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High-dimensional cell phenotyping is a powerful tool to study molecular and cellular changes in health and diseases. CyTOF enables high-dimensional cell phenotyping using tens of surface and intra-cellular markers. To utilize the full potential of CyTOF, we need advanced clustering and machine learning methodologies to enable automated gating of the complex data. Here we show that critical modifications to a machine learning based FlowSOM package and precise parameter optimization can enable us to reliably analyze the complex CyTOF data. We show the impact of key parameters on clustering outcomes while addressing bugs within the publicly available package. We modified the FlowSOM pipeline to fix the bugs, enable scalability to handle large datasets and perform parameter optimization. We further validated this modified pipeline on a substantial external immunological dataset demonstrating the need of data-specific tailored parameter optimization to ensure reliable definition and interrogation of immune cell populations associated with immune disorders. Optimized FlowSOM pipeline for reliable clustering of high-dimensional cytometry data. [ABSTRACT FROM AUTHOR]

Background: The Developmental Origins of Health and Disease Hypothesis (DOHaD) suggests prenatal alcohol exposure (PAE) should have implications for adult physical and mental health. Since the health profile of older adults with PAE and diagnoses of fetal alcohol spectrum disorder (FASD) is unknown, the current study evaluates self‐reported health problems of midlife adults with and without a history of PAE to describe these outcomes. Methods: Participants (N = 357) recruited from longitudinal cohorts in Atlanta, GA and Seattle, WA completed a health survey assessing a range of physical conditions. Initial analysis compared the frequency of conditions between alcohol‐exposed and nonexposed groups. To identify patterns within groups, 10 problem areas were subjected to latent class analysis (LCA). Finally, the direct effect of PAE on health outcomes was evaluated using multilevel modeling, controlling for effects of other factors. Results: Compared with unexposed controls, individuals with PAE reported significantly higher frequencies of problems with hearing, dentition, heart, cancer, gastritis, kidney stones, bladder, diabetes, thyroid, skin, and seizures. LCA found that controls yielded two classes, with 45% reporting sleep and vision problems and 55% reporting sleep, vision, cardiovascular, endocrine, immune, and dental problems. The PAE group yielded three classes, with 13% endorsing few health problems, 43% reporting sleep, vision, immune, and dental problems, and 43% reporting sleep, vision, cardiovascular, urinary, endocrine, skin, immune, dental, and gastrointestinal problems. With multivariate analysis, controlling for other influences, PAE was associated directly with hearing, urinary, dental, and gastrointestinal problems. A similar pattern was found for alcohol‐exposed individuals who did and did not meet criteria for fetal alcohol syndrome (FAS). Discussion: Patients affected by alcohol may report greater frequency and range of health adversity. That PAE was only uniquely associated with a limited set of problems suggests that many health outcomes in midlife result from an initial vulnerability potentiated by postnatal stress resulting from other associated factors. [ABSTRACT FROM AUTHOR]

Cyclic GMP–AMP (cGAMP) synthase (cGAS) senses DNA in a sequence-independent manner, triggering cGAMP synthesis, which activates stimulator of interferon genes (STING) and the subsequent expression of type I interferons, tumour necrosis factor alpha (TNF-α) and other proinflammatory factors in two downstream pathways. However, the function of the cGAS STING pathway in γδ T cells remains unclear. The γδ T-cell population differs from the innate-like lymphocyte population, particularly with respect to tissue distribution, indicating the unique potential of γδ T cells in treating infections and cancers. On the basis of accumulating evidence, cGAS activity is modulated by protein posttranslational modifications (PTMs), including phosphorylation, O-GlcNAcylation, acetylation, ubiquitylation and methylation, which affect multiple cGAS functions. Thus, here, we summarize recent research on PTMs of the cGAS protein that modulate γδ T-cell function. An understanding of cGAS features and modulation mechanisms may facilitate the design of therapies for γδ T-cell-related immune diseases and cancer. • The role of cGAS-STING pathway in γδ T cells. • Posttranslational modifications (PTMs) of the cGAS protein can modulate γδ T-cell function. • Therapies for γδ T-cell-related immune diseases and cancer. [ABSTRACT FROM AUTHOR]

Somatic mutations (also known as acquired mutations) are emerging as common, age-related processes that occur in all cells throughout the body. Somatic mutations are canonically linked to malignant processes but over the past decade have been increasingly causally connected to benign diseases including rheumatic conditions. Here we outline the contribution of somatic mutations to complex and monogenic immunological diseases with a detailed review of unique aspects associated with such causes. Somatic mutations can cause early- or late-onset rheumatic monogenic diseases but also contribute to the pathogenesis of complex inflammatory and immune-mediated diseases, affect disease progression and define new clinical subtypes. Although even variants with a low variant allele fraction can be pathogenic, clonal dynamics could lead to changes over time in the proportion of mutant cells, with possible phenotypic consequences for the individual. Thus, somatic mutagenesis and clonal expansion have relevant implications in genetic testing and counselling. On the basis of both increased recognition of somatic diseases in clinical practice and improved technical and bioinformatic processes, we hypothesize that there will be an ever-expanding list of somatic mutations in various genes leading to inflammatory conditions, particularly in late-onset disease. This Review discusses the involvement of early-stage and late-stage somatic mutations in the pathogenesis of both monogenic and multifactorial rheumatic diseases. The authors highlight new methods of detecting low-frequency variants and the implications for diagnosis and treatment in patients with rheumatic diseases. Key points: Somatic mutations, even at low allele fractions, can have a role in the pathogenesis of monogenic and complex rheumatological diseases, in both early-onset and late-onset conditions. Somatic mutagenesis and clonal expansions are dynamic processes and a change in clinical phenotype might warrant repeated genetic testing. Identification of somatic mutations has major implications for genetic counselling. The identification of pathogenic somatic mutations in patients with immune-mediated disease can inform treatment decisions. As new methodologies and resources for somatic variant detection and interpretation are emerging, they will be instrumental for reshaping disease taxonomy in rheumatology. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a complex autoimmune disease with clinical symptoms of vascular damage, immune disorders, and fibrosis, presenting significant treatment challenges and limited therapeutic options. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been demonstrated in numerous studies as more effective than MSCs in treating autoimmune diseases. Recent studies demonstrate that MSC-EVs can significantly ameliorate the symptoms of SSc and mitigate pathological changes such as vascular injury, immune dysregulation, and fibrosis. These findings underscore the promising therapeutic potential of MSC-EVs in the treatment of SSc. MSC-EVs promote angiogenesis, modulate immune dysfunction, and combat fibrosis. This article summarizes the therapeutic applications and possible mechanisms of MSC-EVs for SSc, thereby offering a novel therapeutic direction for the treatment of SSc. [ABSTRACT FROM AUTHOR]

