, n. 100) or adenovirus-based vaccines (ChAdOx1, n. 50). Anti-cardiolipin, anti-beta2 glycoprotein I, anti-phosphatidylserine/prothrombin immunoglobulin G (IgG), IgA, and IgM before and after vaccination were investigated. Anti-platelet factor 4 immunoglobulins were also investigated as autoantibodies associated with COVID-19 vaccination. Additional organ (anti-thyroid) and non-organ (anti-nuclear) autoantibodies and IgG against human proteome were tested as further post-vaccination autoimmunity markers. The antibodies were tested one or three months after the first injection of ChAdOx1 and BNT162b2, respectively; a 12-month clinical follow-up was also performed. Vaccination occasionally induced low titers of aPL and other autoantibodies but did not affect the titer of pre-existing autoantibodies. No significant reactivities against a microarray of approximately 20,000 human proteins were found in a subgroup of ChAdOx1vaccinees. Consistently, we did not record any clinical manifestation theoretically associated with an underlying autoimmune disorder. The data obtained after the vaccination (two doses for the RNA-based and one dose for the adenovirus-based vaccines), and the clinical follow-up are not supporting the occurrence of an early autoimmune response in this cohort of healthcare workers. [ABSTRACT FROM AUTHOR]

There is growing evidence that preceding the diagnosis or classification of systemic lupus erythematosus (SLE), patients undergo a preclinical phase of disease where markers of inflammation and autoimmunity are already present. Not surprisingly then, even though SLE management has improved over the years, many patients will already have irreversible disease-related organ damage by time they have been diagnosed with SLE. By gaining a greater understanding of the pathogenesis of preclinical SLE, we can potentially identify patients earlier in the disease course who are at-risk of transitioning to full-blown SLE and implement preventative strategies. In this review, we discuss the current state of knowledge of SLE preclinical pathogenesis and propose a screening and preventative strategy that involves the use of promising biomarkers of early disease, modification of lifestyle and environmental risk factors, and initiation of preventative therapies, as examined in other autoimmune diseases such as rheumatoid arthritis and type 1 diabetes. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) mainly affects the respiratory system, but the involvement of other organ systems has also been commonly reported. Acute acro-ischemia or chilblain like lesions were among the first recognized dermatological presentations of COVID-19. Though the occurrence of such lesions has been attributed to the similar interferon-1 mediated immune response in both COVID-19 and systemic lupus erythematosus, we propose another possible explanation based on a common genetic background. In a recent genome-wide association study, the 3p21.31 region was found to be associated with COVID-19 severity. This region also contains the TREX1 gene. Missense mutations of the TREX1 gene are responsible for familial chilblain lupus and its genetic polymorphisms have been implicated in the pathogenesis of systemic lupus erythematosus. Based on this observation, herein we have reviewed other COVID-19 risk loci for potential overlap with dermatological conditions. [ABSTRACT FROM AUTHOR]

A dysregulated immune response toward self-antigens characterizes autoimmune and autoinflammatory (AIF) disorders. Autoantibodies or autoreactive T cells contribute to autoimmune diseases, while autoinflammation results from a hyper-functional innate immune system. Aside from their differences, many studies suggest that monocytes and macrophages (Mo/Ma) significantly contribute to the development of both types of disease. Mo/Ma are innate immune cells that promote an immune-modulatory, pro-inflammatory, or repair response depending on the microenvironment. However, understanding the contribution of these cells to different immune disorders has been difficult due to their high functional and phenotypic plasticity. Several factors can influence the function of Mo/Ma under the landscape of autoimmune/autoinflammatory diseases, such as genetic predisposition, epigenetic changes, or infections. For instance, some vaccines and microorganisms can induce epigenetic changes in Mo/Ma, modifying their functional responses. This phenomenon is known as trained immunity. Trained immunity can be mediated by Mo/Ma and NK cells independently of T and B cell function. It is defined as the altered innate immune response to the same or different microorganisms during a second encounter. The improvement in cell function is related to epigenetic and metabolic changes that modify gene expression. Although the benefits of immune training have been highlighted in a vaccination context, the effects of this type of immune response on autoimmunity and chronic inflammation still remain controversial. Induction of trained immunity reprograms cellular metabolism in hematopoietic stem cells (HSCs), transmitting a memory-like phenotype to the cells. Thus, trained Mo/Ma derived from HSCs typically present a metabolic shift toward glycolysis, which leads to the modification of the chromatin architecture. During trained immunity, the epigenetic changes facilitate the specific gene expression after secondary challenge with other stimuli. Consequently, the enhanced pro-inflammatory response could contribute to developing or maintaining autoimmune/autoinflammatory diseases. However, the prediction of the outcome is not simple, and other studies propose that trained immunity can induce a beneficial response both in AIF and autoimmune conditions by inducing anti-inflammatory responses. This article describes the metabolic and epigenetic mechanisms involved in trained immunity that affect Mo/Ma, contraposing the controversial evidence on how it may impact autoimmune/autoinflammation conditions. [ABSTRACT FROM AUTHOR]

