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Purpose: The objective of this study is to determine the prevalence of certain autoimmune diseases in transgender and gender diverse (TGD) youth. Methods: A multicenter, retrospective analysis was conducted from January 2013 to January 2019 of youth ≤26 years of age with concurrent diagnoses of gender dysphoria (GD) and at least one of the studied autoimmune diseases. Prevalence rates were calculated and compared to previously reported rates. Statistical significance was determined using second generation p-values as pooled estimates of prevalence rates across study sites compared to a range of rates reported in the literature. Results: During the study period, 128 of 3812 (3.4%) youth evaluated for GD had a concurrent diagnosis of at least one of the studied autoimmune diseases. Three autoimmune diseases had prevalence rates significantly higher than those previously documented in the literature (second generation p-value=0.000): type 1 diabetes mellitus (112.8/10,000, 95% confidence interval [CI]: 83.8–151.8), systemic lupus erythematosus (13.1/10,000, 95% CI: 5.5–31.5), and Graves' disease (12.3/10,000, 95% CI: 4.0–38.4). Conclusion: There is an increased prevalence of certain autoimmune diseases in youth who identify as TGD presenting for subspecialty care. Limitations such as retrospective study design, selection bias, and reliance on electronic medical records make it difficult to draw wide-reaching conclusions about these findings. This study highlights the need for more research to delineate the impacts of unrecognized or untreated GD on autoimmune disease development and control. [ABSTRACT FROM AUTHOR]

Protein kinase C delta (PKCδ) has emerged as a key protective molecule against systemic lupus erythematosus (SLE or lupus), an autoimmune disease characterized by anti-double stranded (ds) DNA IgGs. Although PKCδ-deficient mice and lupus patients with mutated PRKCD genes clearly demonstrate the requirement for PKCδ in preventing lupus autoimmunity, this critical tolerance mechanism remains poorly understood. We recently reported that PKCδ acts as a key regulator of B cell tolerance by selectively deleting anti-dsDNA B cells in the germinal center (GC). PKCδ's tolerance function is activated by sphingomyelin synthase 2 (SMS2), a lipid enzyme whose expression is generally reduced in B cells from lupus patients. Moreover, pharmacologic strengthening of the SMS2/PKCδ tolerance pathway alleviated lupus pathogenesis in mice. Here, we review relevant publications in order to provide mechanistic insights into PKCδ's tolerance activity and discuss the potential significance of therapeutically targeting PKCδ's tolerance activity in the GC for selectively inhibiting lupus autoimmunity. [ABSTRACT FROM AUTHOR]

Sjögren's disease (SjD) is a heterogeneous autoimmune disease characterized by severe dryness of mucosal surfaces, particularly the mouth and eyes; fatigue; and chronic pain. Chronic inflammation of the salivary and lacrimal glands, auto-antibody formation, and extra-glandular manifestations occur in subsets of patients with SjD. An aberrant expression of long, non-coding RNAs (lncRNAs) has been described in many autoimmune diseases, including SjD. Here, we review the current literature on lncRNAs in SjD and their role in regulating X chromosome inactivation, immune modulatory functions, and their potential as biomarkers. [ABSTRACT FROM AUTHOR]

More than 20% of American adults live with a mental disorder, many of whom are treatment resistant or continue to experience symptoms. Other approaches are needed to improve mental health care, including prevention. The role of the microbiome has emerged as a central tenet in mental and physical health and their interconnectedness (well-being). Under normal conditions, a healthy microbiome promotes homeostasis within the host by maintaining intestinal and brain barrier integrity, thereby facilitating host well-being. Owing to the multidirectional crosstalk between the microbiome and neuro-endocrineimmune systems, dysbiosis within the microbiome is a main driver of immunemediated systemic and neural inflammation that can promote disease progression and is detrimental to well-being broadly and mental health in particular. In predisposed individuals, immune dysregulation can shift to autoimmunity, especially in the presence of physical or psychological triggers. The chronic stress response involves the immune system, which is intimately involved with the gut microbiome, particularly in the process of immune education. This interconnection forms the microbiota-gut-immune-brain axis and promotes mental health or disorders. In this brief review, we aim to highlight the relationships between stress, mental health, and the gut microbiome, along with the ways in which dysbiosis and a dysregulated immune system can shift to an autoimmune response with concomitant neuropsychological consequences in the context of the microbiota-gut-immune-brain axis. Finally, we aim to review evidenced-based prevention strategies and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Introduction: Systemic autoimmune diseases (SADs) are a significant burden on the healthcare system. Understanding the complexity of the peripheral immunophenotype in SADs may facilitate the differential diagnosis and identification of potential therapeutic targets. Methods: Single-cell mass cytometric immunophenotyping was performed on peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) and therapy-naive patients with rheumatoid arthritis (RA), progressive systemic sclerosis (SSc), and systemic lupus erythematosus (SLE). Immunophenotyping was performed on 15,387,165 CD45+ live single cells from 52 participants (13 cases/group), using an antibody panel to detect 34 markers. Results: Using the t-SNE (t-distributed stochastic neighbor embedding) algorithm, the following 17 main immune cell types were determined: CD4+/ CD57– T cells, CD4+/CD57+ T cells, CD8+/CD161– T cells, CD8+/CD161+/CD28+ T cells, CD8dim T cells, CD3+/CD4–/CD8– T cells, TCRγ/δ T cells, CD4+ NKT cells, CD8+ NKT cells, classic NK cells, CD56dim/CD98dim cells, B cells, plasmablasts, monocytes, CD11cdim/CD172dim cells, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs). Seven of the 17 main cell types exhibited statistically significant frequencies in the investigated groups. The expression levels of the 34 markers in the main populations were compared between HCs and SADs. In summary, 59 scatter plots showed significant differences in the expression intensities between at least two groups. Next, each immune cell population was divided into subpopulations (metaclusters) using the FlowSOM (self-organizing map) algorithm. Finally, 121 metaclusters (MCs) of the 10 main immune cell populations were found to have significant differences to classify diseases. The single-cell T-cell heterogeneity represented 64MCs based on the expression of 34 markers, and the frequency of 23 MCs differed significantly between at least twoconditions. The CD3– non-T-cell compartment contained 57 MCs with 17 MCs differentiating at least two investigated groups. In summary, we are the first to demonstrate the complexity of the immunophenotype of 34 markers over 15 million single cells in HCs vs. therapy-naive patients with RA, SSc, and SLE. Disease specific population frequencies or expression patterns of peripheral immune cells provide a single-cell data resource to the scientific community. [ABSTRACT FROM AUTHOR]

Summary: The discovery of toll‐like receptors (TLRs) and the subsequent recognition that endogenous nucleic acids (NAs) could serve as TLR ligands have led to essential insights into mechanisms of healthy immune responses as well as pathogenic mechanisms relevant to systemic autoimmune and inflammatory diseases. In systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis, NA‐containing immune complexes serve as TLR ligands, with distinct implications depending on the additional immune stimuli available. Plasmacytoid dendritic cells (pDCs), the robust producers of type I interferon (IFN‐I), are providing critical insights relevant to TLR‐mediated healthy immune responses and tissue repair, as well as generation of inflammation, autoimmunity and fibrosis, processes central to the pathogenesis of many autoimmune diseases. In this review, we describe recent data characterizing the role of platelets and NA‐binding chemokines in modulation of TLR signaling in pDCs, as well as implications for how the IFN‐I products of pDCs contribute to the generation of inflammation and wound healing responses by monocyte/macrophages. Chemokine modulators of TLR‐mediated B cell tolerance mechanisms and interactions between TLR signaling and metabolic pathways are also considered. The modulators of TLR signaling and their contribution to the pathogenesis of systemic autoimmune diseases suggest new opportunities for identification of novel therapeutic targets. [ABSTRACT FROM AUTHOR]