UNC13 family (also known as Munc13) proteins are evolutionarily conserved proteins involved in the rapid and regulated secretion of vesicles, including synaptic vesicles and cytotoxic granules. Fast and regulated secretion at the neuronal and immunological synapses requires multiple steps, from the biogenesis of vesicles to membrane fusion, and a complex array of proteins for each step. Defects at these steps can lead to various genetic disorders. Recent studies have shown multiple roles of UNC13D in the secretion of cytotoxic granules by immune cells. Here, the molecular structure and detailed roles of UNC13D in the biogenesis, tethering, and priming of cytotoxic vesicles and in endoplasmic reticulum are summarized. Moreover, its association with immune diseases, including familial hemophagocytic lymphohistiocytosis type 3, macrophage activation syndrome, juvenile idiopathic arthritis, and autoimmune lymphoproliferative syndrome, is reviewed. Finally, the therapeutic application of CRISPR/Cas9-based gene therapy for genetic diseases is introduced. [ABSTRACT FROM AUTHOR]

Progressive multifocal leukoencephalopathy (PML) is a rare central nervous system disease caused by JC virus (JCV) infection. Human immunodeficiency virus (HIV) infection is the greatest risk factor for PML. Other immunological diseases, including systemic sarcoidosis, have also been reported as risk factors for PML. Herein, we report a case of PML co-occurring with neurosarcoidosis. Early diagnosis using brain biopsy and appropriate therapeutic interventions achieved favorable outcomes. PML in patients with active intracranial neurosarcoidosis is extremely rare. We believe that it is important to perform brain biopsy at an early stage to allow diagnosis, even for central nervous system involvement with a progressive parenchymal lesion in patients with sarcoidosis, if PML is possible. [ABSTRACT FROM AUTHOR]

High-dimensional cell phenotyping is a powerful tool to study molecular and cellular changes in health and diseases. CyTOF enables high-dimensional cell phenotyping using tens of surface and intra-cellular markers. To utilize the full potential of CyTOF, we need advanced clustering and machine learning methodologies to enable automated gating of the complex data. Here we show that critical modifications to a machine learning based FlowSOM package and precise parameter optimization can enable us to reliably analyze the complex CyTOF data. We show the impact of key parameters on clustering outcomes while addressing bugs within the publicly available package. We modified the FlowSOM pipeline to fix the bugs, enable scalability to handle large datasets and perform parameter optimization. We further validated this modified pipeline on a substantial external immunological dataset demonstrating the need of data-specific tailored parameter optimization to ensure reliable definition and interrogation of immune cell populations associated with immune disorders. [ABSTRACT FROM AUTHOR]

The editorial in Frontiers in Immunology discusses immune system disorders, focusing on molecular mechanisms and clinical implications. The research highlights the pathogenic consequences of immune system dysfunction, including immunodeficiencies, inflammatory, and autoimmune disorders. Various review articles explore autoimmune diseases, treatments, and potential biomarkers for rheumatic diseases. The research aims to enhance understanding of immune dysregulation and its impact on diseases, paving the way for targeted therapies. [Extracted from the article]

Metabolic memory (MM) is a major factor in the delayed wound healing observed in diabetic patients. While "Nocardia rubrum cell wall skeleton" (Nr-CWS) is utilized to enhance macrophage proliferation in immune diseases, its impact on MM wounds in diabetes is unclear. This study demonstrates that transient hyperglycemia leads to prolonged damage in vascular endothelial cells by decreasing METTL3 expression, leading to decreased RNA methylation and impaired cellular metabolism. Remarkably, Nr-CWS application increases METTL3 levels in these cells, facilitating the recovery of cell function. Further in vivo and in vitro analyses demonstrate that transient hyperglycemia-induced reduction in METTL3 hinders RNA methylation of the downstream gene Cds2, impacting mitochondrial function and energy metabolism and consequently reducing angiogenic capacity in endothelial cells. This impairment significantly influences diabetic wound healing. Our findings highlight the profound impact of transient hyperglycemia on wound healing, establishing METTL3 as a significant role in vascular complications of diabetes. This study not only elucidates the pathophysiological mechanisms behind MM in diabetic wounds but also suggests Nr-CWS as a potential therapeutic agent, offering a novel approach for treating diabetic wounds. METTL3 regulates RNA methylation and mitochondrial function in diabetic wound healing, highlighting Nocardia rubra cell wall skeleton as a potential therapeutic agent for improving vascular recovery in hyperglycemia-impaired wounds. [ABSTRACT FROM AUTHOR]

Background: Premature ovarian insufficiency (POI) is a reproductive disorder characterized by the cessation of ovarian function before the age of 40. Although mitochondrial dysfunction and immune disorders are believed to contribute to ovarian damage in POI, the interplay between these factors remains understudied. Methods: In this research, transcriptomic data related to POI were obtained from the NCBI GEO database. Hub biomarkers were identified through the construction of a protein‒protein interaction (PPI) network and further validated using RT‒qPCR and Western blot. Moreover, their expression across various cell types was elucidated via single-cell RNA sequencing analysis. A comprehensive investigation of the mitochondrial and immune profiles of POI was carried out through correlation analysis. Furthermore, potential therapeutic agents were predicted utilizing the cMap database. Results: A total of 119 mitochondria-related differentially expressed genes (MitoDEGs) were identified and shown to be significantly enriched in metabolic pathways. Among these genes, Hadhb, Cpt1a, Mrpl12, and Mrps7 were confirmed both in a POI model and in human granulosa cells (GCs), where they were found to accumulate in GCs and theca cells. Immune analysis revealed variations in macrophages, monocytes, and 15 other immune cell types between the POI and control groups. Notably, strong correlations were observed between seven hub-MitoDEGs (Hadhb, Cpt1a, Cpt2, Mrpl12, Mrps7, Mrpl51, and Eci1) and various functions, such as mitochondrial respiratory complexes, dynamics, mitophagy, mitochondrial metabolism, immune-related genes, and immunocytes. Additionally, nine potential drugs (calyculin, amodiaquine, eudesmic acid, cefotaxime, BX-912, prostratin, SCH-79797, HU-211, and pizotifen) targeting key genes were identified. Conclusions: Our results highlight the crosstalk between mitochondrial function and the immune response in the development of POI. The identification of MitoDEGs could lead to reliable biomarkers for the early diagnosis, monitoring, and personalized treatment of POI. [ABSTRACT FROM AUTHOR]

Gouty arthritis (GA), a metabolic and immunologic disease, primarily affects joints. Dysbiosis of intestinal flora is an important cause of GA. The metabolic disorders of intestinal flora leading to GA and immune disorders might play an important role in patients with hyperuricemia and established GA. However, the exact mechanisms, through which the dysbiosis of intestinal flora causes the development of GA, are not fully understood yet. Moreover, several therapies commonly used to treat GA might alter the intestinal flora, suggesting that modulation of the intestinal flora might help prevent or treat GA. Therefore, a better understanding of the changes in the intestinal flora of GA patients might facilitate the discovery of new diagnostic and therapeutic approaches. The current review article discusses the effects of intestinal flora dysbiosis on the pathogenesis of GA and the cross-regulatory effects between gut flora and drugs for treating GA. This article also highlights the modulatory effects of gut flora by traditional Chinese medicine (TCM) to lower uric acid levels and relieve joint pain as well as provides a summary and outlook, which might help guide future research efforts. [ABSTRACT FROM AUTHOR]