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Cross-reactivity between different human coronaviruses (HCoVs) might contribute to COVID-19 outcomes. Here, we aimed to predict conserved peptides among different HCoVs that could elicit cross-reacting B cell and T cell responses. Three hundred fifty-one full-genome sequences of HCoVs, including SARS-CoV-2 (51), SARS-CoV-1 (50), MERS-CoV (50), and common cold species OC43 (50), NL63 (50), 229E (50), and HKU1 (50) were downloaded aligned using Geneious Prime 20.20. Identification of epitopes in the conserved regions of HCoVs was carried out using the Immune Epitope Database (IEDB) to predict B- and T-cell epitopes. Further, we identified sequences that bind multiple common MHC and modeled the three-dimensional structures of the protein regions. The search yielded 73 linear and 35 discontinuous epitopes. A total of 16 B-cell and 19 T-cell epitopes were predicted through a comprehensive bioinformatic screening of conserved regions derived from HCoVs. The 16 potentially cross-reactive B-cell epitopes included 12 human proteins and four viral proteins among the linear epitopes. Likewise, we identified 19 potentially cross-reactive T-cell epitopes covering viral proteins. Interestingly, two conserved regions: LSFVSLAICFVIEQF (NSP2) and VVHSVNSLVSSMEVQSL (spike), contained several matches that were described epitopes for SARS-CoV. Most of the predicted B cells were buried within the SARS-CoV-2 protein regions' functional domains, whereas T-cell stretched close to the functional domains. Additionally, most SARS-CoV-2 predicted peptides (80%) bound to different HLA types associated with autoimmune diseases. We identified a set of potential B cell and T cell epitopes derived from the HCoVs that could contribute to different diseases manifestation, including autoimmune disorders. [ABSTRACT FROM AUTHOR]

Glycoprotein nonmetastatic melanoma protein B (GPNMB) is involved in various cell functions such as cell adhesion, migration, proliferation, and differentiation. In this study, we set forth to determine the role of GPNMB in systemic sclerosis (SSc) fibroblasts. Dermal fibroblasts were isolated from skin biopsies from healthy subjects and patients with diffuse cutaneous (dc)SSc. GPNMB was upregulated in dcSSc fibroblasts compared to normal fibroblasts, and correlated negatively with the modified Rodnan skin score. In addition, dcSSc fibroblasts secreted higher levels of soluble (s)GPNMB (147.4 ± 50.2 pg/ml vs. 84.8 ± 14.8 pg/ml, p<0.05), partly due to increased ADAM10. sGPNMB downregulated profibrotic genes in dcSSc fibroblasts and inhibited cell proliferation and gel contraction. The anti-fibrotic effect of sGPNMB was at least in part mediated through CD44, which is regulated by histone acetylation. TGFβ downregulated GPNMB and decreased the release of its soluble form in normal fibroblasts. In dcSSc fibroblasts, GPNMB is upregulated by its own soluble form. Our data demonstrate an anti-fibrotic role of sGPNMB in SSc and established a role for the ADAM10-sGPNMB-CD44 axis in dermal fibroblasts. Upregulating GPNMB expression might provide a novel therapeutic approach in SSc. [ABSTRACT FROM AUTHOR]