The European Journal of Rheumatology is an open access journal that covers various aspects of rheumatology. It publishes original articles, reviews, case-based reviews, and letters to the editor. The journal is aimed at academicians, practitioners, specialists, and students in the field of rheumatology. The document provides a schedule of sessions and presentations at a conference on autoimmune diseases, covering topics such as COVID-19, lupus, vasculitis, and novel approaches to handling autoimmune diseases. It also contains summaries of presentations on topics related to autoimmune diseases, including myositis, post-COVID syndrome, uveitis, and genetic predisposition to autoimmunity. The document discusses cell therapy, novel therapies, and the impact of environmental factors on autoimmune diseases. It explores the potential of CAR-T cell therapy, mesenchymal stromal cell transplantation, cannabis, therapeutic peptides, and RNA gene expression in the treatment and management of autoimmune diseases. The document also highlights the impact of COVID-19 on patients with systemic lupus erythematosus (SLE), finding that SLE patients have an increased risk of severe COVID-19 and higher mortality rates. The document contains summaries of various research studies and discussions related to autoimmune diseases, covering topics such as inflammatory signals in myeloid cells, cardiovascular risk profile of rheumatoid arthritis patients, and immunonutritional status of patients with systemic lupus erythematosus. It also explores subjects such as autoantib [Extracted from the article]

Background: Vitiligo is an immune‑mediated, chronic skin condition that affects both the innate and adaptive immune systems. Antimicrobial peptide overexpression is one of its defining characteristics. Granulysin (GNLY), an antimicrobial peptide, may play a role in the pathogenesis of various autoimmune diseases. Objectives: To estimate the serum GNLY levels in vitiligo patients and to correlate those levels with the severity and activity of the disease. Materials and Methods: This case‑control study included 60 non‑segmental vitiligo patients (Group A) and a control group of 60 people who were matched for age and sex, appeared to be in good health, and were not suffering from vitiligo (Group B). The serum granulysin levels of all subjects were measured using an enzyme‑linked immunosorbent assay. Results: When compared to the control group, vitiligo patients had significantly higher serum GNLY levels (P = 0.001). When compared to patients with stable disease, those with active vitiligo had significantly higher serum GNLY levels (P = 0.008). Additionally, there was a positive correlation between the serum GNLY levels and the vitiligo area severity index and vitiligo disease activity scores (P = 0.004 and <0.001, respectively). Limitations: Study population was relatively small. Evaluation of serum granulysin before and after treatment could have been more beneficial. Conclusions: Blood granulysin levels could contribute to the pathogenesis of vitiligo. A higher serum granulysin level may also be a trustworthy predictor of the severity and progression of a disease. [ABSTRACT FROM AUTHOR]

Summary: Red blood cell autoimmunity and alloimmunity are potentially linked. Quantification of this association can tailor extensively matched red blood cell transfusions in patients with autoimmunity. Using an incident new‐user cohort comprising 47 285 previously non‐transfused, non‐alloimmunised patients, we compared transfusion‐induced red blood cell alloimmunisation incidences in direct antiglobulin test (DAT)‐positive and control patients. Additionally, we performed case–control analyses to handle potential confounding by clinical immunomodulators. Among (IgG and/or C3d) DAT‐positive patients (N = 380), cumulative red blood cell alloimmunisation incidences after 10 units transfused reached 4.5% (95% confidence interval [CI] 2.5–8.2) versus 4.2% (CI 3.9–4.5, p = 0.88) in controls. In case–control analyses, alloimmunisation relative risks among DAT‐positive patients increased to 1.7 (CI 1.1–2.8). Additional adjustments for pre‐DAT transfusion exposure or the extent of Rh/K mismatching did not impact results. In conclusion, while patients with DAT positivity show an intrinsically increased alloimmune red blood cell response, their absolute risk is comparable to control patients due to counteracting co‐existing immunosuppressive conditions. Consequently, isolated DAT positivity in patients lacking overt haemolysis or complicated alloantibody testing does not seem to warrant extended matching strategies. [ABSTRACT FROM AUTHOR]

Scientific outreach activities play an important role in disseminating knowledge, connecting the general public to research and breaking down scientific skepticism barriers. However, the vision‐impaired community is often disadvantaged when the most common audio–visual approach of scientific communication is applied. Here we integrated tactile clues in the scientific communication of immune processes involved in the autoimmune skin disease psoriasis. We fostered the involvement of the vision‐impaired community through interactive experiences, including tactile scientific origami art, a haptic poster and wood‐carved molecular models. Readily accessible science communication that engages a number of senses is a critical step toward making science more inclusive and engaging for individuals with a wide range of sensory abilities. The approach of the 2023 Monash Sensory Science exhibition aligns with the principles of equity, diversity and inclusion and helps to empower a more informed and scientifically literate public. [ABSTRACT FROM AUTHOR]

The gut microbiota and short chain fatty acids (SCFA) have been associated with immune regulation and autoimmune diseases. Autoimmune kidney diseases arise from a loss of tolerance to antigens, often with unclear triggers. In this review, we explore the role of the gut microbiome and how disease, diet, and therapy can alter the gut microbiota consortium. Perturbations in the gut microbiota may systemically induce the translocation of microbiota-derived inflammatory molecules such as liposaccharide (LPS) and other toxins by penetrating the gut epithelial barrier. Once in the blood stream, these pro-inflammatory mediators activate immune cells, which release pro-inflammatory molecules, many of which are antigens in autoimmune diseases. The ratio of gut bacteria Bacteroidetes/Firmicutes is associated with worse outcomes in multiple autoimmune kidney diseases including lupus nephritis, MPO-ANCA vasculitis, and Goodpasture's syndrome. Therapies that enhance SCFA-producing bacteria in the gut have powerful therapeutic potential. Dietary fiber is fermented by gut bacteria which in turn release SCFAs that protect the gut barrier, as well as modulating immune responses towards a tolerogenic anti-inflammatory state. Herein, we describe where the current field of research is and the strategies to harness the gut microbiome as potential therapy. [ABSTRACT FROM AUTHOR]

Objective Primary biliary cholangitis (PBC) is an autoimmune disease of liver that may be associated with other conditions, including autoimmune thyroid diseases. We aimed to investigate the frequency of anti-thyroperoxidase antibodies (TPO-Ab), antithyroglobulin antibodies (TG-Ab), and anti–thyrotropin receptor antibodies (TSHR-Ab) in Tunisian patients with PBC. Methods Sera of 80 patients with PBC were collected over a 9-year period. A total of 189 healthy blood donors (HBD) were included in the control group. Measurements of TPO-Ab and TG-Ab were performed using indirect enzyme-linked immunosorbent assay (ELISA). Competitive ELISA was used to assess TSHR-Ab. Results Antithyroid antibodies (ATA) were significantly more frequent in PBC patients than in the control group (13.7% vs 1.6%; P < 10−3). Out of 11 patients with ATA, 10 (90.9%) were female. Nine patients and 2 HBD had TPO-Ab (11.2% vs 1%; P < 10−3). TG-Ab were more frequent in patients than in healthy subjects but the difference was not statistically significant (6.2% vs 1.6%; P =.1). TPO-Ab and TG-Ab were present together in 3 patients (3.7%). TSHR-Ab were absent in patients and controls. Conclusion This study shows that PBC is associated with a high frequency of ATA but not TG-Ab or TSHR-Ab. [ABSTRACT FROM AUTHOR]