By considering both the single drug dose and the total drug input during the treatment period, we propose a new optimal control problem by maximizing the immune cell levels and minimizing the tumor cell count, as well as the negative effects of the total drug quantity over time. To solve this problem, the control parameterization technique is employed to approximate the control function by a piecewise constant function, which gives rise to a sequence of mathematical programming problems. Then, we derive gradients of the cost function and/or the constraints in the resulting problems. On the basis of this gradient information, we develop a numerical approach to seek the optimal control strategy for a discrete drug administration. Finally, numerical simulations are conducted to assess the impact of the total drug input on the tumor treatment and to evaluate the rationality of the treatment strategy within the anti-cancer cycle. These results provide a theoretical framework that can guide clinical trials in immunotherapy. [ABSTRACT FROM AUTHOR]

Objectives: Cold plasma has shown efficacy in various dermatological applications by reduces inflammatory responses and modulating cytokine expression. Therefore, this study aimed to investigate the therapeutic effects of cold plasma on psoriasis. Methods: In psoriasis HaCaT cells with cold plasma, we confirmed the expression of inflammatory cytokines involved in psoriasis formation and MAPK pathway, cell cycle, and apoptosis‐related factors. In psoriasis‐like BALB/c mice model, the effects of cold plasma treatment on skin were visually assessed. The expression of psoriasis‐related factors was confirmed through qPCR, Western blotting, and Immunohistochemistry. Results: Cold plasma led to a reduction in inflammatory cytokines including IL‐17A, IL‐23A, IL‐24, IL‐1β, and TNF‐α in the psoriasis cell line. It also modulated factors involved in the MAPK pathway and the cell cycle. In the psoriasis‐like mice model, cold plasma resulted in improvements in skin thickness, erythema, scaling, and PASI. Additionally, decreases in inflammatory cytokines like INF‐γ, IL‐23, and S100a7 were observed, along with improvements in MAPK pathway activation, apoptosis, and other psoriasis‐related factors. Conclusion: Through in vitro and in vivo studies, our research highlights the potential of cold plasma as a novel therapeutic approach for psoriasis. Furthermore, cold plasma could serve as an adjunctive treatment for skin immunological diseases. [ABSTRACT FROM AUTHOR]

Summary: Inherited bone marrow failure syndromes (IBMFS) pose significant diagnostic challenges due to overlapping symptoms and variable expressivity, despite evolving genomic insights. The study aimed to elucidate the genomic landscape among 130 Korean patients with IBMFS. We conducted targeted next‐generation sequencing (NGS) and clinical exome sequencing (CES) across the cohort, complemented by whole genome sequencing (WGS) and chromosomal microarray (CMA) in 12 and 47 cases, respectively, with negative initial results. Notably, 50% (n = 65) of our cohort achieved a genomic diagnosis. Among these, 35 patients exhibited mutations associated with classic IBMFSs (n = 33) and the recently defined IBMFS, aplastic anaemia, mental retardation and dwarfism syndrome (AmeDS, n = 2). Classic IBMFSs were predominantly detected via targeted NGS (85%, n = 28) and CES (88%, n = 29), whereas AMeDS was exclusively identified through CES. Both CMA and WGS aided in identifying copy number variations (n = 2) and mutations in previously unexplored regions (n = 2). Additionally, 30 patients were diagnosed with other congenital diseases, encompassing 13 distinct entities including inherited thrombocytopenia (n = 12), myeloid neoplasms with germline predisposition (n = 8), congenital immune disorders (n = 7) and miscellaneous genomic conditions (n = 3). CES was particularly effective in revealing these diverse diagnoses. Our findings underscore the significance of comprehensive genomic analysis in IBMFS, highlighting the need for ongoing exploration in this complex field. [ABSTRACT FROM AUTHOR]

Objectives Rheumatic diseases may impair reproductive success and pregnancy outcomes, but systematic evaluations across diseases are lacking. We conducted a nationwide cohort study to examine the impact of rheumatic diseases on reproductive health measures, comparing the impacts with those of other immune-mediated diseases (IMDs). Methods Out of all of the 5 339 804 Finnish citizens, individuals born 1964–1984 and diagnosed with any of the 19 IMDs before age 30 (women) or 35 (men) were matched with 20 controls by birth year, sex, and education. We used data from nationwide health registers to study the impact of IMDs on reproductive health measures, such as reproductive success and, for women, ever having experienced adverse maternal and perinatal outcomes. Results Several of the rheumatic diseases, particularly SLE, JIA, and seropositive RA, were associated with higher rates of childlessness and fewer children. The risks for pre-eclampsia, newborns being small for gestational age, preterm delivery, non-elective Caesarean sections, and need of neonatal intensive care were increased in many IMDs. Particularly, SLE, SS, type 1 diabetes, and Addison's disease showed >2-fold risks for some of these outcomes. In most rheumatic diseases, moderate (1.1–1.5-fold) risk increases were observed for diverse adverse pregnancy outcomes, with similar effects in IBD, celiac disease, asthma, ITP, and psoriasis. Conclusion Rheumatic diseases have a broad impact on reproductive health, with effects comparable with that of several other IMDs. Of the rheumatic diseases, SLE and SS conferred the largest risk increases on perinatal adverse event outcomes. [ABSTRACT FROM AUTHOR]

Objective: It is believed that gut microbiota alteration leads to both intestinal and non-intestinal diseases in children. Since infants inherit maternal microbiota during pregnancy and lactation, recent studies suggest that changes in maternal microbiota can cause immune disorders as well. This systematic review was designed to assess the association between the child and mother's gut microbiome and allergy development in childhood. Data sources: In this systematic review, international databases including PubMed, Scopus, and ISI/WOS were searched until January 2023 to identify relevant studies. Study selections: Observational studies that analyzed infant or maternal stool microbiome and their association with allergy development in children were included in this study. Data extraction and quality assessment of the included studies were independently conducted by two researchers. Results: Of the 1694 papers evaluated, 21 studies examined neonate gut microbiome by analyzing stool samples and six studies examined maternal gut microbiota. A total of 5319 participants were included in this study. Asthma followed by eczema and dermatitis were the most common allergy disorders among children. Urbanization caused a lack of diversity in the bacterial microbiota as well as lower levels of Bifidobacterium and Lachnospira associated with a higher risk of allergy. In contrast, higher levels of Roseburia and Flavonifractor were associated with lower allergy risk. Conclusions: This systematic review shows that gut microbiota may be associated with allergy development. Further studies are required to provide a definitive answer. [ABSTRACT FROM AUTHOR]

Exposure to perfluoroalkyl acids (PFAAs) has been found to elicit a range of detrimental effects on human health. However, limited research has investigated the impact of PFAAs on immunity and immune disorders such as Sjogren's syndrome, with existing studies yielding inconsistent results. This study was conducted in Hangzhou, China, with an initial cohort comprising 156 healthy individuals and 162 patients diagnosed with Sjogren's syndrome. We quantified serum levels of PFAAs and examined associations between PFAAs and both susceptibilities to the development of Sjogren's syndrome and immune marker concentrations. Nine PFAAs were frequently detected in the serum, with perfluorooctanoate (PFOA) exhibiting the highest concentration, followed by perfluorooctanesulfonate (PFOS). Exposure to PFOA and perfluorotridecanoate (PFTrDA) was inversely associated with the disease. Furthermore, a negative correlation between PFOA and C-reactive protein (CRP) was observed. These findings suggest that exposure to specific PFAAs may impact the immune system and potentially influence the development of Sjogren's syndrome. [ABSTRACT FROM AUTHOR]