Epigenetic alterations in pathogenesis of systemic lupus erythematosus (SLE) have gained more attention recently in adults. We assessed the methylation of CD70 promoter, a costimulatory molecule on T cells, in juvenile SLE (JSLE), and compared this to that found in controls and the literature of adult SLE patients. DNA methylation status was evaluated on peripheral blood from JSLE patients and healthy controls. Twenty-five patients with JSLE and 24 healthy controls were compared. JSLE patients had lower unmethylated CpG islands compared to the control group (mean ± SD; 0.78 ± 0.42 vs 10503.80 ± 39796.95). However, the difference was not significant (P-value; 0.22). Despite hypomethylation of CD70 gene promoter in CD4+ T-cells from adult patients with SLE, no statistically significant differences observed in patients with JSLE compared with healthy controls. This may suggest a mechanism different in JSLE patients than in adults. [ABSTRACT FROM AUTHOR]

Type I interferons (IFN-I) and their cognate receptor, the IFNAR1/2 heterodimer, are critical components of the innate immune system in humans. They have been widely explored in the context of viral infection and autoimmune disease where they play key roles in protection against infection or shaping disease pathogenesis. A false dichotomy has emerged in the study of IFN-I where interferons are thought of as either beneficial or pathogenic. This 'good or bad' viewpoint excludes more nuanced interpretations of IFN-I biology - for example, it is known that IFN-I is associated with the development of systemic lupus erythematosus, yet is also protective in the context of infectious diseases and contributes to resistance to viral infection. Studies have suggested that a shared transcriptomic signature underpins both potential resistance to viral infection and susceptibility to autoimmune disease. This seems to be particularly evident in females, who exhibit increased viral resistance and increased susceptibility to autoimmune disease. The molecular mechanisms behind such a signature and the role of sex in its determination have yet to be precisely defined. From a genomic perspective, several single nucleotide polymorphisms (SNPs) in the IFN-I pathway have been associated with both infectious and autoimmune disease. While overlap between infection and autoimmunity has been described in the incidence of these SNPs, it has been overlooked in work and discussion to date. Here, we discuss the possible contributions of IFN-Is to the pathogenesis of infectious and autoimmune diseases. We comment on genetic associations between common SNPs in IFN-I or their signalling molecules that point towards roles in protection against viral infection and susceptibility to autoimmunity and propose that a shared transcriptomic and genomic immunological signature may underlie resistance to viral infection and susceptibility to autoimmunity in humans. We believe that defining shared transcriptomic and genomic immunological signatures underlying resistance to viral infection and autoimmunity in humans will reveal new therapeutic targets and improved vaccine strategies, particularly in females. [ABSTRACT FROM AUTHOR]

Costimulatory and coinhibitory mechanisms appear to be involved throughout immune responses to control their specificity and level. Many mechanisms operate; therefore, various theoretical models should be considered complementary rather than competing. One such coinhibitory model, pictured in 1971, involves the crosslinking of antigen receptors with inhibitory Fc receptors by antigen/antibody complexes. This model was prompted by observations that the Fc portion of antibody was required for potent suppression of immune responses by antibody. The signal via the antigen receptor wakes up T or B cells, providing specificity, while costimulators and coinhibitors stimulate or inhibit these awoken cells. The recent observations that administration of monoclonal anti‐SARS‐CoV‐2 spike antibodies in early COVID‐19 patients inhibits the induction of clinically damaging autoimmune antibodies suggest they may provide negative Fc signals that are blocked in COVID‐19 patients. Furthermore, the reduced ability of SARS‐CoV‐2 antigen to localize to germinal centres in COVID‐19 patients also suggests a block in binding of the Fc of antibody bound to antigen on FcγRIIb of follicular dendritic cells. The distinction between self and foreign is made not only at the beginning of immune responses but also throughout, and involves multiple mechanisms and models. There are past beginnings (history of models) and current and future beginnings for solving serious clinical problems (such as COVID‐19) and different types of models used for understanding the complexities of fundamental immunology. [ABSTRACT FROM AUTHOR]

