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Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by loss of tolerance to nuclear antigens. The formation of autoantibodies and the deposition of immune complexes trigger inflammatory tissue damage that can affect any part of the body. In most cases, SLE is a complex disease involving multiple genetic and environmental factors. Despite advances in the treatment of SLE, there is currently no cure for SLE and patients are treated with immunosuppressive drugs with significant side effects. The elucidation of rare monogenic forms of SLE has provided invaluable insights into the molecular mechanisms underlying systemic autoimmunity. Harnessing this knowledge will facilitate the development of more refined and reliable biomarker profiles for diagnosis, therapeutic monitoring, and outcome prediction, and guide the development of novel targeted therapies not only for monogenic lupus, but also for complex SLE. [ABSTRACT FROM AUTHOR]

Summary: Apart from serving as a Th1 lineage commitment regulator, transcription factor T-bet is also expressed in other immune cell types and thus orchestrates their functions. In case of B cells, more specifically, T-bet is responsible for their isotype switching to specific IgG sub-classes (IgG2a/c in mice and IgG1/3 in humans). In various autoimmune disorders, such as systemic lupus erythematosus and/or rheumatoid arthritis, subsets of T-bet expressing B cells, known as age-associated B cells (CD19+CD11c+CD21−T-bet+) and/or double-negative B cells (CD19+IgD−CD27−T-bet+), display an expansion and seem to drive disease pathogenesis. According to data, mostly derived from mice models of autoimmunity, the targeting of these specific B-cell populations is capable of ameliorating the general health status of the autoimmune subjects. Here, in this review article, we present a variety of therapeutic approaches for both mice and humans, suffering from an autoimmune disease, and we discuss the effects of each approach on T-bet+ B cells. In general, we highlight the importance of specifically targeting T-bet+ B cells for therapeutic interventions in autoimmunity. Targeting of ABCs/DN, in mice models of autoimmunity and/or humans suffering from autoimmune disorders, leads to diminished levels of T-bet expression in B cells and thus improves the general health status of the subjects. Graphical Abstract [ABSTRACT FROM AUTHOR]

The given text is a list of references to various scientific articles related to immunology and autoimmune diseases. The articles cover topics such as the influence of HLA class II molecules on inflammatory diseases, the role of DNases in health and disease, polymorphisms associated with rheumatoid arthritis, and the overlap in neutrophil transcriptome between lupus and COVID-19. Other articles discuss the role of alternative splicing in cancer and autoimmune diseases, the expression of retroviruses in rheumatoid arthritis and lupus, and the presence of autoantibodies in autoimmune diseases. These articles provide valuable insights into the mechanisms and potential therapeutic targets for these diseases. [Extracted from the article]

Vitamin C is a water-soluble vitamin introduced through the diet with anti-inflammatory, immunoregulatory, and antioxidant activities. Today, this vitamin is integrated into the treatment of many inflammatory pathologies. However, there is increasing evidence of possible use in treating autoimmune and neoplastic diseases. We reviewed the literature to delve deeper into the rationale for using vitamin C in treating this type of pathology. There is much evidence in the literature regarding the beneficial effects of vitamin C supplementation for treating autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) and neoplasms, particularly hematological neoplastic diseases. Vitamin C integration regulates the cytokines microenvironment, modulates immune response to autoantigens and cancer cells, and regulates oxidative stress. Moreover, integration therapy has an enhanced effect on chemotherapies, ionizing radiation, and target therapy used in treating hematological neoplasm. In the future, integrative therapy will have an increasingly important role in preventing pathologies and as an adjuvant to standard treatments. [ABSTRACT FROM AUTHOR]

Despite accumulating evidence linking defective lysosome function with autoimmune diseases, how the catabolic machinery is regulated to maintain immune homeostasis remains unknown. Late endosomal/lysosomal adaptor, MAPK and mTOR activator 5 (Lamtor5) is a subunit of the Ragulator mediating mechanistic target of rapamycin complex 1 (mTORC1) activation in response to amino acids, but its action mode and physiological role are still unclear. Here it is demonstrated that Lamtor5 level is markedly decreased in peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE). In parallel, the mice with myeloid Lamtor5 ablation developed SLE‐like manifestation. Impaired lysosomal function and aberrant activation of mTORC1 are evidenced in Lamtor5 deficient macrophages and PBMCs of SLE patients, accompanied by blunted autolysosomal pathway and undesirable inflammatory responses. Mechanistically, it is shown that Lamtor5 is physically associated with ATP6V1A, an essential subunit of vacuolar H+‐ATPase (v‐ATPase), and promoted the V0/V1 holoenzyme assembly to facilitate lysosome acidification. The binding of Lamtor5 to v‐ATPase affected the lysosomal tethering of Rag GTPase and weakened its interaction with mTORC1 for activation. Overall, Lamtor5 is identified as a critical factor for immune homeostasis by intergrading v‐ATPase activity, lysosome function, and mTOR pathway. The findings provide a potential therapeutic target for SLE and/or other autoimmune diseases. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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]

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]