Using nanostructured drug delivery systems has attracted increasing interest in immunotherapeutic approaches. The intrinsic immunomodulatory properties and versatility of nanoparticles used as carriers were consistently reported to augment treatment efficiency as nanoscaled materials increase drug accumulation at the desired site, enhance cell internalization, and improve therapeutic outcomes. Thus, numerous studies have exploited the potential use of nanostructured drug delivery vehicles in delivering different cargo as a promising alternative for treating conditions like cancer, autoimmune diseases, infectious diseases, and allergic and immune disorders. In this context, this paper presents nanostructured drug delivery systems as a solid basis for immunotherapeutic innovations, highlighting their advantages for improving treatment strategies, reviewing their clinical applications, and discussing existing challenges and ways to overcome them. [ABSTRACT FROM AUTHOR]

Background: Gut microbiota have been previously reported to be related to a variety of immune diseases. However, the causal connection between Sjögren's syndrome (SS) and gut microbiota has yet to be clarified. Methods: We employed a two-sample Mendelian randomization (MR) analysis to evaluate the causal connection between gut microbiota and SS, utilizing summary statistics from genome-wide association studies (GWASs) obtained from the MiBioGen and FinnGen consortia. The inverse variance weighted (IVW) approach represents the primary method of Mendelian randomization (MR) analysis. Sensitivity analysis was used to eliminate instrumental variables heterogeneity and horizontal pleiotropy. In addition, we performed an analysis using independent GWAS summary statistics for SS from the European Bioinformatics Institute (EBI) dataset for further verify our results. Results: IVW results demonstrated that the phylum Lentisphaerae (OR = 0.79, 95% CI: 0.63–0.99, p = 0.037), class Deltaproteobacteria (OR = 0.67, 95% CI: 0.47–0.96, p = 0.030), family Porphyromonadaceae (OR = 0.60, 95% CI: 0.38–0.94, p = 0.026), genus Eubacterium coprostanoligenes group (OR = 0.61, 95% CI: 0.4–0.93, p = 0.021), genus Blautia (OR = 0.62, 95% CI: 0.43–0.90, p = 0.012), genus Butyricicoccus (OR = 0.61, 95% CI: 0.42–0.90, p = 0.012), genus Escherichia.Shigella (OR = 0.7, 95% CI: 0.49–0.99, p = 0.045) and genus Subdoligranulum (OR = 0.61, 95% CI: 0.44–0.86, p = 0.005) exhibited protective effects on SS. Relevant heterogeneity of horizontal pleiotropy or instrumental variables was not detected. Furthermore, repeating our results with an independent cohort provided by the EBI dataset, only the genus Eubacterium coprostanoligenes group remained significantly associated with the protective effect on SS (OR = 0.41, 95% CI: 0.18–0.91, p = 0.029). Two-step MR analysis further revealed that genus Eubacterium coprostanoligenes group exerts its protective effect by reducing CXCL6 levels in SS (OR, 0.87; 95% CI = 0.76–0.99, p = 0.033). Conclusions: Our study using two-sample MR analysis identified a causal association between multiple genera and SS. A two-step MR result calculated that genus Eubacterium coprostanoligenes group mediated its protective effect by reducing CXCL6 levels in SS. However, the datasets available from the MiBioGen and FinnGen consortia do not provide sufficient information or comprehensive demographic data for subgroup analyses. Additional validation using various omics technologies is necessary to comprehend the development of SS in the intricate interplay between genes and the environment over a period of time. [ABSTRACT FROM AUTHOR]

Purpose: Tinnitus, the perception of sound without any external sound source, is a prevalent hearing health concern. Mounting evidence suggests that a confluence of genetic, environmental, and lifestyle factors can influence the pathogenesis of tinnitus. We hypothesized that alteration in DNA methylation, an epigenetic modification that occurs at cytosines of cytosine-phosphate-guanine (CpG) dinucleotide sites, where a methyl group from S-adenyl methionine gets transferred to the fifth carbon of the cytosine, could contribute to tinnitus. DNA methylation patterns are tissue-specific, but the tissues involved in tinnitus are not easily accessible in humans. This pilot study used saliva as a surrogate tissue to identify differentially methylated CpG regions (DMRs) associated with tinnitus. The study was conducted on healthy young adults reporting bilateral continuous chronic tinnitus to limit the influence of age-related confounding factors and health-related comorbidities. Methods: The present study evaluated the genome-wide methylation levels from saliva-derived DNA samples from 24 healthy young adults with bilateral continuous chronic tinnitus (> 1 year) and 24 age, sex, and ethnicity-matched controls with no tinnitus. Genome-wide DNA methylation was evaluated for > 850,000 CpG sites using the Infinium Human Methylation EPIC BeadChip. The association analysis used the Bumphunter algorithm on 23 cases and 20 controls meeting the quality control standards. The methylation level was expressed as the area under the curve of CpG sites within DMRs.The FDR-adjusted p-value threshold of 0.05 was used to identify statistically significant DMRs associated with tinnitus. Results: We obtained 25 differentially methylated regions (DMRs) associated with tinnitus. Genes within or in the proximity of the hypermethylated DMRs related to tinnitus included LCLAT1, RUNX1, RUFY1, NUDT12, TTC23, SLC43A2, C4orf27 (STPG2), and EFCAB4B. Genes within or in the proximity of hypomethylated DMRs associated with tinnitus included HLA-DPB2, PM20D1, TMEM18, SNTG2, MUC4, MIR886, MIR596, TXNRD1, EID3, SDHAP3, HLA-DPB2, LASS3 (CERS3), C10orf11 (LRMDA), HLA-DQB1, NADK, SZRD1, MFAP2, NUP210L, TPM3, INTS9, and SLC2A14. The burden of genetic variation could explain the differences in the methylation levels for DMRs involving HLA-DPB2, HLA-DQB1, and MUC4, indicating the need for replication in large independent cohorts. Conclusion: Consistent with the literature on comorbidities associated with tinnitus, we identified genes within or close to DMRs involved in auditory functions, chemical dependency, cardiovascular diseases, psychiatric conditions, immune disorders, and metabolic syndromes. These results indicate that epigenetic mechanisms could influence tinnitus, and saliva can be a good surrogate for identifying the epigenetic underpinnings of tinnitus in humans. Further research with a larger sample size is needed to identify epigenetic biomarkers and investigate their influence on the phenotypic expression of tinnitus. [ABSTRACT FROM AUTHOR]

Langerhans cells (LCs) are the key antigen‐presenting cells in the epidermis in normal conditions and respond differentially to environmental and/or endogenous stimuli, exerting either proinflammatory or anti‐inflammatory effects. Current knowledge about LCs mainly originates from studies utilizing mouse models, whereas with the development of single‐cell techniques, there has been significant progress for human LCs, which has updated our understanding of the phenotype, ontogeny, differentiation regulation, and function of LCs. In this review, we delineated the progress of human LCs and summarized LCs' function in inflammatory skin diseases, providing new ideas for precise regulation of LC function in the prevention and treatment of skin diseases. [ABSTRACT FROM AUTHOR]