Inflammasomes are multiprotein complexes capable of sensing pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and cellular perturbations. Upon stimulation, the inflammasomes activate the production of the pro-inflammatory cytokines IL-1β and IL-18 and induce gasdermin D-mediated pyroptosis. Dysregulated inflammasome signaling could lead to hyperinflammation in response to environmental triggers, thus contributing to the pathogenesis of childhood autoimmune/autoinflammatory diseases. In this review, we group childhood rheumatic diseases into the autoinflammation to autoimmunity spectrum and discuss about the involvement of inflammasomes in disease mechanisms. Genetic mutations in inflammasome components cause monogenic autoinflammatory diseases, while inflammasome-related genetic variants have been implicated in polygenic childhood rheumatic diseases. We highlight the reported associations of inflammasome signaling-related genetic polymorphisms/protein levels with pediatric autoimmune disease susceptibility and disease course. Furthermore, we discuss about the use of IL-1 receptor antagonist as an adjunctive therapy in several childhood autoimmune diseases, including macrophage activation syndrome (MAS) and multisystem inflammatory syndrome in children (MIS-C) related to COVID-19. A comprehensive multi-cohort comparison on inflammasome gene expression profile in different pediatric rheumatic diseases is needed to identify patient subsets that might benefit from the adjunctive therapy of IL-1β inhibitors. [ABSTRACT FROM AUTHOR]

Current literature regarding systemic autoimmune diseases in X‐chromosome aneuploidies is scarce and limited to case reports. Our aim was to evaluate the frequency of anti‐nuclear (ANAs), extractable nuclear (ENA), anti‐double‐stranded DNA (dsDNAs), anti‐smooth muscle (ASMAs) and anti‐mitochondrial (AMAs) antibodies in a large cohort of adults with Klinefelter's syndrome (KS, 47,XXY) and rare higher‐grade sex chromosome aneuploidies (HGAs) for the first time. Sera from 138 X‐chromosome aneuploid patients [124 adult patients with 47,XXY KS and 14 patients with HGA (six children, eight adults)] and 50 age‐matched 46,XY controls were recruited from the Sapienza University of Rome (2007–17) and tested for ANAs, ENAs, anti‐dsDNAs, ASMAs and AMAs. Non‐organ‐specific immunoreactivity was found to be significantly higher in patients with 47,XXY KS (14%) than in the controls (2%, p = 0.002). Among all the antibodies investigated, only ANAs were observed significantly more frequently in patients with 47,XXY KS (12.1%) than in the controls (2%, p = 0.004). No anti‐dsDNA immunoreactivity was found. Stratifying by testosterone replacement therapy (TRT), non‐organ‐specific autoantibody frequencies were higher in TRT‐naive (p = 0.01) and TRT‐treated groups than in controls. No patients with HGA were found positive for the various autoantibodies. Non‐organ‐specific autoantibodies were significantly present in 47,XXY adult patients. Conversely, HGAs did not appear to be target of non‐organ‐specific immunoreactivity, suggesting that KS and HGAs should be considered as two distinct conditions. The classification and diagnosis of systemic autoimmune diseases is frequently difficult. To support a correct clinical evaluation of KS disease and to prevent eventual secondary irreversible immune‐mediated damages, we highlight the importance of screening for non‐organ‐specific autoimmunity in Klinefelter's syndrome. [ABSTRACT FROM AUTHOR]

