The Impact of Obesity on the Development and Progression of Selected Autoimmune Diseases: Interplay Between Inflammation and Immune Dysregulation – A Review

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a prevalent type of autoimmune encephalitis caused by antibodies targeting the NMDAR's GluN1 subunit. While significant progress has been made in elucidating the pathophysiology of autoimmune diseases, the immunological mechanisms underlying anti-NMDARE remain elusive. This study aimed to characterize immune cell interactionsand dysregulation in anti-NMDARE by leveraging single-cell multi-omics sequencing technologies. Peripheral blood mononuclear cells (PBMCs) from patients in the acute phase of anti-NMDARE and healthy controls were sequenced using single-cell joint profiling of transcriptome and chromatin accessibility. Differential gene expression analysis, transcription factor activity profiling, and cell-cell communication modeling were performed to elucidate the immune mechanisms underlying the disease. In parallel, single-cell B cell receptor sequencing (scBCR-seq) and repertoire analysis were conducted to assess antigen-driven clonal expansion within the B cell population. The study revealed a significant clonal expansion of B cells, particularly plasma cells, in anti-NMDARE patients. The novel finding of type I interferon (IFN-I) pathway activation suggests a regulatory mechanism that may drive this expansion and enhance antibody secretion. Additionally, activation of Toll-like receptor 2 (TLR2) in myeloid cells was noted, which may connect to tumor necrosis factor-alpha (TNF-α) secretion. This cytokine may contribute to the activation of B and T cells, thereby perpetuating immune dysregulation. This study presents a comprehensive single-cell multi-omics characterization of immune dysregulation in anti-NMDARE, highlighting the expansion of B cell and the activation of the IFN-I and TLR2 pathways. These findings provide deeper insights into the molecular mechanism driving the pathogenesis of anti-NMDARE and offer promising targets for future therapeutic intervention. Significant B cell clonal expansion, particularly in plasma cells, driven by antigen recognition. IFN-I pathway activation in plasma cells boosts their antibody production and potentially exacerbates immune dysregulation. TLR2 pathway activation in myeloid cells contributes to TNF-α secretion and could influence adaptive immune responses.

Fecal microbiota transplantation in autoimmune diseases – An extensive paper on a pathogenetic therapy

Chronic infections significantly impact the immune system, contributing to dysregulation and the development of autoimmune diseases. Persistent pathogens, such as viruses and bacteria, can evade immune clearance, leading to a sustained inflammatory response that disrupts the delicate balance of immune tolerance and activation. This review explores the mechanisms through which chronic infections influence immune system dynamics, focusing on the role of cytokines, immune cell modulation, and the alteration of immune signaling pathways. Infections like hepatitis C, Epstein-Barr virus, and others have been linked to autoimmune conditions such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. The persistent presence of these pathogens may lead to molecular mimicry, epitope spreading, and the activation of autoreactive T and B cells, driving the pathogenesis of autoimmunity. Additionally, we discuss the implications of chronic infections on therapeutic strategies for autoimmune diseases, emphasizing the need for a comprehensive understanding of the interplay between infections and autoimmune dysregulation. By elucidating the complex relationships between chronic infections and the immune system, this review aims to highlight potential avenues for developing targeted interventions and improving patient outcomes in autoimmune disorders. Keywords: Chronic Infections, Immune Dysregulation, Autoimmune Diseases, Cytokines, Pathogenesis

MicroRNAs (miRNAs) are small noncoding conserved RNAs containing 19 to 24 nucleotides that are regulators of post-translational modifications and are involved in the majority of biological processes such as immune homeostasis, T helper cell differentiation, central and peripheral tolerance, and immune cell development. Autoimmune diseases are characterized by immune system dysregulation, which ultimately leads to destructive responses to self-antigens. A large body of literature suggests that autoimmune diseases and immune dysregulation are associated with different miRNA expression changes in the target cells and tissues of adaptive or innate immunity. miR-155 is identified as a critical modulator of immune responses. Recently conducted studies on the expression profile of miR-155 suggest that the altered expression and function of miR-155 can mediate vulnerability to autoimmune diseases and cause significant dysfunction of the immune system.