Objectives: The dysregulated immune response is one of the cardinal features of severe coronavirus disease 2019 (COVID‐19). This study was conducted to clarify the occurrence of autoantibodies (AABs) associated with systemic autoimmune rheumatic diseases (SARDs) in hospitalized patients with a moderate, severe, and critical form of COVID‐19. Methods: The serum samples obtained from 176 hospitalized COVID‐19 patients were investigated in this study, including patients with moderate (N = 90), severe (N = 50), and critical (N = 36) forms of COVID‐19. Also, the serum samples collected from healthy subjects before the COVID‐19 pandemic were used as controls (N = 176). The antinuclear antibodies (ANAs), antidouble‐stranded DNA (anti‐dsDNA), cytoplasmic‐anti neutrophil cytoplasmic antibody (c‐ANCA), perinuclear ANCA (p‐ANCA), antiphospholipid antibodies (aPLs), and anticyclic citrullinated peptide (anti‐CCP) occurrence was evaluated using a solid‐phase enzyme‐linked immunosorbent assay (ELISA). Results: The results showed that the occurrence of ANAs, anti‐dsDNA, anti‐CCP, c‐ANCA, and p‐ANCA was significantly higher in the COVID‐19 patients compared to serum obtained from healthy subjects (p <.0001, p <.0001, p <.0001, p <.05, and p <.001, respectively). The positive number of anti‐CCP tests increased significantly in severe COVID‐19 compared to the moderate group (p <.01). Conclusion: Our study further supports the development of autoantibodies related to systemic autoimmune rheumatologic diseases. To the best of our knowledge, this is the first study with a large sample size that reported the occurrence of anti‐CCP in a severe form of COVID‐19. [ABSTRACT FROM AUTHOR]

Aims: To find clinical and immunological signatures of the SARS‐CoV‐2 and the COVID‐19 pandemic on children newly diagnosed with type 1 diabetes (T1D). Methods: A single‐centre, retrospective, observational study comparing the clinical and immunological characteristics of children diagnosed with T1D the year before and during the first 2 years of the COVID‐19 pandemic. Data extracted from the medical records included clinical and demographic parameters, COVID‐19 PCR results and the presence of anti‐islet, thyroid and celiac‐related antibodies. Also obtained from the medical records was a family history of T1D, celiac disease and autoimmune thyroid disease in a first‐degree family member. Results: A total of 376 children were diagnosed with T1D during the study period. A total of 132 in the pre‐COVID era and 246 in the first 2 years of the pandemic. At diagnosis, the pH in children with DKA was lower, and HbA1c tended to be higher in the COVID‐19 group compared to the pre‐COVID‐19 group (7.30 [7.18, 7.35] vs 7.33 [7.19, 7.36], p = 0.046) and (110.9 [86.9, 129.5] vs 100 [80.3, 129.5], p = 0.067]) respectively. Multiple islet antibodies (IA) were significantly more common among patients in the pre‐COVID‐19 group compared to the COVID‐19 group (72% vs 61%, p = 0.032). Tissue transglutaminase antibodies were more common among children diagnosed in the COVID‐19 compared to the pre‐COVID group (16.6% vs 7.9%, p = 0.022). Conclusions: Our findings suggest that SARS‐CoV‐2 and the environmental alterations caused by the pandemic affected the clinical characteristics and the immunological profile of children diagnosed with T1D. It is, therefore, plausible that the virus plays a role in the autoimmune process causing T1D. [ABSTRACT FROM AUTHOR]

Purpose: Juvenile Idiopathic Arthritis (JIA) is a chronic inflammatory disease characterized by chronic synovitis, sometimes associated with fever, rash, pericarditis and uveitis. Limited data are available concerning autoimmune diseases associated with JIA in childhood. The aims of our study were: (a) evaluating the thyroid function in a group of Italian children affected by JIA; (b) identifying which Autoimmune Thyroid Diseases (ATDs) are related to JIA in this population. Methods: A population of 51 patients with JIA was investigated. Each patient enrolled was evaluated clinically (family history for Autoimmune Diseases (ADs), personal history and physical examination). In the sample were evaluated thyroid function, inflammation's index and anti-thyroid antibodies. Results: The 68.6% (35) of our patients had the oligoarticular form, 27.5% (14) had the polyarticular one, 2% (1) had systemic onset and 2% (1) had undifferentiated arthritis. We focused our attention on the differences between the first two forms. We did not find any difference on the gender prevalence (p > 0.05). A higher presence of anti-TPO antibodies was found in the polyarticular form, with a significant difference with the oligoarticular one (p = 0.032). We researched the anti-hTG antibodies (p > 0.05) and ANA for each group (p > 0.05). We found a significant prevalence of family history for ADs in the polyarticular form (p < 0.05). Conclusion: Our findings show the necessity to focus on thyroid function in patients with JIA. Although the oligoarticular form is the most frequent, the polyarticular form shows a higher frequency of thyroid function's alteration. This suggests the need for specific attention in polyarticular form. [ABSTRACT FROM AUTHOR]

BACKGROUND: Genetic aberrations in the NFκB pathway lead to primary immunodeficiencies with various degrees of severity. We previously demonstrated that complete ablation of the RelB transcription factor, a key component of the alternative pathway, results in an early manifested combined immunodeficiency requiring stem cell transplantation. OBJECTIVE: To study the molecular basis of a progressive severe autoimmunity and immunodeficiency in three patients. METHODS: Whole exome sequencing was performed to identify the genetic defect. Molecular and cellular techniques were utilized to assess the variant impact on NFκB signaling, canonical and alternative pathway crosstalk, as well as the resultant effects on immune function. RESULTS: Patients presented with multiple autoimmune progressive severe manifestations encompassing the liver, gut, lung, and skin, becoming debilitating in the second decade of life. This was accompanied by a deterioration of the immune system, demonstrating an age-related decline in naïve T cells and responses to mitogens, accompanied by a gradual loss of all circulating CD19+ cells. Whole exome sequencing identified a novel homozygous c. C1091T (P364L) transition in RELB. The P364L RelB protein was unstable, with extremely low expression, but retained some function and could be transiently and partially upregulated following Toll-like receptor stimulation. Stimulation of P364L patient fibroblasts resulted in a marked rise in a cluster of pro-inflammatory hyper-expressed transcripts consistent with the removal of RelB inhibitory effect on RelA function. This is likely the main driver of autoimmune manifestations in these patients. CONCLUSION: Incomplete loss of RelB provided a unique opportunity to gain insights into NFκBs pathway interactions as well as the pathogenesis of autoimmunity. The P364L RelB mutation leads to gradual decline in immune function with progression of severe debilitating autoimmunity.

IntroductionDespite 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.MethodsHerein, we review the current state of knowledge on known environmental factors associated with the development of SARD and potential areas for future research.ResultsThe 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.ConclusionOwing 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.

This document is an editorial published in the journal Frontiers in Oncology. It discusses the use of immune-checkpoint inhibitors (ICIs) in cancer treatment and the potential risks of developing autoimmunity and immune-related adverse effects (irAEs). The editorial highlights the need for further research to understand the cellular and molecular mechanisms underlying these complications. It also provides a summary of various articles, systematic reviews, and case reports included in the research topic, which explore the incidence, monitoring, and management of irAEs in cancer patients receiving ICIs. The editorial emphasizes the importance of predicting, diagnosing, and managing these complications to optimize cancer treatment outcomes. [Extracted from the article]

This document is an editorial published in the journal Frontiers in Immunology. It discusses the importance of prognostic and predictive factors in autoimmune connective tissue disorders. These disorders are complex and can have variable disease courses, making it difficult to predict outcomes and determine the most effective treatments. The editorial highlights the need for biomarkers that can help predict disease severity and long-term survival. The document also mentions several research articles that were published on this topic, covering various aspects of autoimmune connective tissue disorders and their prognostic factors. [Extracted from the article]