Psoriatic arthritis (PsA) is an underdiagnosed entity with a broad impact on the quality of life. Although the pathogenesis is largely unknown, autoimmune footprints of the inflammation in PsA have increasingly been recognized. Most of the genetic variation predisposing to PsA is mapped to the class I major histocompatibility complex (MHC) region and shared by a variety of autoimmune diseases. Polymorphisms in the genes IL12B, IL23R, IL13, TNIP1, TRAF3IP2, TYK2, and many others explain the nonHLA genetic risk with little known functional consequences. Entheseal and synovial cellular infiltrate with oligoclonal CD8+ T cells and occasional germinal centers, loss of regulatory T cell function, and specific autoantibodies such as anti-PsA peptide, anti-LL-37, and anti-ADAMTSL5 are the immunopathological findings suggestive of autoimmunity. These were supported by clinical observations of autoimmune multimorbidity and treatment response to calcineurin/mTOR and co-stimulation inhibition. [ABSTRACT FROM AUTHOR]

The coronavirus disease (COVID-19) is a respiratory tract infection caused by the new virus SARS-CoV-2. The acute phase of the infection may in certain individuals be followed by another longer phase of disease (long COVID) of unknown etiology probably associated in certain cases with autoimmune activation. It has been shown that COVID-19 can trigger autoantibody production and in genetically predisposed patients may cause the onset or exacerbation of autoimmune diseases. We are reporting a case of mild COVID-19 infection complicated by autoantibody production and cutaneous and gastrointestinal symptoms and subsequently diagnosed with systemic sclerosis (SSc). A 47-year-old man with no history of any autoimmune diseases and in good health became sick together with his family on the 12th of November with mild symptoms: tiredness, fever, cough, and sore throat. Oropharyngeal swab for SARS-CoV-2 tested positive. He was isolated at home and did not require hospitalization. Three weeks later he presented with clinical manifestation compatible with suspicion of SSc. He briefly presented with skin rush, periorbital edema and conjunctivitis, vomiting, dysphagia, burning sensation in the skin, above all in the fingertips and around the mouth, puffy fingers, Raynaud's phenomenon, pain at the fingertip of the middle finger where a depressed area was noticed without a clear ulceration. ANA showed a strongly positive nucleolar pattern. Anti-PM/Scl 75 and PM/Scl 100 resulted positive. High-resolution computed tomography (HCRT) showed early stage of interstitial lung disease (ILD). The patient was diagnosed with SSc based on the persistence of autoantibodies and the clinical and radiological pictures according to the ACR/EULAR classification (scores: puffy finger, 2; ILD, 2; Raynaud's phenomenon, 3; SSc related antibodies, 3; total 10). There are several cases described in the medical literature of possible new onset of SLE after COVID-19 infection. This is the first case that describes a possible new onset of SSc. Conclusion: SARS-CoV-2 may trigger systemic sclerosis. [ABSTRACT FROM AUTHOR]

Microvascular injury is considered an initial event in the pathogenesis of scleroderma and endothelial cells are suspected of being the target of the autoimmune process seen in the disease. EBV has long been proposed as a trigger for autoimmune diseases, including scleroderma. Nevertheless, its contribution to the pathogenic process remains poorly understood. In this study, we report that EBV lytic antigens are detected in scleroderma dermal vessels, suggesting that endothelial cells might represent a target for EBV infection in scleroderma skin. We show that EBV DNA load is remarkably increased in peripheral blood, plasma and circulating monocytes from scleroderma patients compared to healthy EBV carriers, and that monocytes represent the prominent subsets of EBV-infected cells in scleroderma. Given that monocytes have the capacity to adhere to the endothelium, we then investigated whether monocyte-associated EBV could infect primary human endothelial cells. We demonstrated that endothelial cells are infectable by EBV, using human monocytes bound to recombinant EBV as a shuttle, even though cell-free virus failed to infect them. We show that EBV induces activation of TLR9 innate immune response and markers of vascular injury in infected endothelial cells and that up-regulation is associated with the expression of EBV lytic genes in infected cells. EBV innate immune modulation suggests a novel mechanism mediating inflammation, by which EBV triggers endothelial cell and vascular injury in scleroderma. In addition, our data point to up-regulation of EBV DNA loads as potential biomarker in developing vasculopathy in scleroderma. These findings provide the framework for the development of novel therapeutic interventions to shift the scleroderma treatment paradigm towards antiviral therapies. [ABSTRACT FROM AUTHOR]