This article explores the role of O-GlcNAcylation in regulating the immune system. O-GlcNAcylation is a post-translational modification that affects cell signaling, metabolism, and development. It has been linked to immune dysfunction and the development of autoimmune, inflammatory, and allergic diseases, as well as immune cell malignancies. The article includes original research articles and comprehensive reviews that cover various aspects of O-GlcNAcylation in the immune system, such as its impact on leukemia, immune cell infiltration, and inflammation. The collection of articles provides a comprehensive overview of O-GlcNAcylation's role in the immune system, highlighting the potential for therapeutic interventions and improved disease diagnoses. [Extracted from the article]

Autoimmune rheumatic diseases comprise a group of immune-related disorders characterized by non-organ-specific inflammation. These diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, among others. Typically involving the hematologic system, these diseases may also affect multiple organs and systems. The pathogenesis of autoimmune rheumatic immune diseases is complex, with diverse etiologies, all associated with immune dysfunction. The current treatment options for this type of disease are relatively limited and come with certain side effects. Therefore, the urgent challenge remains to identify novel therapeutic targets for these diseases. Sterol regulatory element-binding proteins (SREBPs) are basic helix-loop-helix-leucine zipper transcription factors that regulate the expression of genes involved in lipid and cholesterol biosynthesis. The expression and transcriptional activity of SREBPs can be modulated by extracellular stimuli such as polyunsaturated fatty acids, amino acids, glucose, and energy pathways including AKT-mTORC and AMP-activated protein kinase (AMPK). Studies have shown that SREBPs play roles in regulating lipid metabolism, cytokine production, inflammation, and the proliferation of germinal center B (GCB) cells. These functions are significant in the pathogenesis of rheumatic and immune diseases (Graphical abstract). Therefore, this paper reviews the potential mechanisms of SREBPs in the development of SLE, RA, and gout, based on an exploration of their functions. [ABSTRACT FROM AUTHOR]

Cathepsin K (CatK), a lysosomal cysteine protease, contributes to skeletal abnormalities, heart diseases, lung inflammation, and central nervous system and immune disorders. Currently, CatK inhibitors are associated with severe adverse effects, therefore limiting their clinical utility. This study focuses on exploring quantitative structure–activity relationships (QSAR) on a dataset of CatK inhibitors (1804) compiled from the ChEMBL database to predict the inhibitory activities. After data cleaning and pre-processing, a total of 1568 structures were selected for exploratory data analysis which revealed physicochemical properties, distributions and statistical significance between the two groups of inhibitors. PubChem fingerprinting with 11 different machine-learning classification models was computed. The comparative analysis showed the ET model performed well with accuracy values for the training set (0.999), cross-validation (0.970) and test set (0.977) in line with OECD guidelines. Moreover, to gain structural insights on the origin of CatK inhibition, 15 diverse molecules were selected for molecular docking. The CatK inhibitors (1 and 2) exhibited strong binding energies of −8.3 and −7.2 kcal/mol, respectively. MD simulation (300 ns) showed strong structural stability, flexibility and interactions in selected complexes. This synergy between QSAR, docking, MD simulation and machine learning models strengthen our evidence for developing novel and resilient CatK inhibitors. [ABSTRACT FROM AUTHOR]

Context • Allergic rhinitis (AR) is a common immune disease of the nasal mucosa, and anti-allergenic medications provide only momentary relief. Multiple factors, such as rising pollution, especially in urban areas; dust particles, such as from air conditioners; house mites; and the use of chemicals and aromatic products can stimulate AR. Objective • The literature review intended to examine the effectiveness of homoeopathic remedies in immune- and inflammatory-model systems based on the basic homoeopathic principle-the law of similarity of pharmacological action at the cellular level-and to evaluate the effects of dilution or dynamization on the drug activity of Wyethia tested under controlled settings, interpreting data based on similarity. Design • The research team performeda narrative review by searching Google scholar & Pubmed databases. The search usedthe keywords “Wyethia Helenioides”, “Allergic Rhinitis”, “Homoeopathy”, “Homeopathy”, “Antiinflammatory”, “Invitro”, “Invivo”, “Clinical Trial”, “Case report” & “Flavanoids”. Setting • The study took place at Department of Homoeopathic Materia Medica, Dr. D Y Patil Homoeopathic Medical College and Research Institute, Pimpri, Pune, Maharashtra, India. Results • Clinical observations indicated that the homoeopathic preparations of Wyethia in low concentrations, even beyond Avogadro’s number, may have antimicrobial, antioxidant, and anti-inflammatory properties. The hormesis concept-a biphasic dose response with a low-dose stimulation or beneficial effect and a high dose inhibitory or toxic effect-may explain the effects against human mast cells(HMC-1s). Conclusions • Clinical observations indicate that the homoeopathic preparations of Wyethia in low concentrations, even beyond Avogadro’s number, might show anti-inflammatory properties that the hormesis concept against HMC-1 can explain. The current research team thus anticipates that the analysis of this little-known material will provide a novel and insightful look at the state-of-the-art of homoeopathy without drawing any firm judgments for or against this treatment. Although it could be challenging to accept, it’s currently the most receptive stance. [ABSTRACT FROM AUTHOR]

Immune response occurs in a variety of cellular stresses that severely disrupt function of endoplasmic reticulum (ER), leading to accumulation of misfolded or unfolded protein in ER lumen, resulting in endoplasmic reticulum stress (ERS) . ERS triggers unfolded protein response to restore ER homeostasis, but its duration is too long and can lead to cell apoptosis. Although sustained ERS can lead to an increase in pro-inflammatory cytokines that induce inflammatory responses and activate immune responses, causal relationship between ERS and immune responses has not been established. This review summarizes role of ERS in inducing immune cell differentiation, cytokine expression and immune function, and further illustrates regulatory role of ERS in pathogenesis of immune disorders, which is helpful to explore new therapies for ERS-related diseases. [ABSTRACT FROM AUTHOR]

Summary: The critical importance of the immunoregulatory mechanisms, which prevent adverse responses to dietary proteins is demonstrated by the consequences of their failure in two common but distinct human pathological conditions, food allergy and celiac disease. The mechanisms of tolerance to dietary proteins have been extensively studied in mouse models but the extent to which the results in mice can be extrapolated to humans remains unclear. Here, after summarizing the mechanisms known to control oral tolerance in mouse models, we discuss how the monogenic immune disorders associated with food allergy on the one hand, and celiac disease, on the other hand, represent model diseases to gain insight into the key immunoregulatory pathways that control immune responses to food antigens in humans. The spectrum of monogenic disorders, in which the dysfunction of a single gene, is strongly associated with TH2‐mediated food allergy suggests an important overlap between the mechanisms that regulate TH2 and IgE responses to food antigens in humans and mice. In contrast, celiac disease provides a unique example of the link between autoimmunity and loss of tolerance to a food antigen. [ABSTRACT FROM AUTHOR]