Regulatory T cells in myositis — Good Samaritans at the site of inflammation?

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by widespread inflammation and immune system dysregulation. Recent research suggests that the gut microbiota may play a role in the development of SLE by modulating immune system responses, affecting cytokine production, and altering the activity of T and B cells lymphocytes. As a result, there is a growing interest in microbiota-targeted therapies, including probiotics, dietary changes, and fecal microbiota transplantation. These methods may help restore the balance of microbes and reduce disease activity, but there are still a number of problems to solve. For example, microbiota composition varies greatly from person to person, and it is not clear how dysbiosis causes disease onset. There are also safety concerns about fecal microbiota transplantation. Experimental and clinical studies have started to shed light on the complicated ways in which microbial communities and immune function affect each other in SLE. These studies provide useful information, but their results are often inconsistent. As research continues, integrative methods like metagenomics and metabolomics may help find microbial signatures linked to disease, helping create more accurate and personalized treatments. The gut microbiome is a promising yet still developing area of research that could help us learn more about autoimmune diseases and their treatment, such as SLE. SIGNIFICANCE STATEMENT: Grasping the complex interplay between gut microbiota and systemic lupus erythematosus (SLE) has provided an avenue for therapeutic intervention. This study emphasizes the importance of gut dysbiosis in immune dysregulation, with connections between microbial translocation, molecular mimicry, and inflammatory pathways as contributing factors to the progression of SLE. This work sets the stage for novel and targeted approaches to treating SLE and improving patient outcomes by investigating microbiota-centric treatment options, such as probiotics, dietary interventions, and fecal microbiota transplantation.

Glucose metabolism is controlled by non-coding RNAs in autoimmune diseases; a glimpse into immune system dysregulation.

MicroRNAs (miRNAs) are differentially regulated in healthy, activated, inflamed, neoplastic, or otherwise pathological cells and tissues. While their main functions are executed intracellularly, many miRNAs can reproducibly be detected extracellularly in plasma and serum. This circulating, extracellular miRNA is protected against degradation by complexation with carrier proteins and/or by being enclosed in subcellular membrane vesicles. This, together with their tissue- and disease-specific expression, has fuelled the interest in using circulating microRNA profiles as harbingers of disease, i.e., as diagnostic analytes and as clues to dysregulated pathways in disease. Many studies show that inflammation and immune dysregulation, e.g., in autoimmune diseases, are associated with distinct miRNA expression changes in targeted tissues and in innate and adaptive immunity cells such as lymphocytes, natural killer cells, neutrophil granulocytes, and monocyte-macrophages. Exploratory studies (only validated in a few cases) also show that specific profiles of circulating miRNAs are associated with different systemic autoimmune diseases including systemic lupus erythematosus (SLE), systemic sclerosis, and rheumatoid arthritis. Even though the link between cellular alterations and extracellular profiles is still unpredictable, the data suggest that circulating miRNAs in autoimmunity may become diagnostically useful. Here, we review important circulating miRNAs in animal models of inflammation and in systemic autoimmunity and summarize some proposed functions of miRNAs in immune regulation and dysregulation. We conclude that the studies suggest new hypotheses and additional experiments, and that further diagnostic development is highly dependent on analytical method development and on obtaining sufficient numbers of uniformly processed samples from clinically well-characterized patients and controls.