Introductıon: Celiac disease (CD) is an autoimmune disease caused by gluten ingestion in genetically susceptible individuals. Although gastrointestinal system symptoms are common, extraintestinal symptoms may be seen during the disease course. Due to similar genetic features and pathogenetic pathways for autoimmunity, increasing rheumatological diseases have been reported in CD in recent years. In this study, we aimed to evaluate patients with CD in terms of musculoskeletal symptomatology and presence of rheumatic disease and autoantibody positivity. Methods: The study was designed as a cross-sectional, retrospective cohort study. Between January 2020-2022, 65 patients with CD who were followed-up in the gastroenterology clinic of our hospital and consulted to the rheumatology outpatient clinic for any reason were included in the study. Medical records were reviewed, laboratory and imaging results were recorded. Results: Admission to the rheumatology clinic, the most common symptoms were inflammatory back pain(IBP) (43.1%) followed by xerophthalmia (15.4%). None of the patients with IBP had radiographically active sacroiliitis. In total, concomitant rheumatological diseases were 6 (9.2%): 2 patients (3.1%) had Sjögren's syndrome and one undifferentiated connective tissue disease, systemic lupus erythematosus, psoriatic arthritis and familial Mediterranean fever. Except for the CD autoantibodies, the frequency of anti-nuclear antibodies (ANA) was 38%, and the most common extractable nuclear antigen (ENA) patterns were DFS-70 and SSA. Conclusion: Although the most common symptom is IBP, the absence of radiographic findings of spondyloarthritis in CD patients suggests these to be a non-rheumatological cause associated with CD. On the other hand, CD patients with xerophthalmia and/or ANA positivity may need to be evaluated for connective tissue diseases, especially SjS. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are multifactorial and include environmental as well as genetic drivers. Although much progress has been made in understanding the nature of genetic underpinnings of autoimmune disease, by comparison much less is understood regarding how environmental factors interact with genetics in the development of autoimmunity and autoimmune disease. In this report, we utilize the (New Zealand black × New Zealand white [NZB × NZW]) F1 mouse model of systemic lupus erythematosus (SLE). Mercury is a xenobiotic that is environmentally ubiquitous and is epidemiologically linked with the development of autoimmunity. Among other attributes of human SLE, (NZB × NZW) F1 mice spontaneously develop autoimmune-mediated kidney disease. It has been previously shown that if (NZB × NZW) F1 mice are exposed to inorganic mercury (Hg2+), the development of autoimmunity, including autoimmune kidney pathology, is accelerated. We now show that in these mice, the development of kidney disease is correlated with a decreased percentage of marginal zone (MZ) B-cells in the spleen. In Hg2+-intoxicated mice, kidney disease is significantly augmented, and matched by a greater decrease in MZ B-cell splenic percentages than found in control mice. In Hg2+- intoxicated mice, the decrease in MZ B-cells appears to be linked to aberrant B-cell receptor signal strength in transitory 2 (T2) B-cells, developmental precursors of MZ B-cells. [ABSTRACT FROM AUTHOR]

Background In the United States, anal squamous cell carcinoma rates have increased rapidly, particularly among women 50 or older than 66 years of age. As immunosuppression is associated with increased risk, autoimmune conditions may be associated with greater risk of anal squamous cell carcinoma. Methods We conducted a population-based, case-control study using Surveillance, Epidemiology, and End Results–Medicare data (2000-2017). Anal squamous cell carcinoma cases (n = 4505) were matched to 200 000 cancer-free controls. Using multivariable logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between 47 autoimmune conditions diagnosed before selection, identified using Medicare claims, and anal squamous cell carcinoma. The Bonferroni threshold was used to correct for multiple comparisons. Population attributable fractions were calculated for conditions nominally associated with anal squamous cell carcinoma. Results In total, 18% of anal squamous cell carcinoma cases and 15% of cancer-free controls had a diagnosed autoimmune condition. Any autoimmune condition was associated with an increased risk of anal squamous cell carcinoma (OR = 1.11, 95% CI = 1.02 to 1.21; population attributable fraction = 1.8%). Anal squamous cell carcinoma was associated with systemic lupus erythematosus (OR = 1.79, 95% CI = 1.32 to 2.42; population attributable fraction = 0.4%) and nominally associated (P  < .05) with sarcoidosis (OR = 2.09, 95% CI = 1.30 to 3.37; population-attributable fraction = 0.2%) and psoriasis (OR = 1.28, 95% CI = 1.06 to 1.56; population attributable fraction = 0.5%). Stratified by sex, only women showed statistically significant associations for systemic lupus erythematosus (OR = 1.97, 95% CI = 1.46 to 2.68). Statistically significant interaction was observed by sex for psoriasis (men vs women: OR = 1.68 [95% CI = 1.03 to 4.28] vs OR = 1.12 [95% CI = 0.88 to 1.43]) and polymyalgia rheumatica (OR = 0.33 [95% CI = 0.12 to 0.89] vs OR = 0.99 [95% CI = 0.75 to 1.30]). Conclusion Systemic lupus erythematosus, sarcoidosis, and psoriasis were associated with a moderately increased risk of anal squamous cell carcinoma. Given these conditions' rarity and moderate associations with anal squamous cell carcinoma, autoimmune diseases cannot explain the rising trend in this disease. [ABSTRACT FROM AUTHOR]

UNC93B1 is critical for trafficking and function of nucleic acid–sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self–nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype–specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE. Editor's summary: Toll-like receptor (TLR) 7 activates innate immune signaling after recognition of endosomal single-stranded RNA but is also believed to contribute to the development of autoimmunity. In four patients with childhood-onset lupus, Wolf et al. identified variants in the transmembrane chaperone protein UNC93B1 that led to TLR7 hyperactivation and constitutive type I interferon production. Mishra et al. also identified a patient with lupus bearing a mutation in UNC93B1 that disrupted its interaction with the endosomal BORC complex, which they found controlled homeostatic TLR7 turnover. Together, these findings demonstrate that disruptions to TLR7's regulatory machinery can contribute to human autoimmune disease. See related Research Article by Mishra et al. in this issue. —Claire Olingy [ABSTRACT FROM AUTHOR]