To assess the prevalence of systemic and organ-specific autoimmunity among individuals with human inborn errors of immunity (IEI). Retrospective study. We recorded demographic variables, type of immunodeficiency, and systemic and organ specific autoimmunity. We included 48 patients (54.1% men) with mean age of 32.1 years. The most common IEIs included combined immunodeficiency with syndromic features (31.2%) and predominantly antibody deficiency (20.1%). We observed autoimmunity in 15 patients (31.2%): 12 organ-specific autoimmunity and 5 systemic autoimmunity, not mutually exclusive groups. Organ-specific autoimmunity preceded the onset of IEI in 5 patients, was concurrent in one patient, and developed after the diagnosis of IEI in 6 cases. From the systemic autoimmunity group, we observed polyarteritis nodosa (n = 2), antiphospholipid syndrome (APS) (n = 2), and overlap of limited systemic sclerosis/APS/Sjögren's syndrome (n = 1), and in all cases, this occurred after the IEI diagnosis. Our findings confirm the coexistence of autoimmunity and IEI. This overlap may be attributed to B and T cell disorders, as well as potential alterations in the microbiota in these patients. [ABSTRACT FROM AUTHOR]

Background: Occupational exposure to silica is related to autoimmune diseases and features of autoimmunity, mainly autoantibodies. The study objectives were to estimate the prevalence of silicosis with associated autoimmune findings or diagnosed autoimmune diseases in Spain, and to assess the clinical and functional characteristics of affected patients. Methods: This is a multicentre prospective study in patients diagnosed with silicosis. Autoantibodies analysed were antinuclear antibodies, isotypes IgA, IgM and IgG, rheumatoid factor, anticyclic citrullinated peptide, anti-Scl70, anti-Ro, and anti-LA. Pulmonary function tests were performed. Results: Autoimmunity was assessed in 105 patients. Autoimmune findings were recorded in 29 (27%) patients, including antinuclear antibodies (n=21), anti-Ro (n=7), rheumatoid factor (n=5) and anti-Scl70 (n=3). Autoimmune disease was diagnosed in 16 (15%) patients, mainly rheumatoid arthritis (n=7) and systemic lupus erythematosus (n=4). Patients with silicosis and autoimmune findings had a lower mean time of exposure to silica and showed a trend toward lower values in pulmonary function tests. Conclusions: Autoimmune findings and diagnosis of autoimmune diseases were frequent in patients with silicosis in Spain.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis by modulating how the immune system is activated. Several studies have documented the critical role of Tregs in suppressing the functions of effector T cells and antigen-presenting cells. Under certain conditions, Tregs can lose their suppressive capability, leading to a compromised immune system. For example, mutations in the Treg transcription factor, Forkhead box P3 (FOXP3), can drive the development of autoimmune diseases in multiple organs within the body. Furthermore, mutations leading to a reduction in the numbers of Tregs or a change in their function facilitate autoimmunity, whereas an overabundance can inhibit anti-tumor and anti-pathogen immunity. This review discusses the characteristics of Tregs and their mechanism of action in select autoimmune skin diseases, transplantation, and skin cancer. We also examine the potential of Tregs-based cellular therapies in autoimmunity.

Thymic epithelial tumors (TETs) are rare mediastinal cancers originating from the thymus, classified in two main histotypes: thymoma and thymic carcinoma (TC). TETs affect a primary lymphoid organ playing a critical role in keeping T-cell homeostasis and ensuring an adequate immunological tolerance against "self". In particular, thymomas and not TC are frequently associated with autoimmune diseases (ADs), with Myasthenia Gravis being the most common AD present in 30% of patients with thymoma. This comorbidity, in addition to negatively affecting the quality and duration of patients' life, reduces the spectrum of the available therapeutic options. Indeed, the presence of autoimmunity represents an exclusion criteria for the administration of the newest immunotherapeutic treatments with checkpoint inhibitors. The pathophysiological correlation between TETs and autoimmunity remains a mystery. Several studies have demonstrated the presence of a residual and active thymopoiesis in adult patients affected by thymomas, especially in mixed and lymphocytic-rich thymomas, currently known as type AB and B thymomas. The aim of this review is to provide the state of art in regard to the histological features of the different TET histotype, to the role of the different immune cells infiltrating tumor microenvironments and their impact in the break of central immunologic thymic tolerance in thymomas. We discuss here both cellular and molecular immunologic mechanisms inducing the onset of autoimmunity in TETs, limiting the portfolio of therapeutic strategies against TETs and greatly impacting the prognosis of associated autoimmune diseases. [ABSTRACT FROM AUTHOR]

Introduction: The autoimmune response in type 1 diabetes (T1D), in which the beta cells expressing aberrant or modified proteins are killed, resembles an effective antitumor response. Defective ribosomal protein products in tumors are targets of the anti-tumor immune response that is unleashed by immune checkpoint inhibitor (ICI) treatment in cancer patients. We recently described a defective ribosomal product of the insulin gene (INS-DRiP) that is expressed in stressed beta cells and targeted by diabetogenic T cells. T1D patient-derived INSDRiP specific T cells can kill beta cells and are present in the insulitic lesion. T cells reactive to INS-DRiP epitopes are part of the normal T cell repertoire and are believed to be kept in check by immune regulation without causing autoimmunity. Method: T cell autoreactivity was tested using a combinatorial HLA multimer technology measuring a range of epitopes of islet autoantigens and neoantigen INS-DRiP. INS-DRiP expression in human pancreas and insulinoma sections was tested by immunohistochemistry. Results: Here we report the induction of islet autoimmunity to INS-DRiP and diabetes after ICI treatment and successful tumor remission. Following ICI treatment, T cells of the cancer patient were primed against INS-DRiP among other diabetogenic antigens, while there was no sign of autoimmunity to this neoantigen before ICI treatment. Next, we demonstrated the expression of INSDRiP as neoantigen in both pancreatic islets and insulinoma by staining with a monoclonal antibody to INS-DRiP. Discussion: These results bridge cancer and T1D as two sides of the same coin and point to neoantigen expression in normal islets and insulinoma that may serve as target of both islet autoimmunity and tumor-related autoimmunity. [ABSTRACT FROM AUTHOR]

Disease-modifying drugs have transformed the treatment options for many systemic autoimmune diseases. However, an evolving understanding of disease mechanisms, which might vary between individuals, is paving the way for the development of novel agents that operate in a patient-tailored manner through immunophenotypic regulation of disease-relevant cells and the microenvironment of affected tissue domains. Immunoengineering is a field that is focused on the application of engineering principles to the modulation of the immune system, and it could enable future personalized and immunoregulatory therapies for rheumatic diseases. An important aspect of immunoengineering is the harnessing of material chemistries to design technologies that span immunologically relevant length scales, to enhance or suppress immune responses by re-balancing effector and regulatory mechanisms in innate or adaptive immunity and rescue abnormalities underlying pathogenic inflammation. These materials are endowed with physicochemical properties that enable features such as localization in immune cells and organs, sustained delivery of immunoregulatory agents, and mimicry of key functions of lymphoid tissue. Immunoengineering applications already exist for disease management, and there is potential for this new discipline to improve disease modification in rheumatology. Immunoengineering involves the design of materials with specific properties relating to the immune system. In this Review the authors consider the application of immunoengineering to systemic autoimmune diseases via site-specific and antigen-specific immunoregulation, the facilitation of immune cell therapy, novel approaches to immunodiagnostics and the generation of models to study autoimmunity. Key points: An unmet need exists for immunoregulatory disease-modifying agents for patients with rheumatological conditions who cannot tolerate immunosuppression and for partial responders and non-responders to current standards of care. Immunoengineering is an emerging research area with a major focus on a systems-based approach to rescue disorders of the immune system by leveraging material chemistries to generate immunoregulators. Immunoengineering advances now offer the possibility of a new class of therapeutics aimed at immunomodulation rather than at immunosuppression, which could synergize with standard-of-care therapies and personalize treatment in systemic autoimmunity. Immunomodulation, tolerization and measurement of disease activity are facilitated by nanoparticles; microparticles enable sustained, localized release of immunomodulatory compounds; and macroscale materials have uses in cell therapy and as immunological niches. To improve the safety, efficacy and specificity of T cell-based therapies, immunoengineering can be leveraged to enrich specific cell subsets, generate transient T cells in vivo and improve target identification. Immunoengineering could aid in the diagnosis of disease, immunophenotyping for patient-stratification purposes and in developing in vitro models to study autoimmunity. [ABSTRACT FROM AUTHOR]