In the autoimmune disease Systemic Lupus Erythematosus (SLE), autoantibodies are formed that promote inflammation and tissue damage. There has been significant interest in understanding the B cell derangements involved in SLE pathogenesis. The past few years have been particularly fruitful in three domains: the role of PI3K signaling in loss of B cell tolerance, the role of IFNγ signaling in the development of autoimmunity, and the characterization of changes in chromatin accessibility in SLE B cells. The PI3K pathway coordinates various downstream signaling molecules involved in B cell development and activation. It is governed by the phosphatases PTEN and SHIP-1. Murine models lacking either of these phosphatases in B cells develop autoimmune disease and exhibit defects in B cell tolerance. Limited studies of human SLE B cells demonstrate reduced expression of PTEN or increased signaling events downstream of PI3K in some patients. IFNγ has long been known to be elevated in both SLE patients and mouse models of lupus. New data suggests that IFNγR expression on B cells is required to develop autoreactive germinal centers (GC) and autoantibodies in murine lupus. Furthermore, IFNγ promotes increased transcription of BCL6, IL-6 and T-bet in B cells, which also promote GC and autoantibody formation. IFNγ also induces epigenetic changes in human B cells. SLE B cells demonstrate significant epigenetic reprogramming, including enhanced chromatin accessibility at transcription factor motifs involved in B cell activation and plasma cell (PC) differentiation as well as alterations in DNA methylation and histone modifications. Histone deacetylase inhibitors limit disease development in murine lupus models, at least in part via their ability to prevent B cell class switching and differentiation into plasma cells. This review will discuss relevant discoveries of the past several years pertaining to these areas of SLE B cell biology. [ABSTRACT FROM AUTHOR]

Haploinsufficiency of A20 (HA20) is a newly described immune dysregulation disease due to the loss-of-function mutation in TNFAIP3. In the present study, we report six patients from four unrelated Chinese families with distinct pathogenic mutations in TNFAIP3, including three novel variants. All of the patients presented with early-onset autoimmune/auto-inflammatory diseases, including Crohn's disease, Behcet's disease, systemic lupus erythematosus, and unclassified auto-inflammatory syndrome. Immunological phenotype tests showed elevated levels of serum pro-inflammatory cytokines, reduced naïve B cells and TFH cells, an inverted CD4:CD8 ratio, and increased susceptibility to restimulation-induced cell death (RICD) and FASL-induced apoptosis in derived T cells. Insufficient expression of A20 was found in these patients. A20 truncated protein was detected in mutant-transfected 293T cells. Upon TNF-α stimulation, the NF-κB pathway was over-activated in both derived T cells of these patients and mutant-transfected Hela cells. In conclusion, clinical manifestations are diverse in patients with HA20, even in those with the same TNFAIP3 mutation. A20 inhibits the NF-κB pathway and plays a crucial role in the regulation of cell death. Haploinsufficiency of A20 leads to defects in both innate and adaptive immunity. [ABSTRACT FROM AUTHOR]

Autoimmune disease is a substantial cause of morbidity and is strongly influenced by genetic risk. Extensive efforts have characterized the overall genetic basis of many autoimmune diseases, typically by investigation of common variants. While these common variants have modest effects and may cumulatively predispose to disease, it is also increasingly apparent that rare variants have significantly greater effect on phenotype and are likely to contribute to autoimmune disease. Recent advances have illustrated the next fundamental step in elucidating the genetic basis of autoimmunity, moving beyond association to demonstrate the functional consequences of these variants. [ABSTRACT FROM AUTHOR]

DNA methylation as a process that regulates gene expression is crucial in immune cells biology. Global and gene specific methylation changes have been described in autoimmunity, especially in Systemic Lupus Erythematosus. These changes not only contribute to the understanding of the disease, but also some have been proposed as diagnostic or disease activity biomarkers. The present review compiles the most recent discoveries on this field on each type of immune cells, including specific changes in signalling pathways, genes of interest and its possible applications on diagnosis or treatment. [ABSTRACT FROM AUTHOR]