During transfusion of red blood cells (RBCs), recipients are exposed to both ABO and non-ABO 'minor' antigens. RBC donor units and recipient RBCs are not routinely matched for non-ABO antigens. Thus, recipients are exposed to many RBC alloantigens that can lead to RBC alloantibody production and subsequent clinically significant hemolysis. RBC alloantibodies also significantly limit the provision of compatible RBC units for recipients. Prior studies indicate that the frequency of RBC alloimmunization is increased during inflammatory responses and in patients with autoimmune diseases. Still, mechanisms contributing to alloimmune responses in patients with autoimmunity are not well understood. More than half of adult patients with systemic lupus erythematosus (SLE) produce type 1 interferons (IFNa/b) and express IFNa/b stimulated genes (ISGs). Previously, we reported that IFNa/b promote RBC alloimmune responses in the pristane mouse model, which develops a lupus-like phenotype that is dependent on IFNa/b signaling. However, it is unclear whether IFNa/b or the lupus-like phenotype induces alloimmunization in lupus models. Therefore, we tested the hypothesis that IFNa/b promotes RBC alloimmune responses in lupus by examining alloimmune responses in IFNa/b-independent (MRL-lpr) and IFNa/b-dependent (pristane) lupus models. Whereas pristane treatment significantly induced interferon-stimulated genes (ISGs), MRL-lpr mice produced significantly lower levels that were comparable to levels in untreated WT mice. Transfusion of murine RBCs that express the KEL antigen led to anti-KEL IgG production by pristanetreated WT mice. However, MRL-lpr mice produced minimal levels of anti-KEL IgG. Treatment of MRL-lpr mice with recombinant IFNa significantly enhanced alloimmunization. Collectively, results indicate that a lupus-like phenotype in preclinical models is not sufficient to induce RBC alloantibody production, and IFNa/b gene signatures may be responsible for RBC alloimmune responses in lupus mouse models. If these findings are extended to alternate pre-clinical models and clinical studies, patients with SLE who express an IFNa/b gene signature may have an increased risk of developing RBC alloantibodies and may benefit from more personalized transfusion protocols. [ABSTRACT FROM AUTHOR]

Autoimmune diseases encompass a broad spectrum of disorders characterized by disturbed immunoregulation leading to the development of specific autoantibodies, resulting in inflammation and multiple organ involvement. A distinction should be made between connective tissue diseases (mainly systemic lupus erythematosus, systemic scleroderma, inflammatory muscle diseases, and rheumatoid arthritis) and vasculitides (mainly small-vessel vasculitis such as antineutrophil cytoplasmic antibody-associated vasculitis and immune-complex mediated vasculitis). Admission of patients with autoimmune diseases to the intensive care unit (ICU) is often triggered by disease flare-ups, infections, and organ failure and is associated with high mortality rates. Management of these patients is complex, including prompt disease identification, immunosuppressive treatment initiation, and life-sustaining therapies, and requires multi-disciplinary involvement. Data about autoimmune diseases in the ICU are limited and there is a need for multicenter, international collaboration to improve patients' diagnosis, management, and outcomes. The objective of this narrative review is to summarize the epidemiology, clinical features, and selected management of severe systemic autoimmune diseases. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder which may affect the gastrointestinal system. Half of patients with SLE experience gastrointestinal symptoms, with the most common being nausea, vomiting, anorexia, and abdominal pain. Mesenteric vasculitis is a severe and rare complication of SLE and one of the most frequent causes of severe acute abdominal pain. The authors present the case of a 57-year-old woman with SLE who was diagnosed with necrotizing mesenteric vasculitis following a urinary septic shock. The patient was treated with high-dose corticosteroid therapy and cyclophosphamide, with resolution of the clinical picture. [ABSTRACT FROM AUTHOR]

We investigated the impact of synthetic nucleic acid antigens on the autoantibody profiles in patients with localized scleroderma, an autoimmune skin disease. Anti-DNA antibodies, including double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA), are common among autoimmune diseases, such as systemic lupus erythematosus and localized scleroderma. Based on recent studies, we hypothesized that the sequence of nucleic acid antigens has an impact on the autoimmune reactions in localized scleroderma. To test our hypothesis, we synthesized a panel of DNA and RNA antigens and used them for autoantibody profiling of 70 children with localized scleroderma compared with the healthy controls and patients with pediatric systemic lupus erythematosus (as a disease control). Among the tested antigens, dsD4, which contains the sequence of the human oncogene BRAF, showed a particularly strong presence in localized scleroderma but not systemic lupus erythematosus. Disease activity in patients was significantly associated with dsD4 autoantibody levels. We confirmed this result in vivo by using a bleomycin-induced mouse model of localized scleroderma. When administered intraperitoneally, dsD4 promoted an active polyclonal response in the mouse model. Our study highlights sequence specificity for nucleic acid antigens in localized scleroderma that could potentially lead to developing novel early-stage diagnostic tools. [ABSTRACT FROM AUTHOR]

Introduction: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease that presents a challenge for clinicians. To identify potential biomarkers for diagnosis and disease activity in SLE, we investigated a selected yet broad panel of cytokines and autoantibodies in patients with SLE, healthy controls (HC), and patients with other autoimmune diseases (AIDs). Methods: Serum samples from 422 SLE patients, 546 HC, and 1223 other AIDs were analysed within the frame of the European PRECISESADS project (NTC02890121). Cytokine levels were determined using Luminex panels, and autoantibodies using different immunoassays. Results: Of the 83 cytokines analysed, 29 differed significantly between patients with SLE and HC. Specifically, CCL8, CXCL13, and IL-1RA levels were elevated in patients with active, but not inactive, SLE versus HC, as well as in patients with SLE versus other AIDs. The levels of these cytokines also correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) scores, among five other cytokines. Overall, the occurrence of autoantibodies was similar across SLEDAI-2K organ domains, and the correlations between autoantibodies and activity in different organ domains were weak. Discussion: Our findings suggest that, upon validation, CCL8, CXCL13, and IL-1RA could serve as promising serum biomarkers of activity in SLE. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with hyperactive innate and adaptive immune systems that cause dermatological, cardiovascular, renal, and neuropsychiatric problems in patients. SLE's multifactorial nature and complex pathogenesis present significant challenges in its clinical classification. In addition, unpredictable treatment responses in patients emphasize the need for highly specific and sensitive SLE biomarkers that can assist in understanding the exact pathogenesis and, thereby, lead to the identification of novel therapeutic targets. Recent studies on microRNA (miRNA), a non-coding region involved in the regulation of gene expression, indicate its importance in the development of the immune system and thus in the pathogenesis of various autoimmune disorders such as SLE. miRNAs are fascinating biomarker prospects for SLE categorization and disease monitoring owing to their small size and high stability. In this paper, we have discussed the involvement of a wide range of miRNAs in the regulation of SLE inflammation and how their modulation can be a potential therapeutic approach. [ABSTRACT FROM AUTHOR]