Systemic autoinflammatory diseases are a group of disorders characterized by sterile episodes of inflammation resulting from defects in the innate immune system. In contrast to classical autoimmune diseases, where circulating autoantibodies and the adaptive immune system are involved, these conditions involve excessive presence of proinflammatory cytokines leading to inflammatory attacks. Excessive cytokine production, functional mutations in regulatory pathways, excessive interferon production, defects in the nuclear factor-kappa B signaling pathway, abnorARCHmal protein folding, and complement activation are the mechanisms leading to autoinflammatory diseases. A defect in the mTOR pathway and trained immunity are newly discovered possible causes in pathogenesis. Early onset and severe forms of classical rheumatological diseases have been more frequently associated with autoinflammatory diseases in the last decade. Therefore, monogenic autoinflammatory diseases should be considered in rheumatic diseases with family history, consanguinity, early onset, and severe disease. The combination of functional and genotyping research will help to identify unclassified patients. The optimal treatment strategy remains uncertain, functional studies such as interferon signature and cytokine profiling, may prove valuable in guiding the treatment process. Stem cell transplantation strategies in autoinflammatory diseases with partial response to biological therapies can be considered. Autoinflammatory diseases are becoming increasingly complex and are bringing new perspectives to already known rheumatic diseases. Although we have effective treatments, we are still far from personalized recommendations. [ABSTRACT FROM AUTHOR]

• Cystic fibrosis patients have a specific systemic immune profile similar to other immune diseases. • Lung function heterogeneity is linked to impaired B-cell function and tregs homeostasis. • Specific microbes contribute to disrupting the balance of the immune response. Excessive inflammation and recurrent airway infections characterize people with cystic fibrosis (pwCF), a disease with highly heterogeneous clinical outcomes. How the overall immune response is affected in pwCF, its relationships with the lung microbiome, and the source of clinical heterogeneity have not been fully elucidated. Peripheral blood and sputum samples were collected from 28 pwCF and an age-matched control group. Systemic immune cell subsets and surface markers were quantified using multiparameter flow cytometry. Lung microbiome composition was reconstructed using metatranscriptomics on sputum samples, and microbial taxa were correlated to circulating immune cells and surface markers expression. In pwCF, we found a specific systemic immune profile characterized by widespread hyperactivation and altered frequencies of several subsets. These included substantial changes in B-cell subsets, enrichment of CD35+/CD49d+ neutrophils, and reduction in dendritic cells. Activation markers and checkpoint molecule expression levels differed from healthy subjects. CTLA-4 expression was increased in Tregs and, together with impaired B-cell subsets, correlated with patients' lung function. Concentrations and frequencies of key immune cells and marker expression correlated with the relative abundance of commensal and pathogenic bacteria in the lungs. The CF-specific immune signature, involving hyperactivation, immune dysregulation with alteration in Treg homeostasis, and impaired B-cell function, is a potential source of lung function heterogeneity. The activity of specific microbes contributes to disrupting the balance of the immune response. Our data provide a unique foundation for identifying novel markers and immunomodulatory targets to develop the future of cystic fibrosis treatment and management. [ABSTRACT FROM AUTHOR]

Oxygen sensing is of paramount importance for maintaining cellular and systemic homeostasis. In response to diminished oxygen levels, the hypoxia-inducible factors (HIFs) orchestrate various biological processes. These pivotal transcription factors have been identified as key regulators of several biological events. Notably, extensive research from our group and others has demonstrated that HIF1α exerts an inverse regulatory effect on steroidogenesis, leading to the suppression of crucial steroidogenic enzyme expression and a subsequent decrease in steroid levels. These steroid hormones occupy pivotal roles in governing a myriad of physiological processes. Substantial or prolonged fluctuations in steroid levels carry detrimental consequences across multiple organ systems and underlie various pathological conditions, including metabolic and immune disorders. MicroRNAs serve as potent mediators of multifaceted gene regulatory mechanisms, acting as influential epigenetic regulators that modulate a broad spectrum of gene expressions. Concomitantly, phosphodiesterases (PDEs) play a crucial role in governing signal transduction. PDEs meticulously manage intracellular levels of both cAMP and cGMP, along with their respective signaling pathways and downstream targets. Intriguingly, an intricate interplay seems to exist between hypoxia signaling, microRNAs, and PDEs in the regulation of steroidogenesis. This review highlights recent advances in our understanding of the role of microRNAs during hypoxia-driven processes, including steroidogenesis, as well as the possibilities that exist in the application of HIF prolyl hydroxylase (PHD) inhibitors for the modulation of steroidogenesis. [ABSTRACT FROM AUTHOR]

Aim: Saliva can reflect an individual's physiological status or susceptibility to systemic disease. However, little attention has been given to salivary analysis in children with idiopathic nephrotic syndrome (INS). We aimed to perform a comprehensive analysis of saliva from INS children. Methods: A total of 18 children (9 children with INS and 9 normal controls) were recruited. Saliva was collected from each INS patient in the acute and remission phases. 16S rRNA gene sequencing, widely targeted metabolomics, and 4D‐DIA proteomics were performed. Results: Actinobacteria and Firmicutes were significantly enriched in the pretreatment group compared with the normal control group, while Bacteroidota and Proteobacteria were significantly decreased. A total of 146 metabolites were identified as significantly different between INS children before treatment and normal controls, which covers 17 of 23 categories. KEGG enrichment analysis revealed three significantly enriched pathways, including ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and terpenoid backbone biosynthesis (P < 0.05). A total of 389 differentially expressed proteins were selected between INS children before treatment and normal controls. According to the KEGG and GO enrichment analyses of the KOGs, abnormal ribosome structure and function and humoral immune disorders were the most prominent differences between INS patients and normal controls in the proteomic analysis. Conclusion: Oral microbiota dysbiosis may modulate the metabolic profile of saliva in children with INS. It is hypothesized that children with INS might have "abnormal ribosome structure and function" and "humoral immune disorders". Summary at a glance: This study performed a comprehensive analysis of saliva from INS children and revealed that oral microbiota dysbiosis may modulate the metabolic profile of saliva in children with INS. It is hypothesized that children with INS might have "abnormal ribosome structure and function" and "humoral immune disorders". [ABSTRACT FROM AUTHOR]

A recent article in Global Medical Genetics discusses the use of mesenchymal stem cells (MSCs) in clinical trials for immune disorders. MSCs have unique properties, including regeneration and immunomodulation, which make them a promising therapeutic approach. The article highlights a phase I trial that used human umbilical cord-derived MSCs (UC-MSCs) to treat refractory immune thrombocytopenia (ITP), a hemorrhagic disease resulting from an immune imbalance. The trial showed that UC-MSCs increased platelet counts and improved bleeding symptoms in patients with refractory ITP. MSCs have the potential to treat various immune-related conditions, and further research is needed to understand their distribution and metabolism in organ tissues. [Extracted from the article]