Introduction: Drug-induced lupus (DIL) can comprise up to 10% of new lupus cases annually, and the list of medications associated with DIL is increasing. However, it can be difficult to recognize the connection between symptoms and a medication-induced autoimmune syndrome, which can lead to an invasive, costly workup. Given that the prognosis is usually good if therapy with the offending agent is stopped, it is important to identify this clinical entity promptly. Case Presentation: A healthy, 44-year-old man with hypertension was seen initially because of shoulder pain and again after development of fevers and chest pain. He underwent a thorough infectious workup and then oncologic workup, with his clinical course complicated by a Histoplasma infection. After evaluation by subspecialists, the patient was thought to have an autoimmune condition related to DIL. His symptoms improved after he discontinued the offending drug therapy and received a course of corticosteroids. Discussion: Our case highlights how DIL should be on the differential when seemingly disparate symptoms develop in a patient receiving DIL-associated medications. Lupus is one of the "great imitators," in which symptoms can be ascribed to many different underlying causes. Although this patient's presentation may have been confounded by concomitant histoplasmosis, his improvement with cessation of hydralazine treatment argues in favor of DIL. His continued atypical serologic test results could be residual from his DIL and should normalize with time. However, it raises the question whether this bout of DIL has unmasked a previously quiescent autoimmune condition, requiring continued observation. [ABSTRACT FROM AUTHOR]

Aryl hydrocarbon receptor (AhR), a type of transcriptional factor, is widely expressed in immune cells. The activation of AhR signaling pathway depends on its ligands, which exist in environment and can also be produced by metabolism. Normal expressions of AhR and AhR-mediated signaling may be essential for immune responses, and effects of AhR signaling on the development and function of innate and adaptive immune cells have also been revealed in previous studies. Recent studies also indicate that aberrant AhR signaling may be related to autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), autoimmune uveitis (AU), autoimmune diabetes, Behcet's disease (BD) and myasthenia gravis (MG). Moreover, administration of AhR ligands or drugs has been proven effective for improving pathological outcomes in some autoimmune diseases or models. In this review, we summarize the effects of AhR on several innate and adaptive immune cells associated with autoimmunity, and the mechanism on how AhR participates in autoimmune diseases. In addition, we also discuss therapeutic potential and application prospect of AhR in autoimmune diseases, so as to provide valuable information for exploring novel and effective approaches to autoimmune disease treatments. [ABSTRACT FROM AUTHOR]

Infections are considered important environmental triggers of autoimmunity and can contribute to autoimmune disease onset and severity. Nucleic acids and the complexes that they form with proteins—including chromatin and ribonucleoproteins—are the main autoantigens in the autoimmune disease systemic lupus erythematosus (SLE). How these nuclear molecules become available to the immune system for recognition, presentation, and targeting is an area of research where complexities remain to be disentangled. In this review, we discuss how bacterial infections participate in the exposure of nuclear autoantigens to the immune system in SLE. Infections can instigate pro-inflammatory cell death programs including pyroptosis and NETosis, induce extracellular release of host nuclear autoantigens, and promote their recognition in an immunogenic context by activating the innate and adaptive immune systems. Moreover, bacterial infections can release bacterial DNA associated with other bacterial molecules, complexes that can elicit autoimmunity by acting as innate stimuli of pattern recognition receptors and activating autoreactive B cells through molecular mimicry. Recent studies have highlighted SLE disease activity-associated alterations of the gut commensals and the expansion of pathobionts that can contribute to chronic exposure to extracellular nuclear autoantigens. A novel field in the study of autoimmunity is the contribution of bacterial biofilms to the pathogenesis of autoimmunity. Biofilms are multicellular communities of bacteria that promote colonization during chronic infections. We review the very recent literature highlighting a role for bacterial biofilms, and their major components, amyloid/DNA complexes, in the generation of anti-nuclear autoantibodies and their ability to stimulate the autoreactive immune response. The best studied bacterial amyloid is curli, produced by enteric bacteria that commonly cause infections in SLE patients, including Escherichia coli and Salmonella spps. Evidence suggests that curli/DNA complexes can trigger autoimmunity by acting as danger signals, molecular mimickers, and microbial chaperones of nucleic acids. [ABSTRACT FROM AUTHOR]