Substantial evidence highlights divergences in immune responses between men and women. Women are more susceptible to autoimmunity, whereas men suffer from the more severe presentation of autoimmune disorders. The molecular mechanism of this sexual dimorphism remains elusive. Herein, we conducted a comprehensive analysis of sex differences in whole-blood gene expression focusing on alternative splicing (AS) events in systemic lupus erythematosus (SLE), which is a prototype sex-biased disease. This study included 79 SLE patients with active disease and 58 matched healthy controls who underwent whole-blood RNA sequencing. Sex differences in splicing events were widespread, existent in both SLE and a healthy state. However, we observed distinct gene sets and molecular pathways targeted by sex-dependent AS in SLE patients as compared to healthy subjects, as well as a notable sex dissimilarity in intron retention events. Sexually differential spliced genes specific to SLE patients were enriched for dynamic cellular processes including chromatin remodeling, stress and inflammatory responses. Remarkably, the extent of sexual differences in AS in the SLE patients and healthy individuals exceeded those in gene expression. Overall, this study reveals an unprecedent variation in sex-dependent splicing events in SLE and the healthy state, with potential implications for understanding the molecular basis of sexual dimorphism in autoimmunity. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cells (MDSCs) are well recognized as critical factors in the pathology of tumors. However, their roles in autoimmune diseases are still unclear, which hampers the development of efficient immunotherapies. The role of different MDSCs subsets in multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, type 1 diabetes, and systemic lupus erythematosus displayed different mechanisms of immune suppression, and several studies pointed to MDSCs' capacity to induce T‐helper (Th)17 cells and tissue damage. These results also suggested that MDSCs could be present in different functional states and utilize different mechanisms for controlling the activity of T and B cells. Therefore, various therapeutic strategies should be employed to restore homeostasis in autoimmune diseases. The therapies harnessing MDSCs could be designed either as cell therapy or rely on the expansion and activation of MDSCs in vivo, or their depletion. Cumulatively, MDSCs are inevitable players in autoimmunity, and rational approaches in developing therapies are required to avoid the adverse effects of MDSCs and harness their suppressive mechanisms to improve the overall efficacy of autoimmunity therapy. [ABSTRACT FROM AUTHOR]

Protein tripartite motif-containing 21 (TRIM21/Ro52), an E3 ubiquitin ligase, is an essential regulator of innate immunity, and its dysregulation is closely associated with the development of autoimmune diseases, predominantly systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS). TRIM21 /Ro52 also features anti-cancer and carcinogenic functions according to different malignancies. The interconnected role of TRIM21/Ro52 in regulating autoimmunity and cell metabolism in autoimmune diseases and malignancies is implicated. In this review, we summarize current findings on how TRIM21/Ro52 affects inflammation and tumorigenesis, and investigate the relationship between TRIM21/Ro52 expression and the formation of lymphoma and breast cancer in SLE and pSS populations. [ABSTRACT FROM AUTHOR]

Autoimmune diseases arise from atypical immune responses that attack selftissue epitopes, and their development is intricately connected to the disruption of the JAK-STAT signaling pathway, where SOCS proteins play crucial roles. Conditions such as autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis exhibit immune system dysfunctions associated with JAK-STAT signaling dysregulation. Emerging therapeutic strategies utilize JAK-STAT inhibitors and SOCS mimetics to modulate immune responses and alleviate autoimmune manifestations. Although more research and clinical studies are required to assess their effectiveness, safety profiles, and potential for personalized therapeutic approaches in autoimmune conditions, JAK-STAT inhibitors and SOCS mimetics show promise as potential treatment options. This review explores the action, effectiveness, safety profiles, and future prospects of JAK inhibitors and SOCS mimetics as therapeutic agents for psoriasis, autoimmune uveitis, systemic lupus erythematosus, and autoimmune encephalitis. The findings underscore the importance of investigating these targeted therapies to advance treatment options for individuals suffering from autoimmune diseases. [ABSTRACT FROM AUTHOR]

PD‐1 and CTLA‐4 can play an important role in addressing the issue of autoimmune diseases. PD‐1 is a transmembrane glycoprotein expressed on T, B, and Dentric cells. This molecule functions as a checkpoint in T cell proliferation. Ligation of PD‐1 with its ligands inhibits the production of IL‐2, IL‐7, IL‐10, and IL‐12 as well as other cytokines by macrophages, natural killer (NK) cells, and T cells, which can suppress cell proliferation and inflammation. Today, scientists attempt to protect against autoimmune diseases by PD‐1 inhibitory signals. In this review, we discuss the structure, expression, and signaling pathway of PD‐1. In addition, we discuss the importance of PD‐1 in regulating several autoimmune diseases, reflecting how manipulating this molecule can be an effective method in the immunotherapy of some autoimmune diseases. Significance statement: 1.The structure, expression, and signaling pathway of PD‐1 were discussed in this article.2.The importance of PD‐1 in regulating several autoimmune diseases reflects how manipulating this molecule can effectively treat some autoimmune diseases. [ABSTRACT FROM AUTHOR]

Introduction: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an Xlinked enzymatic disorder that is particularly prevalent in Africa, Asia, and the Middle East. This study aimed to assess the long-term health risks associated with G6PD deficiency. Methods: A retrospective cohort study was conducted using data from a national healthcare provider in Israel (Leumit Health Services). A total of 7,473 G6PDdeficient individuals were matched with 29,892 control subjects in a 1:4 ratio, based on age, gender, socioeconomic status, and ethnic groups. The exposure of interest was recorded G6PD diagnosis or positive G6PD diagnostic test. The main outcomes and measures included rates of infectious diseases, allergic conditions, and autoimmune disorders between 2002 and 2022. Results: Significantly increased rates were observed for autoimmune disorders, infectious diseases, and allergic conditions in G6PD-deficient individuals compared to the control group. Specifically, notable increases were observed for rheumatoid arthritis (odds ratio [OR] 2.41, p<0.001), systemic lupus erythematosus (OR 4.56, p<0.001), scleroderma (OR 6.87, p<0.001), pernicious anemia (OR 18.70, p<0.001), fibromyalgia (OR 1.98, p<0.001), Graves' disease (OR 1.46, p=0.001), and Hashimoto's thyroiditis (OR 1.26, p=0.001). These findings were supported by elevated rates of positive autoimmune serology and higher utilization of medications commonly used to treat autoimmune conditions in the G6PD-deficient group. Discussion: In conclusion, individuals with G6PD deficiency are at a higher risk of developing autoimmune disorders, infectious diseases, and allergic conditions. This large-scale observational study provides valuable insights into the comprehensive association between G6PD deficiency and infectious and immune-related diseases. The findings emphasize the importance of considering G6PD deficiency as a potential risk factor in clinical practice and further research is warranted to better understand the underlying mechanisms of these associations. [ABSTRACT FROM AUTHOR]