Immune dysregulation is an entity that consists of primary immunodeficiency disorders (PIDs), autoimmune diseases (adaptive immunity dysregulation), and autoinflammatory syndromes (innate immunity dysregulation). It reflects inadequate immune function, which leads to exaggerated chronic inflammatory responses and so tissue damage [1]. Immune dysregulation disorders are clinically and genetically heterogenous disorders. The clinical phenotypes derived from distinct genotype can overlap, and different disorders can share the same phenotype. Thus, in many cases, a precise diagnosis and effective management are difficult to achieve. Over the last decade, remarkable progress has been made particularly in finding disease-causing genes for a number of rare monogenic immune dysregulatory disorders. With the explosion of multi-omics technologies, such as genomics, proteomics, and transcriptomics, high throughput sequencing approaches have been widely applied in the immune dysregulation studies. This has led to increase awareness and a quantum jumb in the number of these monogenic immune dysregulation disorders, as well as pathways that underlie their pathogenesis. Moreover, this has facilitated the identification of new biomarkers that can help in early diagnosis, prognosis, spectacular novel therapeutic successes in the clinic and prediction of therapeutic responses [2]. Given the complexity of our immune system, diversity of immune dysregulation disorders, the heterogenous phenotypes, and advent of next-generation sequencing (NGS) data that is becoming increasingly available, putting all of these together and moving these big data to the clinic is becoming ever more critical. In a recent study by Stray-Pedersen and colleagues, the authors sought to investigate the ability of whole exome sequencing (WES) to detect disease-causing variants in patients with PIDs. They used computational copy number variant prediction pipelines. A likely molecular diagnosis was achieved in 40% of unrelated probands. Clinical diagnosis was revised in nearly half, and management was directly altered in nearly a quarter of families based on molecular findings [3]. This approach will lead to timely diagnosis, alter medical management; provide accurate information about recurrence risks for family planning, and may result in healthcare savings by ending diagnostic odysseys. Despite these many successes, there are some challenges and obstacles we face with the big data created in the last decade. We, as physicians, have to choose the right patient to do the genetic testing on to get the highest yield. This can be done with the focus on the phenotypes and clinical manifestations. These days, many phenotype databases, such as PHO have made this process easier. Another challenge is that clinical NGS technology has evolved rapidly, outpacing resources for generating guidelines, standards, and resources such as data storage. Bioinformatics and NGS-based precision medicine has mainly focused on cancer and remains under-utilized in rare diseases such as immune dysregulation disorders. Our goal is to encourage the use of immunoinformatics to accelerate immune system research. There have been several bio-tools to study Immune disorders, such as patients’ registries, genomic databases, phenotype ontologies, and decision support systems. Genome-Phenome mapping can be very helpful in studying genotype-phenotype correlation and in determining the presence of gene variants in asymptomatic family members. In summary, with the recent breakthroughs in rare monogenic immune dysregulatory disorders, there have been renaissance in the field of immune dysregulation. Future clinical initiatives that incorporate NGS into medical care (NGS-based precision medicine), in addition to decision supporting systems, will help to shape the trajectory of broader incorporation. This will establish a firm foundation for investigating more complex immune disorders, and will facilitate the field of precision medicine in a world of bioinformatics paradigm. Given the rapid pace, all medical providers will have to keep a weather eye open for changes in this transformative field.

Objective: To analyze the clinical characteristics of spondyloenchondrodysplasia with immune dysregulation (SPENCDI). Methods: The clinical manifestations, laboratory examinations, treatment and genetic analysis of a patient diagnosed with SPENCDI who was admitted to the Department of Pediatrics in Peking Union Medical College Hospital in October 2016 were analyzed. Then literature review was done after searching articles in PubMed and several Chinese databases with the key words "spondyloenchondrodysplasia with immune dysregulation" up to the date of November 2017. Results: A 12-year-old girl was admitted to local hospital for complaint of "recurrent fever over one month" in October 2016. She was diagnosed with type Ⅱ autoimmune hepatitis for abnormal liver function, elevated immunoglobulin G, positive anti-liver-kidney microsomal antibody and medium to severe interface hepatitis verified by liver biopsy. Systemic lupus erythematosus was also suspected based on positive antinuclear antibody and anti-dsDNA antibody, decreased complements, reduced white blood cells and hemoglobin. Methylprednisolone and azathioprine were started based on the diagnosis. However, she experienced mycoplasma pneumoniae and suspected fungal infections during the treatment. Detailed history revealed the history of developmental retardation since birth, and cerebral palsy diagnosed when she was 2 years old. She also underwent surgery at the age of eight for eversion of her right foot. Based on the abnormal findings of immune system, skeleton and nervous system, certain primary immunodeficiency disease was speculated. Gene sequencing was performed, which revealed compound heterozygous mutations in ACP5 gene (NM_001111035.2) (c.798dupC, p. S267Lfs*20, paternal; c.716G>A, p. G239D, maternal). With X-ray of the vertebrae showed multiple platyspondyly, the diagnosis was corrected as SPENCDI and type Ⅱ autoimmune hepatitis. Then she was treated with prednisone (60 mg/d) and mycophenolate mofetil (1.5 g/d). All symptoms resolved on 3-month follow-up, with normalized activity indexes of autoimmune hepatitis and systemic lupus erythematosus. A total of 25 articles (1 Chinese, 24 English) were reviewed, with 74 SPENCDI patients reported. The most common manifestations were skeletal abnormalities (74/74, 100%), autoimmune diseases (47/74, 63.5%), dwarfism (45/74, 60.8%), and nervous system symptoms (25/74, 33.8%). A few patients with simple spondyloenchondrodysplasia were treated with growth hormone, and those who with autoimmune diseases were treated with immunosuppressants, all of whom were improved to certain extent. Conclusions: Vertebral and metaphyseal dysplasia, nervous system symptoms, and strong predisposition to autoimmune diseases are the hallmarks of SPENCDI. SPENCDI should be considered in dwarf with or without autoimmune diseases or nervous system symptoms.