Systemic rheumatic diseases, including conditions such as rheumatoid arthritis, Sjögren's syndrome, systemic sclerosis, and systemic lupus erythematosus, represent a complex array of autoimmune disorders characterized by chronic inflammation and diverse clinical manifestations. This study focuses on unraveling the genetic underpinnings of these diseases by examining polymorphisms in key genes related to their pathology. Utilizing a comprehensive genetic analysis, we have documented the involvement of these genetic variations in the pathogenesis of rheumatic diseases. Our study has identified several key polymorphisms with notable implications in rheumatic diseases. Polymorphism at chr11_112020916 within the IL-18 gene was prevalent across various conditions with a potential protective effect. Concurrently, the same IL18R1 gene polymorphism located at chr2_103010912, coding for the IL-18 receptor, was observed in most rheumatic conditions, reinforcing its potential protective role. Additionally, a further polymorphism in IL18R1 at chr2_103013408 seems to have a protective influence against the rheumatic diseases under investigation. In the context of emerging genes involved in rheumatic diseases, like PARK2, a significant polymorphism at chr6_161990516 was consistently identified across different conditions, exhibiting protective characteristics in these pathological contexts. The findings underscore the complexity of the genetic landscape in rheumatic autoimmune disorders and pave the way for a deeper understanding of their etiology and the possible development of more targeted and effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Autoimmunity seems to be present in a large proportion of women with spontaneous premature ovarian insufficiency (POI). Whether these women are at increased risk for autoimmune disease has not been determined to date. Therefore, the aim of this study was to investigate a large series of antibodies in order to shed more light into the autoimmune risk of POI women. In a prospective case–control study, blood samples from 66 patients with spontaneous POI and 66 healthy controls were analyzed for a series of autoimmune antibodies. POI women revealed significantly increased thyroglobulin antibodies (TGAb) (p = 0.045) and thyroid peroxidase antibodies (TPOAb) (p = 0.002). At least one abnormal autoimmune parameter was present in 37.9% of POI women, compared to 18.2% in healthy controls (p = 0.045). A strong association between POI and increased TGAb (adjusted odds ratio 3.586, p = 0.028), increased TPOAb (adjusted odds ratio 7.496, p = 0.003) and any increased autoimmune parameter (adjusted odds ratio 3.189, p = 0.008) could be demonstrated in a binary logistic regression model. A high prevalence of autoimmunity in POI women compared to a healthy young collective could be demonstrated. Thyroid antibodies were significantly increased in POI women. Our data highlight the increased risk for autoimmune diseases, especially for thyroid disorders. [ABSTRACT FROM AUTHOR]

Background: Intravenous immunoglobulins (IVIgs) derived from the pooled plasma of thousands of donors contain numerous types of IgG molecules, including autoantibodies commonly used to diagnose autoimmunity. While these autoantibodies can cause misinterpretation of serological tests for IVIg recipients, their profiles in IVIg preparations are not fully understood. Study Design and Methods: Using binding‐capability based immune assays, we measured 18 varieties of clinically relevant autoantibodies in domestic blood donor‐derived IVIg products. In addition, we analyzed an IVIg product from a US brand to evaluate the influence of regional and racial differences. Based on the determined autoantibody titers, pharmacokinetics of passively acquired autoantibodies and their possible detection period in serum were estimated. Results: Anti‐thyroglobulin (Tg), anti‐thyroidperoxidase (TPO), and anti‐Sjögren's‐syndrome‐related antigen A (SS‐A) antibodies were present in considerable amounts in IVIg products. Notably, these three autoantibodies can be detected in IVIg recipients' sera for up to 3 months after infusion. Discussion: To the best of our knowledge, this is the first study that analyzed multiple autoantibody profiles in both pooled plasma and IVIg products and that further evaluated their potential influences on diagnosis of autoimmunity. Clinicians should keep in mind that IVIgs contain several autoantibodies and that their infusion can produce false‐positive serology results. To establish an accurate diagnosis, serological tests must be carefully interpreted and clinical symptoms should be more purposefully considered if patients are receiving IVIg therapy. [ABSTRACT FROM AUTHOR]

Spontaneously formed germinal centers (GCs) have been reported in most mouse models of human autoimmune disease and autoimmune patients, and have long been considered a source of somatically-mutated and thus high affinity autoantibodies, but their role in autoimmunity is becoming increasingly controversial, particularly in the context of systemic autoimmune diseases like lupus. On the one hand, there is good evidence that some pathogenic lupus antibodies have acquired somatic mutations that increase affinity for self-antigens. On the other hand, recent studies that have genetically prevented GC formation, suggest that GCs are dispensable for systemic autoimmunity, pointing instead to pathogenic extrafollicular (EF) B-cell responses. Furthermore, several lines of evidence suggest germinal centers may in fact be somewhat protective in the context of autoimmunity. Here we review how some of the conflicting evidence arose, and current views on the role of GCs in autoimmunity, outlining mechanisms by which GC may eliminate self-reactivity. We also discuss recent advances in understanding extrafollicular B cell subsets that participate in autoimmunity. [ABSTRACT FROM AUTHOR]

Objective: We present the case of a patient with clinical and imaging features of sporadic Creutzfeldt-Jakob disease (sCJD) and positive IgLON5 antibodies (Abs) in the serum and CSF. Case report: A 66-year-old Chinese man presented to the hospital with a stroke-like episode, followed by rapidly progressive cognitive decline, mutism, and parkinsonism. The MRI results showed a cortical ribboning sign in diffusionweighted MRI, periodic triphasic waves with a slow background in EEG, and positive protein 14-3-3 in CSF. There were matching IgLON5 Abs in the serum and CSF. A literature review showed positive autoimmune encephalitis Abs or autoimmune inflammatory disease between 0.5 and 8.6% among patients with clinical suspicion of CJD, most commonly anti-voltage-gated potassium channel (VGKC) complex and anti-N-methyl-D-aspartate receptor (NMDAR) Abs; however, IgLON5 autoimmunity in CJD has been rarely reported. This is an intriguing association as both conditions have been associated with brain deposits of phosphorylated tau protein. Conclusion: IgLON5 Abs may be observed in patients with a diagnosis of CJD; it is unknown whether a synergistic effect of IgLON5 Abs with CJD exists, increasing neurodegenerative changes. [ABSTRACT FROM AUTHOR]

Interleukin-27 (IL-27) is a member of the IL-12 family. The gene encoding IL-27 is located at chromosome 16p11. IL-27 is considered as a heterodimeric cytokine, which consists of Epstein-Barr virus (EBV)-induced gene 3 (Ebi3) and IL-27p28. Based on the function of IL-27, it binds to receptor IL-27ra or gp130 and then regulates downstream cascade. To date, findings show that the expression of IL-27 is abnormal in different inflammatory autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, Behcet's disease, inflammatory bowel disease, multiple sclerosis, systemic sclerosis, type 1 diabetes, Vogt-Koyanagi-Harada, and ankylosing spondylitis). Moreover, in vivo and in vitro studies demonstrated that IL-27 is significantly in3volved in the development of these diseases by regulating innate and adaptive immune responses, playing either an anti-inflammatory or a pro-inflammatory role. In this review, we comprehensively summarized information about IL-27 and autoimmunity based on available evidence. It is hoped that targeting IL-27 will hold great promise in the treatment of inflammatory autoimmune disorders in the future. [ABSTRACT FROM AUTHOR]