Introduction: Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) consists of a wide spectrum of symptoms and immunological features that are believed to develop in predisposed individuals after exposure to an adjuvant, including a silicone breast implant (SBI). Different autoimmune diseases (AIDs) have been associated with ASIA, but ASIA development after SBI in women with Hashimoto thyroiditis (HT) and familial autoimmunity has rarely been described. Case report: A 37-year-old woman presented in 2019 with arthralgia, sicca symptoms, fatigue, + antinuclear antibody (ANA), + anti SSA, and + anticardiolipin Immunoglobulin G (IgG) antibodies. She was diagnosed with HT and vitamin D deficiency in 2012. The familial autoimmunity was present: the patient's mother had been diagnosed with systemic lupus erythematosus and secondary Sjogren's syndrome and her grandmother with cutaneous lupus and pernicious anemia. In 2017, the patient had a cosmetic SBI procedure that was complicated by repeated right breast capsulitis. After 2 years of irregular visits due to COVID-19, she presented with + ANA, + anticentromere antibodies both in sera and seroma, sicca syndrome, arthralgias, twinkling in extremities, abnormal capillaroscopic findings, and reduced diffusing capacity of the lungs for carbonmonoxide. She was diagnosedwith ASIA, and antimalarial and corticosteroid therapy were introduced. Conclusion: In patients with HT and familial autoimmunity, SBI should be carefully considered due to the possibility of ASIA development. Hashimoto thyroiditis, familial autoimmunity, and ASIA seem to be interconnected in the complex mosaic of autoimmunity in predisposed individuals. [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]

The relationship between viral infection and onset of autoimmune diseases such as systemic lupus erythematosus remains uncertain. During the COVID-19 pandemic, organ-specific and multisystemic autoimmune phenomena temporally related to the viral infection have been described. Immune dysregulation triggered by the SARS-CoV-2 virus leading to hyperactivation of both the innate and adaptive immune systems contributes to the excessive production of pro-inflammatory cytokines, autoantibodies, and subsequent autoimmune manifestations. We report two patients without known autoimmune diseases who developed lupus nephritis shortly after a documented mild SARS-CoV-2 infection. Together with other similar cases in the literature, the observation supports a viral trigger of the development of systemic lupus erythematosus in susceptible individuals. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder exhibiting variable disease courses and multiple clinical manifestations. SLE's aetiology remains unclear; however, different environmental (e.g., ultraviolet light, infections, drugs, etc.), genetic, and hormonal factors are potentially involved. A positive family history and history of having other autoimmune illnesses are considered high‐risk factors for SLE; nevertheless, most SLE cases are scattered. The 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for SLE include at least one positive antinuclear antibody test as a mandatory entry criterion, followed by additive weighted standards grouped in seven clinical (constitutional, haematological, neuropsychiatric, serosal, musculoskeletal, renal, and mucocutaneous) and three immunological (antiphospholipid antibodies, complement proteins, and SLE‐specific antibodies) domains weighted from 2 to 10, with patients accumulating ≥10 points being diagnosed with SLE. Herein, we report a case of neuropsychiatric lupus, a rare and severe form of SLE. [ABSTRACT FROM AUTHOR]

Background: The aryl hydrocarbon receptor (AhR) is a critical regulator of the pathogenesis of autoimmune disorders. We aimed to investigate the therapeutic effect of the AhR agonist tapinarof during the development of systemic lupus erythematosus (SLE). Methods: MRL/lpr mice were intraperitoneally injected with 1 or 5 mg/kg tapinarof for 6 weeks. Kidney histopathology was evaluated using hematoxylin and eosin (H&E) and Periodic‐Acid‐Schiff (PAS) staining. Immunofluorescence microscopy was performed to detect immune complex renal depositions. Flow cytometry (FCM) analysis was carried out to determine the proportions of T and B cell subsets. Realtime qPCR was used to quantify the expression of Tfh cell‐associated genes. We conducted an in vitro polarization experiment to observe the effect of tapinarof on Tfh differentiation. Western blotting was used to detect the expression of target proteins. Results: We found that tapinarof treatment ameliorated lupus phenotypes, including splenomegaly, lymph node enlargement, kidney damages, immune complex deposition, and excessive secretion of antibodies. Additionally, we showed that Treg subpopulation frequencies significantly increased in MRL/lpr mice treated with tapinarof, while the proportion of Th1/Th2 cells was reduced after tapinarof administration. Moreover, tapinarof suppressed Tfh cell differentiation and germinal center (GC) reaction in vivo. The inhibitory effect of tapinarof on Tfh cells was further verified in the in vitro Tfh cell polarization experiment. Realtime qPCR revealed that tapinarof repressed the expression of Tfh signature genes. Mechanistically, tapinarof significantly inhibited the phosphorylation levels of JAK2 and STAT3. The capacity for Tfh differentiation was partially rescued by the STAT3 activator Colivelin TFA. Furthermore, our in vitro Tfh polarization experiments indicated that tapinarof suppressed Tfh cell development in SLE. Conclusions: Our data demonstrated that tapinarof modulated the JAK2‐STAT3 pathway to suppress Tfh cell differentiation for the treatment of lupus symptoms in MRL/lpr mice. [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells are heterogeneous and mainly characterized by expressing surface markers CXCR5, ICOS, and PD-1; cytokine IL-21; and transcription factor Bcl6. They are crucial for B-cell differentiation into longlived plasma cells and high-affinity antibody production. T follicular regulatory (Tfr) cells were described to express markers of conventional T regulatory (Treg) cells and Tfh cells and were able to suppress Tfh-cell and B-cell responses. Evidence has revealed that the dysregulation of Tfh and Tfr cells is positively associated with the pathogenic processes of autoimmune diseases. Herein, we briefly introduce the phenotype, differentiation, and function of Tfh and Tfr cells, and review their potential roles in autoimmune diseases. In addition, we discuss perspectives to develop novel therapies targeting Tfh/Tfr balance. [ABSTRACT FROM AUTHOR]