The treatment of food allergy (FA) needs improvement. The treatment of immune disorders can be improved by regulating epigenetic marks, which is a promising method. The objective of this research is to alleviate experimental FA by employing an inhibitor of DNA methyltransferase-1 (DNMT1). Ovalbumin was used as the specific antigen to establish a mouse model of FA. Intestinal IL-35+ regulatory B cells (Breg cells) were isolated from FA mice, and characterized using immunological approaches. FA mice had a lower frequency of IL-35+ Breg cells, which was inversely correlated with their FA response. The quantity of IL-35 was lower in intestinal Breg cells from FA mice. Hypermethylation status was detected in the Il35 promoter, which was accompanied with high levels of H3K9me3. Enforced expression of DNMT1 hindered the promoter activity of the IL35 gene. Administration of an inhibitor of DNMT1 (RG108) restored the immune regulatory capacity of FA intestinal Bregs, and effectively suppressed the expression of DNMT1, and attenuated experimental FA. The elevated quantity of DNMT1 in intestinal Breg cells compromises the expression of IL-35 and affects the immune regulatory functions, which facilitates the development of FA. The immune regulatory functions of intestinal Breg cells are restored and experimental FA is attenuated by inhibiting DNMT1. • The frequency of Breg cells was lower in FA mice. • The quantity of IL-35 was lower in intestinal Breg cells from FA mice. • Inhibition of DNMT1 attenuated experimental FA. [ABSTRACT FROM AUTHOR]

The cross‐regulation of immunity and metabolism is currently a research hotspot in life sciences and immunology. Metabolic immunology plays an important role in cutting‐edge fields such as metabolic regulatory mechanisms in immune cell development and function, and metabolic targets and immune‐related disease pathways. Protein post‐translational modification (PTM) is a key epigenetic mechanism that regulates various biological processes and highlights metabolite functions. Currently, more than 400 PTM types have been identified to affect the functions of several proteins. Among these, metabolic PTMs, particularly various newly identified histone or non‐histone acylation modifications, can effectively regulate various functions, processes and diseases of the immune system, as well as immune‐related diseases. Thus, drugs aimed at targeted acylation modification can have substantial therapeutic potential in regulating immunity, indicating a new direction for further clinical translational research. This review summarises the characteristics and functions of seven novel lysine acylation modifications, including succinylation, S‐palmitoylation, lactylation, crotonylation, 2‐hydroxyisobutyrylation, β‐hydroxybutyrylation and malonylation, and their association with immunity, thereby providing valuable references for the diagnosis and treatment of immune disorders associated with new acylation modifications. [ABSTRACT FROM AUTHOR]

Interleukin‐41 (IL‐41) is a newly discovered cytokine, named Cometin, Subfatin, meteorin‐like transcription (Metrnl), and so forth. It is widely expressed in animals and can exert its biological roles through autocrine and paracrine forms. It has functions such as anti‐inflammatory, improving body metabolism, regulating immunity, regulating fat metabolism and participates in the process of autoimmune disease or inflammatory injury. It plays an important role in psoriasis, diabetes, Crohn's disease (CD), osteoarthritis, Kawasaki disease (KD), Graves' disease, autoimmune hepatitis, infertility, obesity, sepsis, cardiovascular diseases and respiratory diseases. This paper reviews the biological functions of IL‐41, the relationship between IL‐41 and diseases, the effects of IL‐41 in the cytokine network and the possible signalling pathways. In order to explore the same target or the same drug for the treatment of different diseases from the perspective of homotherapy for heteropathy, cytokine strategies based on IL‐41 have been put forward for the precise treatment of immune diseases and inflammatory diseases. It is worth noting that IL‐41 related preparations for lung protection and smoking cessation are interesting research fields. [ABSTRACT FROM AUTHOR]

Calcineurin inhibitors (CnIs) are effective immunosuppressants with decades of accumulated experience in treating immune disorders and, most notably, solid organ transplantation. While CnIs have significantly increased graft survival and transformed the patient standard of care, their use has been overshadowed by a number of undesired side effects. For instance, CnI‐associated nephrotoxicity has been reported since early studies and remains a major therapeutic concern. The occurrence of several ion imbalances alongside hypertension was also noted early on, indicating the involvement of the renin–angiotensin–aldosterone system (RAAS) in CnI‐mediated toxicity. However, the literature in this field is crowded with conflicting reports from clinical trials as well as studies using animal and invitro models. With this review, we aim to provide a structured and updated overview of the physiological and pathophysiological evidence supporting the involvement of the classical RAAS in CnI‐associated toxicity. [ABSTRACT FROM AUTHOR]

ARHGAP25, a crucial molecule in immunological processes, serves as a Rac-specific GTPase-activating protein. Its role in cell migration and phagocyte functions, affecting the outcome of complex immunological diseases such as rheumatoid arthritis, renders it a promising target for drug research. Despite its importance, our knowledge of its intracellular interactions is still limited. This study employed proteomic analysis of glutathione S-transferase (GST)-tag pulldowns and co-immunoprecipitation from neutrophilic granulocyte cell lysate, revealing 76 candidates for potential physical interactions that complement ARHGAP25's known profile. Notably, four small GTPases (RAC2, RHOG, ARF4, and RAB27A) exhibited high affinity for ARHGAP25. The ARHGAP25–RAC2 and ARHGAP25–RHOG interactions appeared to be affected by the activation state of the small GTPases, suggesting a GTP–GDP cycle-dependent interaction. In silico dimer prediction pinpointed ARHGAP25's GAP domain as a credible binding interface, suggesting its suitability for GTP hydrolysis. Additionally, a list of Fc receptor-related kinases, phosphatases, and three of the 14-3-3 members were identified as potential partners, with in silico predictions highlighting eight binding sites, presenting novel insight on a potential regulatory mechanism for ARHGAP25. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune diseasewith a complex etiology. Neutrophil extracellular traps (NETs are NETwork protein structures activated by neutrophils to induce the cleavage and release of DNA-protein complexes). Current studies have shown the critical involvement of NETs in the progression of autoimmune diseases, Neutrophils mostly gather in the inflammatory sites of patients and participate in the pathogenesis of autoimmune diseases in various ways. NETs, as the activated state of neutrophils, have attracted much attention in immune diseases. Many molecules released in NETs are targeted autoantigens in autoimmune diseases, such as histones, citrulline peptides, and myeloperoxidase. All of these suggest that NETs have a direct causal relationship between the production of autoantigens and autoimmune diseases. For RA in particular, as a disorder of the innate and adaptive immune response, the pathogenesis of RA is inseparable from the generation of RA. In this article, we investigate the emerging role of NETs in the pathogenesis of RA and suggest that NETsmay be an important target for the treatment of inflammatory autoimmune diseases. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory bowel disease (IBD), as a chronic and recurrent inflammatory bowel diseases with limited therapeutic outcomes, is characterized by immune disorders and intestinal barrier dysfunction. Currently, the most medications used to cure IBD in clinic just temporarily induce and maintain remission with poor response rates and limited outcomes. Therefore, it is urgently necessary to develop an appropriate therapeutic candidate with preferable efficacy and less adverse reaction for curing IBD. Methods: Five groups of mice were utilized: control that received saline, DSS group (mice received 2.5% DSS or 4% DSS), KPV group (mice received KPV), FK506 group (mice received FK506) and NPs groups (mice received NPs). The effect of NP on the inflammatory factors of macrophage was evaluated using CCK-8, quantitative polymerase chain reaction (PCR), Elisa and Western blot (WB). Immunofluorescent staining revealed the targeting relationship between NP and Petp-1. Immunohistochemistry staining showed the effect of NP on tight junction proteins. Moreover, in vivo animal experiments confirmed that NPs reduced inflammatory levels in IBD. Results and Discussion: After administering with NPs, mice with DSS-induced acute or chronic colitis exhibited significant improvement in body weight, colon length, and disease activity index, decreased the level of the factors associated with oxidative stress (MPO, NO and ROS) and the inflammatory cytokines (TNF-α, IL-1β and IL-6),which implied that NPs could amelioratemurine colitis effectively. Furthermore, treating by NPs revealed a notable reduction of the expressions of CD68 and CD3, restoring the expression levels of tight junction proteins (Claudin- 5, Occludin-1, and ZO-1) were significantly restored, surpassing those observed in the KPV and FK506 groups. which indicated that NPs can reduce inflammation and enhance epithelial barrier integrity by decreasing the infiltration of macrophages and T-lymphocytes. Collectively, those results demonstrated the effectively therapeutic outcome after using NPs in both acute and chronic colitis, suggesting that the newly co-assembled of NPs can be as a potential therapeutic candidate for colitis. [ABSTRACT FROM AUTHOR]