The research & development (R&D) of novel therapeutic agents for the treatment of autoimmune diseases is challenged by highly complex pathogenesis and multiple etiologies of these conditions. The number of targeted therapies available on the market is limited, whereas the prevalence of autoimmune conditions in the global population continues to rise. Mathematical modeling of biological systems is an essential tool which may be applied in support of decision-making across R&D drug programs to improve the probability of success in the development of novel medicines. Over the past decades, multiple models of autoimmune diseases have been developed. Models differ in the spectra of quantitative data used in their development and mathematical methods, as well as in the level of "mechanistic granularity" chosen to describe the underlying biology. Yet, allmodels strive towards the same goal: to quantitatively describe various aspects of the immune response. The aim of this review was to conduct a systematic review and analysis of mathematical models of autoimmune diseases focused on the mechanistic description of the immune system, to consolidate existing quantitative knowledge on autoimmune processes, and to outline potential directions of interest for future model-based analyses. Following a systematic literature review, 38 models describing the onset, progression, and/or the effect of treatment in 13 systemic and organ-specific autoimmune conditions were identified, mostmodels developed for inflammatory bowel disease, multiple sclerosis, and lupus (5 models each). =70% of the models were developed as nonlinear systems of ordinary differential equations, others - as partial differential equations, integro-differential equations, Boolean networks, or probabilistic models. Despite covering a relatively wide range of diseases, most models described the same components of the immune system, such as T-cell response, cytokine influence, or the involvement of macrophages in autoimmune processes. All models were thoroughly analyzed with an emphasis on assumptions, limitations, and their potential applications in the development of novel medicines. [ABSTRACT FROM AUTHOR]

Idiopathic granulomatous mastitis (IGM) is a noncancerous, chronic inflammatory disorder of breast with unknown causes, posing significant challenges to the quality of life due to its high refractoriness and local aggressiveness. The typical symptoms of this disease involve skin redness, a firm and tender breast mass and mastalgia; others may include swelling, fistula, abscess (often without fever), nipple retraction, and peau d'orange appearance. IGM often mimics breast abscesses or malignancies, particularly inflammatory breast cancer, and is characterized by absent standardized treatment options, inconsistent patient response and unknown mechanism. Definite diagnosis of this disease relies on core needle biopsy and histopathological examination. The prevailing etiological theory suggests that IGM is an autoimmune disease, as some patients respond well to steroid treatment. Additionally, the presence of concurrent erythema nodosum or other autoimmune conditions supports the autoimmune nature of the disease. Based on current knowledge, this review aims to elucidate the autoimmune-favored features of IGM and explore its potential etiologies. Furthermore, we discuss the immune-mediated pathogenesis of IGM using existing research and propose immunotherapeutic strategies for managing this condition. [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]

Regulatory T cells (Tregs) are a specialized subgroup of T-cell lymphocytes that is crucial for maintaining immune homeostasis and preventing excessive immune responses. Depending on their differentiation route, Tregs can be subdivided into thymically derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which originate from conventional T cells after extrathymic differentiation at peripheral sites. Although the regulatory attributes of tTregs and pTregs partially overlap, their modes of action, protein expression profiles, and functional stability exhibit specific characteristics unique to each subset. Over the last few years, our knowledge of Treg differentiation, maturation, plasticity, and correlations between their phenotypes and functions has increased. Genetic and functional studies in patients with numeric and functional Treg deficiencies have contributed to our mechanistic understanding of immune dysregulation and autoimmune pathologies. This review provides an overview of our current knowledge of Treg biology, discusses monogenetic Treg pathologies and explores the role of Tregs in various other autoimmune disorders. Additionally, we discuss novel approaches that explore Tregs as targets or agents of innovative treatment options. [ABSTRACT FROM AUTHOR]

T cells help orchestrate immune responses to pathogens, and their aberrant regulation can trigger autoimmunity. Recent studies highlight that a threshold number of T cells (a quorum) must be activated in a tissue to mount a functional immune response. These collective effects allow the T cell repertoire to respond to pathogens while suppressing autoimmunity due to circulating autoreactive T cells. Our computational studies show that increasing numbers of pathogenic peptides targeted by T cells during persistent or severe viral infections increase the probability of activating T cells that are weakly reactive to self-antigens (molecular mimicry). These T cells are easily re-activated by the self-antigens and contribute to exceeding the quorum threshold required to mount autoimmune responses. Rare peptides that activate many T cells are sampled more readily during severe/persistent infections than in acute infections, which amplifies these effects. Experiments in mice to test predictions from these mechanistic insights are suggested. [ABSTRACT FROM AUTHOR]

Little is known about the association between coronavirus disease 2019 (COVID-19) and autoimmune diseases, especially in the case of systemic lupus erythematosus (SLE). SLE patients met with many questions during the pandemic in COVID-19, such as how to minimize risk of infection, the complex pathological features and cytokine profiles, diagnosis and treatment, rational choice of drugs and vaccine, good nursing, psychological supervision, and so on. In this study, we review and discuss the multifaceted effects of the COVID-19 pandemic on patients living with SLE using the available literature. Cross-talk in implicated inflammatory pathways/mechanisms exists between SLE and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and SARS-CoV-2 displays similar clinical characteristics and immuno-inflammatory responses to SLE. Current epidemiological data inadequately assess the risk and severity of COVID-19 infection in patients with SLE. More evidence has shown that hydroxychloroquine and chloroquine cannot prevent COVID-19. During the pandemic, patients with SLE had a higher rate of hospitalization. Vaccination helps to reduce the risk of infection. Several therapies for patients with SLE infected with COVID-19 are discussed. The cases in the study can provide meaningful information for clinical diagnosis and management. Our main aim is to help preventing infection and highlight treatment options for patients with SLE infected with COVID-19. [ABSTRACT FROM AUTHOR]

Summary: Since their description by Metchnikoff in 1905, phagocytes have been increasingly recognized to be the entities that traffic to sites of infection and inflammation, engulf and kill infecting organisms, and clear out apoptotic debris all the while making antigens available and accessible to the lymphoid organs for future use. Therefore, phagocytes provide the gateway and the first check in host protection and immune response. Disorders in killing and chemotaxis lead not only to infection susceptibility, but also to autoimmunity. We aim to describe chronic granulomatous disease and the leukocyte adhesion deficiencies as well as myeloperoxidase deficiency and G6PD deficiency as paradigms of critical pathways. [ABSTRACT FROM AUTHOR]

Summary: Over 200,000 individuals in the United States alone live with Down Syndrome (DS), the most common genetic disorder associated with intellectual disability. DS has a constellation of features across the body, including dysregulation of the immune system. Individuals with DS have both a higher frequency of autoimmunity and more severe infections than the general population, highlighting the importance of understanding the immune system in this population. Individuals with DS present with dysregulation of both the innate and adaptive immune systems. Elevated cytokine levels, increased type I and type II IFN signaling, a shift toward memory phenotypes in T cells, and a decrease in the size of the B‐cell compartment are observed in individuals with DS, which contribute to both autoinflammation and severe infections. Herein, we discuss the current knowledge of the immune system in individuals with Down Syndrome as well as ideas of necessary further investigations to decipher the mechanisms by which trisomy 21 leads to immune dysregulation, with the ultimate goal of identifying clinical targets to improve treatment. [ABSTRACT FROM AUTHOR]