The association of dysregulated metabolism in systemic lupus erythematosus (SLE) pathogenesis has prompted investigations into metabolic rewiring and the involvement of mitochondrial metabolism as a driver of disease through NLRP3 inflammasome activation, disruption of mitochondrial DNA maintenance, and pro-inflammatory cytokine release. The use of Agilent Seahorse Technology to gain functional in situ metabolic insights of selected cell types from SLE patients has identified key parameters that are dysregulated during disease. Mitochondrial functional assessments specifically can detect dysfunction through oxygen consumption rate (OCR), spare respiratory capacity, and maximal respiration measurements, which, when coupled with disease activity scores could show potential as markers of disease activity. CD4+ and CD8 + T cells have been assessed in this way and show that oxygen consumption rate, spare respiratory capacity, and maximal respiration are blunted in CD8 + T cells, with results not being as clear cut in CD4 + T cells. Additionally, glutamine, processed by mitochondrial substrate level phosphorylation is emerging as a key role player in the expansion and differentiation of Th1, Th17, ¡δ T cells, and plasmablasts. The role that circulating leukocytes play in acting as bioenergetic biomarkers of diseases such as diabetes suggests that this may also be a tool to detect preclinical SLE. Therefore, the metabolic characterization of immune cell subsets and the collection of metabolic data during interventions is also essential. The delineation of the metabolic tuning of immune cells in this way could lead to novel strategies in treating metabolically demanding processes characteristic of autoimmune diseases such as SLE. [ABSTRACT FROM AUTHOR]

Epigenetics, as a discipline that aims to explain the differential expression of phenotypes arising from the same gene sequence and the heritability of epigenetic expression, has received much attention in medicine. Epigenetic mechanisms are constantly being discovered, including DNA methylation, histone modifications, noncoding RNAs and m6A. The immune system mainly achieves an immune response through the differentiation and functional expression of immune cells, in which epigenetic modification will have an important impact. Because of immune infiltration in the tumor microenvironment, immunotherapy has become a research hotspot in tumor therapy. Epigenetics plays an important role in autoimmune diseases and cancers through immunology. An increasing number of drugs targeting epigenetic mechanisms, such as DNA methyltransferase inhibitors, histone deacetylase inhibitors, and drug combinations, are being evaluated in clinical trials for the treatment of various cancers (including leukemia and osteosarcoma) and autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis). This review summarizes the progress of epigenetic regulation for cancers and autoimmune diseases to date, shedding light on potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

To better understand the impact of gut dysbiosis on four autoimmune diseases [Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS)], this review investigated the altered gut bacteria in each disease and the shared ones among the four diseases. The enriched gut bacteria shared by three of the four autoimmune diseases were Streptococcus, Prevotella, and Eggerthella, which are associated with autoantibody production or activation of Th17 cells in immune-related diseases. On the other hand, Faecalibacterium comprises depleted gut bacteria shared by patients with SLE, MS, and SS, which is associated with various antiinflammatory activities. The indexes of gut dysbiosis, defined as the number of altered gut bacterial taxa divided by the number of studies in SLE, MS, RA, and SS, were 1.7, 1.8, 0.7, and 1.3, respectively. Interestingly, these values presented a positive correlation trend with the standardized mortality rates --2.66, 2.89, 1.54, and 1.41, respectively. In addition, shared altered gut bacteria among the autoimmune diseases may correlate with the prevalence of polyautoimmunity in patients with SLE, SS, RA, and MS, that is, 41 percent, 32.6 percent, 14 percent, and 1-16.6 percent, respectively. Overall, this review suggests that gut dysbiosis in autoimmune diseases may be closely related to the failure of the gut immune system to maintain homeostasis. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are life-threatening disorders that cause increasing disability over time. Systemic lupus erythematosus (SLE) and other autoimmune diseases arise when immune stimuli override mechanisms of self-tolerance. Accumulating evidence has demonstrated that protein glycosylation is substantially altered in autoimmune disease development, but the mechanisms by which glycans trigger these autoreactive immune responses are still largely unclear. In this study, we found that presence of microbial-associated mannose structures at the surface of the kidney triggers the recognition of DC-SIGN–expressing γδ T cells, inducing a pathogenic interleukin-17a (IL-17a)–mediated autoimmune response. Mice lacking Mgat5, which have a higher abundance of mannose structures in the kidney, displayed increased γδ T cell infiltration into the kidney that was associated with spontaneous development of lupus in older mice. N-acetylglucosamine supplementation, which promoted biosynthesis of tolerogenic branched N-glycans in the kidney, was found to inhibit γδ T cell infiltration and control disease development. Together, this work reveals a mannose–γδ T cell–IL-17a axis in SLE immunopathogenesis and highlights glycometabolic reprogramming as a therapeutic strategy for autoimmune disease treatment. Branching out: Differential glycosylation patterns on proteins are becoming increasingly implicated in inflammatory diseases. Here, Alves et al. identified aberrant mannosylation patterns on the surface of kidney cells as a potential driver of lupus nephritis. Mice lacking Mgat5 had more mannosylation on the surface of kidney cells, which was also associated with activation of IL-17a–producing γδ T cells and spontaneous development of lupus-like disease in older mice. Therapeutic supplementation of N-acetylglucosamine, which promoted tolerogenic branched N-glycan synthesis, inhibited γδ T cell-driven pathogenesis, suggesting that glycometabolic reprogramming could be a therapeutic strategy for lupus nephritis. —CM [ABSTRACT FROM AUTHOR]