Women and men exhibit differences in innate and adaptive immunity, and women are more susceptible to numerous autoimmune disorders. Two or more X chromosomes increases the risk for some autoimmune diseases, and increased expression of some X‐linked immune genes is frequently observed in female lymphocytes from autoimmune patients. Evidence from mouse models of autoimmunity also supports the idea that increased expression of X‐linked genes is a feature of female‐biased autoimmunity. Recent studies have begun to elucidate the correlation between abnormal X‐chromosome inactivation (XCI), an essential mechanism female somatic cells use to equalize X‐linked gene dosage between the sexes, and autoimmunity in lymphocytes. In this review, we highlight research describing overexpression of X‐linked immunity‐related genes and female‐biased autoimmunity in both humans and mouse models, and make connections with our recent work elucidating lymphocyte‐specific mechanisms of XCI maintenance that become altered in lupus patients. [ABSTRACT FROM AUTHOR]

Autoimmune diseases can be chronic with relapse of inflammatory symptoms, but it can be also acute and life-threatening if immune cells destroy life-supporting organs, such as lupus nephritis. The etiopathogenesis of autoimmune diseases has been revealed as that genetics and environmental factors-mediated dysregulated immune responses contribute to the initiation and development of autoimmune disorders. However, the current understanding of pathogenesis is limited and the underlying mechanism has not been well defined, which lows the development of novel biomarkers and new therapeutic strategies for autoimmune diseases. To improve this, broadening and deepening our understanding of pathogenesis is an unmet need. As genetic susceptibility cannot explain the low accordance rate of incidence in homozygous twins, epigenetic regulations might be an additional explanation. Therefore, this review will summarize current progress of studies on epigenetic dysregulations contributing to autoimmune diseases, including SLE, rheumatoid arthritis (RA), psoriasis, type 1 diabetes (T1D), and systemic sclerosis (SSc), hopefully providing opinions on orientation of future research, as well as discussing the clinical utilization of potential biomarkers and therapeutic strategies for these diseases. [ABSTRACT FROM AUTHOR]

Various intracellular pattern recognition receptors (PRRs) recognize cytosolic pathogen‐associated molecular patterns (PAMPs) and damage‐associated molecular patterns (DAMPs). Cyclic GMP‐AMP synthase (cGAS), a cytosolic PRR, recognizes cytosolic nucleic acids including dsDNAs. The recognition of dsDNA by cGAS generates cyclic GMP‐AMP (GAMP). The cGAMP is then recognized by STING generating type 1 IFNs and NF‐κB‐mediated generation of pro‐inflammatory cytokines and molecules. Thus, cGAS‐STING signaling mediated recognition of cytosolic dsDNA causing the induction of type 1 IFNs plays a crucial role in innate immunity against cytosolic pathogens, PAMPs, and DAMPs. The overactivation of this system may lead to the development of autoinflammation and autoimmune diseases. The article opens with the introduction of different PRRs involved in the intracellular recognition of dsDNA and gives a brief introduction of cGAS‐STING signaling. The second section briefly describes cGAS as intracellular PRR required to recognize intracellular nucleic acids (dsDNA and CDNs) and the formation of cGAMP. The cGAMP acts as a second messenger to activate STING‐ and TANK‐binding kinase 1‐mediated generation of type 1 IFNs and the activation of NF‐κB. The third section of the article describes the role of cGAS‐STING signaling in the induction of autoinflammation and various autoimmune diseases. The subsequent fourth section describes both chemical compounds developed and the endogenous negative regulators of cGAS‐STING signaling required for its regulation. Therapeutic targeting of cGAS‐STING signaling could offer new ways to treat inflammatory and autoimmune diseases. [ABSTRACT FROM AUTHOR]