ABSTRACT.Autoimmunity has been extensively established as a characteristic feature of the post-COVID-19 syndrome. There is evolving evidence of immune system dysregulation leading to the development of autoimmune phenomena in patients with COVID-19. This immune dysregulation may range from the production of autoantibodies to the new onset of rheumatic autoimmune diseases. An extensive literature search in databases from December 2019 to date revealed that no cases of autoimmune pulmonary alveolar proteinosis (PAP) were reported in post-COVID patients. In this context, we report a novel case series of two cases of new-onset autoimmune PAP in post-COVID patients, an entity that has not been described before. We recommend further studies to better understand this association between new-onset autoimmune PAP and SARS-CoV-2.

Targeting Immune Dysregulation in Childhood Evans Syndrome

Background: Systemic sclerosis (SSc), also known as scleroderma, is a complex, chronic autoimmune disease characterized by fibrosis of the skin and internal organs, vasculopathy, and immune system dysregulation. The treatment of SSc has historically focused on symptom management and slowing down disease progression through conventional immune-suppressive agents. New therapeutic approaches have been emerging due to advances in understanding of the disease mechanisms, particularly in the areas of fibrosis, vascular involvement, and immune dysregulation. Methods: In this review of the literature, we discuss the current stage of development of B-cell-depleting immune therapies in SSc. Results: B-cell depletion therapy has become an area of growing interest in the treatment of SSc due to the role played by B cells in the pathogenesis of the disease. There is increasing evidence that B cells contribute to disease progression through multiple mechanisms. B cells in SSc are implicated in autoantibody production, cytokine production, and fibroblast activation. B cells are responsible for producing autoantibodies, such as anti-topoisomerase I (Scl-70) and anti-centromere antibodies, which are hallmarks of SSc. B cells release pro-inflammatory cytokines (such as interleukin-6 [IL-6] and transforming growth factor β [TGF-β]), which promote fibrosis and inflammation, they also contribute to the activation of fibroblasts, the cells responsible for excessive collagen production and fibrosis, a key feature of SSc. Conclusions: In light of these findings, therapies that target B cells are being investigated for their potential to modify the disease course in SSc, particularly by reducing autoantibody production, inflammation, and fibrosis.