Summary: A body of evidence has re‐energized the interest on the role neutrophils in inflammatory and autoimmune conditions. For decades, neutrophils have been considered a homogenous population. Nevertheless, accumulating evidence suggests that neutrophils are more versatile and heterogeneous than initially considered. The notion of neutrophil heterogeneity has been supported by the identification of low‐density granulocytes (LDGs) in systemic lupus erythematosus (SLE) and other systemic autoimmune and autoinflammatory conditions. Transcriptomic, epigenetic, proteomic, and functional analyses support that LDGs are a distinct subset of proinflammatory neutrophils implicated in the pathogenesis of SLE and other autoimmune diseases. Importantly, it remains incompletely characterized whether LDGs detected in other inflammatory/autoimmune conditions display the same phenotype that those present in SLE. A shared feature of LDGs across diseases is their association with vascular damage, an important contributor to morbidity and mortality in chronic inflammatory conditions. Additionally, the lack of specific markers to identify LDGs in circulation or in tissue, makes it a challenge to elucidate their role in the pathogenesis of inflammatory and autoimmune conditions. In this review, we aim to examine the evidence on the biology and the putative pathogenic role of LDGs in systemic autoimmune diseases. [ABSTRACT FROM AUTHOR]

Autoimmune diseases (AIDs) are the consequence of a breach in immune tolerance, leading to the inability to sufficiently differentiate between self and non-self. Immune reactions that are targeted towards self-antigens can ultimately lead to the destruction of the host's cells and the development of autoimmune diseases. Although autoimmune disorders are comparatively rare, the worldwide incidence and prevalence is increasing, and they have major adverse implications for mortality and morbidity. Genetic and environmental factors are thought to be the major factors contributing to the development of autoimmunity. Viral infections are one of the environmental triggers that can lead to autoimmunity. Current research suggests that several mechanisms, such as molecular mimicry, epitope spreading, and bystander activation, can cause viral-induced autoimmunity. Here we describe the latest insights into the pathomechanisms of viral-induced autoimmune diseases and discuss recent findings on COVID-19 infections and the development of AIDs. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease. The sex hormones estrogen and testosterone may have an influence on the production of antibodies. In addition, the gut microbiota also shows an effect on the onset and progression of SLE. Hence, the molecular interplay between sex hormones in terms of gender difference, gut microbiota and SLE is being clarified day after day. The aim of this review is to investigate the dynamic relationship of the gut microbiota with sex hormones in systemic lupus erythematosus taking into account the bacterial strains shown to be affected, effects of antibiotics and other factors that affect the gut microbiome, which itself strongly affects the pathogenesis of SLE. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are crucial post-transcriptional regulators of gene expression in ubiquitous biological processes, including immune-related pathways. This review focuses on the miR-183/96/182 cluster (miR-183C), which contains three miRNAs, miR-183, -96, and -182, having almost identical seed sequences with minor differences. The similarity among seed sequences allows these three miRNAs to act cooperatively. In addition, their minor differences permit them to target distinct genes and regulate unique pathways. The expression of miR-183C was initially identified in sensory organs. Subsequently, abnormal expression of miR-183C miRNAs in various cancers and autoimmune diseases has been reported, implying their potential role in human diseases. The regulatory effects of miR-183C miRNAs on the differentiation and function of both innate and adaptive immune cells have now been documented. In this review, we have discussed the complex role of miR-183C in the immune cells in both normal and autoimmune backgrounds. We highlighted the dysregulation of miR-183C miRNAs in several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ocular autoimmune disorders, and discussed the potential for utilizing miR-183C as biomarkers and therapeutic targets of specific autoimmune diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Systemic Sclerosis (SSc) is a rare autoimmune disease characterized by scarring of the tissues and organs. This scarring, or fibrosis, has a major impact on a patient's quality of life; for example, lung fibrosis reduces the efficiency of breathing and is a significant cause of death for SSc patients. To develop novel therapeutic strategies, it is important to understand what causes fibrosis to occur and progress. It was recently found that plasmacytoid dendritic cells (pDCs) are key immune cells in the development of fibrosis in SSc. These cells are innate immune cells that are specialized in anti-viral responses, and they are also involved in autoimmune diseases. This review will examine the recent research that has started to uncover the molecular mechanisms through which pDCs impact SSc. Systemic sclerosis (SSc) is a debilitating autoimmune disease that affects multiple systems. It is characterized by immunological deregulation, functional and structural abnormalities of small blood vessels, and fibrosis of the skin, and, in some cases, internal organs. Fibrosis has a devastating impact on a patient's life and lung fibrosis is associated with high morbimortality. Several immune populations contribute to the progression of SSc, and plasmacytoid dendritic cells (pDCs) have been identified as crucial mediators of fibrosis. Research on murine models of lung and skin fibrosis has shown that pDCs are essential in the development of fibrosis, and that removing pDCs improves fibrosis. pDCs are a subset of dendritic cells (DCs) that are specialized in anti-viral responses and are also involved in autoimmune diseases, such as SSc, systemic lupus erythematosus (SLE) and psoriasis, mostly due to their capacity to produce type I interferon (IFN). A type I IFN signature and high levels of CXCL4, both derived from pDCs, have been associated with poor prognosis in patients with SSc and are correlated with fibrosis. This review will examine the recent research on the molecular mechanisms through which pDCs impact SSc. [ABSTRACT FROM AUTHOR]