Long non-coding RNA (lncRNA) is a type of non-protein-coding RNA with a length of at least 200 nucleotides. Existing evidence shows that lncRNA affects the growth and development of humans and the occurrence of diseases through various mechanisms, and plays an irreplaceable role in the differentiation and activation of immune cells and the development process of autoim-mune diseases. In recent years, lncRNA H19 has been found to play a unique regulatory function in pathological processes related to autoimmune diseases, such as inflammation and fibrosis. Therefore, the molecular mechanism involved in H19 is expected to become a potential target for the treatment of autoimmune diseases. In this review, we discussed the related mechanisms of H19 involved in the pathogenesis of autoimmune diseases based on the known functions of H19 and summarized the research results of H19 in several common autoimmune diseases. [ABSTRACT FROM AUTHOR]

Introduction: Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and IgG4-related disease (IgG4-RD) are distinct immune disorders with overlapping clinical and laboratory features. While ANCA positivity excludes IgG4-RD in the 2019 ACR/EULAR classification, this criterion is not uniformly applied, and AAV can form inflammatory masses in various organs and show increase in IgG4 + plasma cells, similar to IgG4-RD. Case diagnosis/treatment: A 5-year-old female with history of orbital mass diagnosed as IgG4-RD presents with acute kidney injury. She has a myeloperoxidase ANCA, and kidney biopsy shows pauci-immune crescentic glomerulonephritis and acute tubulointerstitial nephritis with increased IgG4 + plasma cells and tubular basement membrane (TBM) deposits. Conclusion: In isolation, TBM deposits and increased IgG4 + plasma cells are suggestive of IgG4-RD. In the context of a positive ANCA and pauci-immune crescentic glomerulonephritis, however, increased IgG4 + plasma cells due to AAV are favored. In cases with features of IgG4-RD, ANCA positivity suggests an alternate diagnosis of AAV to be more likely. [ABSTRACT FROM AUTHOR]

• KCNA2 autoimmunity is diverse ranging from dementia to seizures and encephalitis. • Patients can respond to immunotherapy, in particular if initiated early. • CSF KCNA2 autoantibodies are associated with cognitive impairment. • KCNA2 IgGs react with intracellular epitopes and reach their targets in vivo. • IgG3 and IgG1 autoantibodies predominate and target distinct CNS and PNS structures. Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their diagnostic and pathophysiological role is currently unknown, imposing challenges to medical practice. We retrospectively collected comprehensive clinical and paraclinical data of 35 patients with KCNA2 IgG autoantibodies detected in cell-based and tissue-based assays. Patients' sera and cerebrospinal fluid (CSF) were used for characterization of the antigen, clinical-serological correlations, and determination of IgG subclasses. KCNA2 autoantibody-positive patients (n = 35, median age at disease onset of 65 years, range of 16–83 years, 74 % male) mostly presented with cognitive impairment and/or epileptic seizures but also ataxia, gait disorder and personality changes. Serum autoantibodies belonged to IgG3 and IgG1 subclasses and titers ranged from 1:32 to 1:10,000. KCNA2 IgG was found in the CSF of 8/21 (38 %) patients and in the serum of 4/96 (4.2 %) healthy blood donors. KCNA2 autoantibodies bound to characteristic anatomical areas in the cerebellum and hippocampus of mammalian brain and juxtaparanodal regions of peripheral nerves but reacted exclusively with intracellular epitopes. A subset of four KCNA2 autoantibody-positive patients responded markedly to immunotherapy alongside with conversion to seronegativity, in particular those presenting an autoimmune encephalitis phenotype and receiving early immunotherapy. An available brain biopsy showed strong immune cell invasion. KCNA2 autoantibodies occurred in less than 10 % in association with an underlying tumor. Our data suggest that KCNA2 autoimmunity is clinically heterogeneous. Future studies should determine whether KCNA2 autoantibodies are directly pathogenic or develop secondarily. Early immunotherapy should be considered, in particular if autoantibodies occur in CSF or if clinical or diagnostic findings suggest ongoing inflammation. Suspicious clinical phenotypes include autoimmune encephalitis, atypical dementia, new-onset epilepsy and unexplained epileptic seizures. [ABSTRACT FROM AUTHOR]

Different CD4+ T cell subsets have been described to have 'stem-like' features, frequently without a clear indication of what that means functionally or devoid of a systematic set of criteria for how to apply the terminology. Bona fide stem cells are themselves varied and their definitions have been evolving recently. CD4+ T cell types with clear stem-like features are naive cells and subsets of memory cells [central memory (Tcm) and stem cell memory (Tscm)]. These also display stability over time, specific niche homing, high replicative potential, and the capacity to differentiate into many other T cell types. Other cells fall along a continuum of more versus less stem-like features. In some cases, more functional characterization of these cells is required before appending a 'stem-like' moniker is justified. For others, substituting 'progenitor' or 'precursor' terminology along the lines of the hematopoietic system is likely to be more accurate. T cells with stem-like features mediate durable immunity to pathogens and tumors but can also promote tissue damage. The complexity of the literature labeling T cells as 'stem-like' suggests that both the criteria for ascribing stem cell character to T cells, and the nomenclature used to relate them to one another, need refinement. This would help systemize the field, allowing better inference of function from name. Mammalian stem cells govern development, tissue homeostasis, and regeneration. Following years of study, their functions have been delineated with increasing precision. The past decade has witnessed heightened widespread use of stem cell terminology in association with durable T cell responses to infection, antitumor immunity, and autoimmunity. Interpreting this literature is complicated by the fact that descriptions are diverse and criteria for labeling 'stem-like' T cells are evolving. Working under the hypothesis that conceptual frameworks developed for actual stem cells can be used to better evaluate and organize T cells described to have stem-like features, we outline widely accepted properties of stem cells and compare these to different 'stem-like' CD4+ T cell populations. [ABSTRACT FROM AUTHOR]

Chronic and aberrant nucleic acid sensing causes type I IFN-driven autoimmune diseases, designated type I interferonopathies. We found a significant reduction of regulatory T cells (Tregs) in patients with type I interferonopathies caused by mutations in ADAR1 or IFIH1 (encoding MDA5). We analyzed the underlying mechanisms using murine models and found that Tregs-specific deletion of Adar1 caused peripheral Treg loss and scurfy-like lethal autoimmune disorders. Similarly, knock-in mice with Treg-specific expression of an MDA5 gain-of-function mutant caused apoptosis of peripheral Tregs and severe autoimmunity. Moreover, the impact of ADAR1 deficiency on Tregs is multifaceted, involving both MDA5 and PKR sensing. Together, our results highlight the dysregulation of Treg homeostasis by intrinsic aberrant RNA sensing as a potential determinant for type I interferonopathies. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are characterized by a breakdown of immune tolerance, leading to inflammation and irreversible end-organ tissue damage. Platelet extracellular vesicles are cellular elements that are important in blood circulation and actively participate in inflammatory and immune responses through intercellular communication and interactions between inflammatory cells, immune cells, and their secreted factors. Therefore, platelet extracellular vesicles are the "accelerator" in the pathological process of autoimmune diseases; however, this robust set of functions of platelet extracellular vesicles has also prompted new advances in therapeutic strategies for autoimmune diseases. In this review, we update fundamental mechanisms based on platelet extracellular vesicles communication function in autoimmune diseases. We also focus on the potential role of platelet extracellular vesicles for the treatment of autoimmune diseases. Some recent studies have found that antiplatelet aggregation drugs, specific biological agents can reduce the release of platelet extracellular vesicles. Platelet extracellular vesicles can also serve as vehicles to deliver drugs to targeted cells. It seems that we can try to silence or inhibit microRNA carried by platelet extracellular vesicles transcription and regulate the target cells to treat autoimmune diseases as platelet extracellular vesicles can transfer microRNA to other cells to regulate immune-inflammatory responses. Hopefully, the information presented here will provide hope for patients with autoimmune diseases. Autoimmune diseases patients are characterized by autoimmune disorders, whose immune system cannot distinguish between auto- and foreign-antigens. Autoimmune diseases is the third significant disease threatening human health after cardiovascular disease and cancer. However, the exact etiology of autoimmune diseases has yet to be fully elucidated. Several studies have shown that platelet extracellular vesicle content is elevated in multiple autoimmune disorders and positively correlates with disease activity. However, our knowledge about the details of the mechanisms still remains limited and fragmentary. This article updates the communication function of platelet extracellular vesicles in accelerating autoimmune and inflammatory responses. The interesting thing is every coin has two sides. We put forward a new treatment idea for AD based on the particular volume and powerful intercellular communication function of platelet extracellular vesicles. Inhibition of the communication function of platelet extracellular vesicles seems to be considered in the future, or silence or block miRNA of platelet extracellular vesicles involved in the pathogenesis of AD. We can even use it as a drug carrier to deliver the drug to the relevant target cells, thereby enhancing the role of the medicine in regulating immune response and inhibiting inflammation. This paper not only provides a deeper understanding of the pathogenesis of autoimmune diseases but also provides theoretical support for the use of platelet extracellular vesicles to achieve targeted therapy. [ABSTRACT FROM AUTHOR]