PT018 / #183Topic:AS12 - Genetics, Epigenetics, TranscriptomicsPOSTER TOUR 05: SLE PATHOGENESIS24-05-2025 10:00 AM - 10:20 AMBackground/PurposeSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by complex immunological disturbances. Early detection is challenging due to heterogeneous clinical manifestations. Understanding cellular and molecular changes from preclinical (pre-SLE) to clinical stages is essential for early intervention. Polygenic risk score (PRS) has been widely used to identify subjects at risk. However, the immune dysregulation of subjects with high SLE-PRS has never been demonstrated. This study aims to delineate the cellular transcriptomic landscapes of healthy controls, pre-SLE, and SLE patients using single-cell RNA sequencing (scRNA-seq) to identify molecular signatures associated with disease progression.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from 10 healthy controls, 23 pre-SLE patients with top 5% SLE-PRS without previous diagnosis of SLE, and 12 SLE patients. scRNA-seq was performed using the BD Rhapsody. Data was processed and analyzed with Seurat and other bioinformatics tools to identify differentially expressed genes and pathway enrichments across cell types and patient groups.ResultsThe analysis revealed distinct transcriptional profiles among the 3 groups. PBMCs (peripheral blood mononuclear cells) were clustered and annotated into 5 major cell types: B cells, CD4+ T cells, CD8+ T cells, monocytes, and NK cells, as shown by UMAP (Uniform Manifold Approximation and Projection). Additionally, the cells were further categorized into myeloid and lymphoid lineages. The myeloid-to-lymphoid (M/L) ratio progressively increased in the healthy controls to pre-SLE and SLE patients, indicating an elevated myeloid cell presence as the disease progresses (Figure 1). To identify key immune cell types within the lymphoid subsets, further clustering and analysis of immune cell were performed to resolve immune subpopulations (Figure 2). Differential gene expression between pre-SLE patients and healthy controls was visualized using volcano plots across key immune cell populations (Figure 3). Notably, pre-SLE patients exhibited significant upregulation of genes associated with early immune activation and dysregulation, such as IFI44L and IGKC, suggesting that these genes may act as potential molecular drivers in the pathogenesis of SLE.Figure 1.UMAP clustering of immune cells from healthy controls, pre-SLE, and SLE patients with distinct color-coded cell types. The accompanying table and scatter plot demonstrate an elevated myeloid-to-lymphoid ratio in pre-SLE and SLE, highlighting immune composition shifts.Figure 2.UMAP with subcluster analysis of immune cell types, displaying specific populations such as memory B cells and T cell subsets.Figure 3.Volcano plots show differentially expressed genes in various immune cell populations between pre-SLE and healthy controls.ConclusionsOur findings demonstrate progressive immune dysregulation at the single-cell level from pre-SLE to SLE patients. The identified molecular signatures, altered cell subsets, and immune composition shifts provide insights into SLE pathogenesis and suggest potential biomarkers for early diagnosis and therapeutic targets.

Experimental evidence from animal models has provided a framework for our current understanding of autoimmune disease pathogenesis and supports the importance of genetic predisposition, molecular mimicry, and immune dysregulation. However, only recently has evidence emerged to support the role of immune dysregulation in human organ-specific autoimmune disease. In the current study of the "late" manifestation of autoimmune thyroid disease (AITD) in a cohort of human immunodeficiency virus (HIV)-positive patients following highly active antiretroviral therapy (HAART), we discuss how immune dysregulation and factors associated with the immunopathology of HIV infection fit the current understanding of autoimmunity and provide a plausible basis for our clinical observations. De novo diagnoses of thyroid disease were identified between 1996 and 2002 in 7 HIV treatment centers (5/7 centers completed the study). Patients were diagnosed as clinical case entities and not discovered through thyroid function test screening. Paired plasma specimens were used to demonstrate sequential rise in thyroid antibodies. Seventeen patients were diagnosed with AITD (median age, 38 yr; 65% were of black African or black Caribbean ethnicity; and 82% were female). The median duration of immune reconstitution was 17 months. Graves disease (GD) was diagnosed in 15 of 17 patients. One patient developed hashithyrotoxicosis with atypically raised C-reactive protein, and another developed hypothyroidism. One GD patient had associated secondary hypoadrenalism. The estimated combined prevalence of GD for 4 treatment centers for female patients was 7/234 and for males was 2/1289. The denominator numbers were matched controls, from 4 centers able to provide data, who commenced HAART during the same time (January 1996 to July 2002) and who did not develop clinical AITD. The mean baseline pre-HAART CD4 count was 67 cells/mL, and the mean increase from nadir to AITD presentation was 355 cells/mL. AITD patients were more likely than controls (95% confidence interval, chi-square test) to be severely compromised at baseline (as defined by a CD4 count < 200 cells/mL or the presence of an acquired immunodeficiency syndrome [AIDS]-defining diagnosis), and to experience greater CD4 increments following HAART. AITD may be a late manifestation of immune reconstitution in HIV-positive patients taking HAART, and immune dysregulation may be an important factor.