A comprehensive search of published literature in brain volumetry was conducted in three autoimmune diseases — systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and ulcerative colitis (UC) — with the intention of performing a meta-analysis of published data. Due to the lack of data in RA and UC, the reported meta-analysis was limited to SLE. The MEDLINE database was searched for studies from 1988 to March 2022. A total of 175 papers met the initial inclusion criteria, and 16 were included in a random-effects meta-analysis. The reduction in the number of papers included in the final analysis is primarily due to the lack of overlap in measured and reported brain regions. A significantly lower volume was seen in patients with SLE in the hippocampus, corpus callosum, and total gray matter volume measurements as compared to age- and sex-matched controls. There were not enough studies to perform a meta-analysis for RA and UC; instead, we include a summary of published volumetric studies. The meta-analyses revealed structural brain abnormalities in patients with SLE, suggesting that lower global brain volumes are associated with disease status. This volumetric difference was seen in both the hippocampus and corpus callosum and total gray matter volume measurements. These results indicate both gray and white matter involvements in SLE and suggest there may be both localized and global reductions in brain volume. [ABSTRACT FROM AUTHOR]

Growing evidence indicates the pathogenic role of autoreactive IgE in autoimmune diseases. Incidence of autoimmune and allergic diseases in the industrialized countries is consistently icreasing, thus leading to concerted efforts to comprehend the regulation of IgE-mediated mechanisms. The first reports of a presence of IgE autoantibodies in patients with autoimmune diseases have been published a long time ago, and it is now recognized that self-reactive IgE can mediate inflammatory response in bullous pemhigoid, systemic lupus erythematosus, chronic urticaria, and atopic dermatitis. The advances in understanding the pathomechanisms of these disorders brought to a successful use of anti-IgE strategies in their management. The present review discusses the current state of knowledge on the IgE-mediated autoimmunity and anti-IgE treatment, and pave the way for further exploration of the subject. [ABSTRACT FROM AUTHOR]

The emergence, survival, growth and maintenance of autoreactive (AR) B-cell clones, the hallmark of humoral autoimmunity, leave their footprints in B-cell receptor repertoires. Collecting IgH sequences related to polyreactive (PR) ones from adaptive immune receptor repertoire (AIRR) datasets make the reconstruction and analysis of PR/AR B-cell lineages possible. We developed a computational approach, named ImmChainTracer, to extract members and to visualize clonal relationships of such B-cell lineages. Our approach was successfully applied on the IgH repertoires of patients suffering from monogenic hypomorphic RAG1 and 2 deficiency (pRD) or polygenic systemic lupus erythematosus (SLE) autoimmune diseases to identify relatives of AR IgH sequences and to track their fate in AIRRs. Signs of clonal expansion, affinity maturation and class-switching events in PR/AR and non-PR/AR B-cell lineages were revealed. An extension of our method towards B-cell expansion caused by any trigger (e.g., infection, vaccination or antibody development) may provide deeper insight into antigen specific B-lymphogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Uncommon patterns on Human Epithelial 2 (Hep 2) substrate during Antinuclear Antibody (ANA) screening by Indirect Immunofluorescence (IIF) microscopy are not routinely reported by many laboratories since their clinical relevance is not well established. Aim: To elucidate rare ANA patterns on Hep 2 and their possible association with clinical presentation. Materials and Methods: A retrospective study was conducted on ANA reports in the duration January 2021 to March 2022 at the Department of Laboratory Medicine, Dr. Sulaiman Al Habib Medical Group, Olaya Medical Complex, Riyadh, Saudi Arabia, to recognise rare ANA patterns. Gold standard method of IIF on Hep 2 was used for screening. Statistical evaluation was done to obtain frequencies of various ANA patterns. Those with frequency of less than 1% were classified as rare patterns. Results: Overall, 4207 consecutive ANA reports were evaluated out of which 1388 were positive and 210 (4.99%) demonstrated rare ANA patterns including nuclear, cytoplasmic and mitotic subtypes. Most commonly encountered among the rare ANA patterns was intercellular bridge (AC 27) with frequency of 0.78% (n=33). Systemic Lupus Erythematosus (SLE) (10/210) was the most often observed clinical association with rare cytoplasmic and mitotic patterns at titer ≥ 1:160. Conclusion: Uncommon ANA patterns may be useful in initial work-up of autoimmune illness hence, should be routinely reported. Further studies to enlighten the significance of these patterns, analogous antibodies could be of diagnostic relevance in autoimmune and other diseases. [ABSTRACT FROM AUTHOR]

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Autoimmunity reflects an altered immune status. The coexistence of three or more autoimmune diseases in a patient constitutes multiple autoimmune syndrome. Here, an interesting case with a history of Hashimoto's thyroiditis and got the diagnosis of systemic lupus erythematosus during her evaluation, in which the clinical signs of neuromyelitis optica spectrum disorder (NMOSD) and miyasthenia gravis co-occurred will be discussed. In addition to high-dose pulse steroid, plasmapheresis and intravenous immunoglobulin treatments, rituximab treatment was started and the patient is followed up without clinical worsening and disability in the three-year follow-up. Patients with diagnosis of NMOSD need special attention as multiple immune-mediated disorders may be present simultaneously or sequentially during the course of the disease process. This case report emphasizes the importance of a multidisciplinary team approach for a better understanding of disorders related to the breakdown of immune tolerance. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, characterized by a breakdown of immune tolerance and the development of autoantibodies against nucleic self-antigens. Immunometabolism is a rapidly expanding scientific field investigating the metabolic programming of cells of the immune system. During the normal immune response, extensive reprogramming of cellular metabolism occurs, both to generate adenosine triphosphate and facilitate protein synthesis, and also to manage cellular stress. Major pathways upregulated include glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle and the pentose phosphate pathway, among others. Metabolic reprogramming also occurs to aid resolution of inflammation. Immune cells of both patients with SLE and lupus-prone mice are characterized by metabolic abnormalities resulting in an altered functional and inflammatory state. Recent studies have described how metabolic reprogramming occurs in many cell populations in SLE, particularly CD4+ T cells, e.g. favouring a glycolytic profile by overactivation of the mechanistic target of rapamycin pathway. These advances have led to an increased understanding of the metabolic changes affecting the inflammatory profile of T and B cells, monocytes, dendritic cells and neutrophils, and how they contribute to autoimmunity and SLE pathogenesis. In the current review, we aim to summarize recent advances in the field of immunometabolism involved in SLE and how these could potentially lead to new therapeutic strategies in the future. [ABSTRACT FROM AUTHOR]