Background: Barraquer-Simons syndrome (BSS) is a rare, acquired form of lipodystrophy characterized by progressive loss of upper body subcutaneous fat, which affects face, upper limbs, and trunk. The pathogenesis of the disease is not entirely known and may involve autoimmune mechanisms. Aim: This study aimed to provide a comprehensive picture of the clinical, immunological, and metabolic features of a large cohort of patients with BSS. Our primary objectives included the validation of existing diagnostic tools, the evaluation of novel diagnostic approaches, and the exploration of potential disease triggers or genetic predispositions. Subjects and Methods: Twenty-six patients were diagnosed with BSS based on accepted criteria defined by international guidelines. Anthropometric parameters, biochemical tests, organ- and non-organ-specific autoantibodies, HLA status, and screening of the LMNB2 gene were performed. Results: Patients were predominantly females (73%); fat loss occurred mostly during childhood (77%) at a median age of 8 years. Among various anthropometric measures, the ratio between the proportion of fat mass in upper limbs and lower limbs showed the best predictive value for diagnosis. A total of 11.5% of patients had diabetes, 34.6% dyslipidemia, and 26.9% hepatic steatosis. Seventy-five percent of children and 50% of adults had C3 hypocomplementemia; 76% of patients were positive for 1 or more autoantibodies. HLA-DRB1 11:03 had higher allelic frequencies compared with the general population. A single variant in the LMNB2 gene was found in 1 patient. Conclusion: BSS has a childhood onset and is often associated with autoimmune diseases. Skinfold thickness measurements and fat assessment by dual energy X-ray absorptiometry are useful tools to identify the disease. C3 hypocomplementemia and the presence of autoantibodies may be used as additional diagnostic supportive criteria but the prevalence of C3 hypocomplementemia may be lower than previously reported. [ABSTRACT FROM AUTHOR]

Background: Crystalline silica (cSiO2) is a mineral found in rocks; workers from the construction or denim industries are particularly exposed to cSiO2 through inhalation. cSiO2 inhalation increases the risk of silicosis and systemic autoimmune diseases. Inhaled cSiO2 microparticles can reach the alveoli where they induce inflammation, cell death, auto-immunity and fibrosis but the specific molecular pathways involved in these cSiO2 effects remain unclear. This systematic review aims to provide a comprehensive state of the art on omic approaches and exposure models used to study the effects of inhaled cSiO2 in mice and rats and to highlight key results from omic data in rodents also validated in human. Methods: The protocol of systematic review follows PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Eligible articles were identified in PubMed, Embase and Web of Science. The search strategy included original articles published after 1990 and written in English which included mouse or rat models exposed to cSiO2 and utilized omic approaches to identify pathways modulated by cSiO2. Data were extracted and quality assessment was based on the SYRCLE's Risk of Bias tool for animal studies. Results: Rats and male rodents were the more used models while female rodents and autoimmune prone models were less studied. Exposure of animals were both acute and chronic and the timing of outcome measurement through omics approaches were homogeneously distributed. Transcriptomic techniques were more commonly performed while proteomic, metabolomic and single-cell omic methods were less utilized. Immunity and inflammation were the main domains modified by cSiO2 exposure in lungs of mice and rats. Less than 20% of the results obtained in rodents were finally verified in humans. Conclusion: Omic technics offer new insights on the effects of cSiO2 exposure in mice and rats although the majority of data still need to be validated in humans. Autoimmune prone model should be better characterised and systemic effects of cSiO2 need to be further studied to better understand cSiO2-induced autoimmunity. Single-cell omics should be performed to inform on pathological processes induced by cSiO2 exposure. [ABSTRACT FROM AUTHOR]

Context Autoantibodies directed against the 65-kilodalton isoform of glutamic acid decarboxylase (GAD65Abs) are markers of autoimmune type 1 diabetes (T1D) but are also present in patients with Latent Autoimmune Diabetes of Adults and autoimmune neuromuscular diseases, and also in healthy individuals. Phenotypic differences between these conditions are reflected in epitope-specific GAD65Abs and anti-idiotypic antibodies (anti-Id) against GAD65Abs. We previously reported that 7.8% of T2D patients in the GRADE study have GAD65Abs but found that GAD65Ab positivity was not correlated with beta-cell function, glycated hemoglobin (HbA1c), or fasting glucose levels. Context In this study, we aimed to better characterize islet autoantibodies in this T2D cohort. This is an ancillary study to NCT01794143. Methods We stringently defined GAD65Ab positivity with a competition assay, analyzed GAD65Ab-specific epitopes, and measured GAD65Ab-specific anti-Id in serum. Results Competition assays confirmed that 5.9% of the patients were GAD65Ab positive, but beta-cell function was not associated with GAD65Ab positivity, GAD65Ab epitope specificity or GAD65Ab-specific anti-Id. GAD65-related autoantibody responses in GRADE T2D patients resemble profiles in healthy individuals (low GAD65Ab titers, presence of a single autoantibody, lack of a distinct epitope pattern, and presence of anti-Id to diabetes-associated GAD65Ab). In this T2D cohort, GAD65Ab positivity is likely unrelated to the pathogenesis of beta-cell dysfunction. Conclusion Evidence for islet autoimmunity in the pathophysiology of T2D beta-cell dysfunction is growing, but T1D-associated autoantibodies may not accurately reflect the nature of their autoimmune process. [ABSTRACT FROM AUTHOR]

Primary Sjögren's disease (pSD) (also referred to as Sjögren's syndrome) is an autoimmune disease that primarily occurs in women. In addition to exocrine gland dysfunction, pSD patients exhibit B cell hyperactivity. B cell–intrinsic TLR7 activation is integral to the pathogenesis of systemic lupus erythematosus, a disease that shares similarities with pSD. The role of TLR7-mediated B cell activation in pSD, however, remains poorly understood. We hypothesized that age-associated B cells (ABCs) were expanded in pSD and that TLR7-stimulated ABCs exhibited pathogenic features characteristic of disease. Our data revealed that ABC expansion and TLR7 expression were enhanced in a pSD mouse model in a Myd88-dependent manner. Splenocytes from pSD mice showed enhanced sensitivity to TLR7 agonism as compared with those derived from control animals. Sort-purified marginal zone B cells and ABCs from pSD mice showed enhanced inflammatory cytokine secretion and were enriched for antinuclear autoantibodies following TLR7 agonism. Finally, IgG from pSD patient sera showed elevated antinuclear autoantibodies, many of which were secreted preferentially by TLR7-stimulated murine marginal zone B cells and ABCs. These data indicate that pSD B cells are hyperresponsive to TLR7 agonism and that TLR7-activated B cells contribute to pSD through cytokine and autoantibody production. Thus, therapeutics that target TLR7 signaling cascades in B cells may have utility in pSD patients. [ABSTRACT FROM AUTHOR]