This study aims to illustrate epidemiology of comorbid CVD in the real-world clinical setting of patients with psoriasis in China. We used data of adult patients with psoriasis who were registered in the register of China National Clinical Center for Skin and Immune Diseases between August 2020 and September 2021. Psoriasis was clinically diagnosed following the national guidelines. Univariate and multivariate logistic regression models were used to examine the factors associated with comorbid CVD in patients with psoriasis. Of the 11,560 psoriasis patients (age ≥ 18 years, mean age 41.87 years, 64.88% males), 236 were ascertained with CVD, with the overall prevalence being 2.62%. Multivariate logistic regression analysis suggested that the odds ratio (95% confidence interval) of CVD in psoriasis patients was 2.27 (2.03–2.54) for older age (per 10-year increment), 0.65 (0.48–0.90) for female, 2.07 (1.39–3.06) for obesity (BMI ≥ 28 vs. < 24 kg/m2), 2.55 (1.85–2.52) for smoking, 7.63 (5.86–9.94) for hypertension, 4.27 (3.76–4.85) for diabetes, 1.14 (1.00–1.30) for having a history of drug allergy, 2.27 (1.61–3.20) for having family history of psoriasis, and 1.76 (1.16–2.67) for severe disease (severe vs. mild) with a dose–response relationship (Ptrend < 0.001). In patients with psoriasis, comorbid CVD was associated with smoking, obesity, hypertension, diabetes, history of drug allergy, family history of psoriasis, and the psoriasis severity. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction and impaired production, leading to an elevated bleeding tendency. Recent studies have demonstrated an important link between the gut microbiota and the onset and progression of several immune diseases in humans, emphasizing that gut microbiota-derived metabolites play a non-negligible role in autoimmune diseases. The gut microbiota and its metabolites, such as short-chain fatty acids, oxidized trimethylamine, tryptophan metabolites, secondary bile acids and lipopolysaccharides, can alter intestinal barrier permeability by modulating immune cell differentiation and cytokine secretion, which in turn affects the systemic immune function of the host. It is therefore reasonable to hypothesize that ecological dysregulation of the gut microbiota may be an entirely new factor in the triggering of ITP. This article reviews the potential immune-related mechanisms of the gut microbiota and representative metabolites in ITP, as well as the important influence of leaky gut on the development of ITP, with a view to enriching the theoretical system of ITP-related gut microecology and providing new ideas for the study of ITP. [ABSTRACT FROM AUTHOR]

This article presents the findings of a long-term study on the clinical outcomes, safety, and efficacy of the Visian implantable collamer lens (ICL) for myopia correction. The study followed patients for a mean duration of 17.52 years and found that the ICL procedure resulted in favorable visual outcomes with a low risk of complications. The study also found that the ICL did not cause a significant loss of endothelial cell density and had an optimal vaulting range to minimize complications. However, a small number of cases experienced complications such as angle-closure glaucoma and cataracts. The study concludes that the Visian ICL is a safe and effective long-term solution for myopia correction. [Extracted from the article]

BACKGROUND: Organophosphate esters (OPEs) are flame retardants and plasticizers used in consumer products. OPEs are found ubiquitously throughout the environment with high concentrations in indoor house dust. Exposure to individual OPEs is associated with immune dysfunction, particularly in macrophages. However, OPEs exist as complex mixtures and the effects of environmentally relevant mixtures on the immune system have not been investigated. OBJECTIVES: The objectives of this study were to evaluate the toxicity of an environmentally relevant mixture of OPEs that models Canadian house dust on macrophages using phenotypic and functional assessments in vitro. METHODS: High-content live-cell fluorescent imaging for phenotypic biomarkers of toxicity in THP-1 macrophages treated with the OPE mixture was undertaken. We used confocal microscopy and cholesterol analysis to validate and expand on the observed OPE-induced lipid phenotype. Then, we used flow cytometry and live-cell imaging to conduct functional tests and uncover mechanisms of OPE-induced phagocytic suppression. Finally, we validated our THP-1 findings in human primary peripheral blood mononuclear cells (hPBMC) derived macrophages. RESULTS: Exposure to non-cytotoxic dilutions of the OPE mixture resulted in higher oxidative stress and disrupted lysosome and lipid homeostasis in THP-1 and primary macrophages. We further observed that phagocytosis of apoptotic cells in THP-1 and primary macrophages was lower in OPE-exposed cells vs. controls. In THP-1 macrophages, phagocytosis of both Gram-positive and Gram-negative bacteria was also lower in OPE-exposed cells vs. controls. Additionally, the OPE mixture altered the expression of phagocytic receptors linked to the recognition of phosphatidylserine and pathogen-associated molecular patterns. DISCUSSION: The results of this in vitro study suggested that exposure to an environmentally relevant mixture of OPEs resulted in higher lipid retention in macrophages and poor efferocytic response. These effects could translate to enhanced foam cell generation resulting in higher cardiovascular mortality. Furthermore, bacterial phagocytosis was lower in OPE-exposed macrophages in an in vitro setting, which may indicate the potential for reduced bacterial clearance in models of infections. Taken together, our data provide strong evidence that mixtures of OPEs can influence the biology of macrophages and offer new mechanistic insights into the impact of OPE mixtures on the immune system. [ABSTRACT FROM AUTHOR]

This document is a summary of articles published in the journal International Immunology. The first article discusses the roles of natural killer T cells (NKT cells) in cardiovascular diseases, specifically their involvement in vascular diseases and myocardial remodeling and failure. The second article focuses on the development of a bivalent outer membrane vesicles-based meningitis vaccine that covers serogroups B and W. The third article explores antigen-independent complement-binding sites in IgG C L domains and their potential for therapeutic manipulation. The final article examines how lymphopenia-induced proliferation can break tolerance and allow psoriasis to develop. These articles provide valuable insights into various aspects of immunology and offer potential implications for the treatment of related diseases. [Extracted from the article]

Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) is a valuable experimental tool to study the immune state in health and following immune challenges such as infectious diseases, (auto)immune diseases, and cancer. Several tools have been developed to reconstruct B cell and T cell receptor sequences from AIRR-seq data and infer B and T cell clonal relationships. However, currently available tools offer limited parallelization across samples, scalability or portability to high-performance computing infrastructures. To address this need, we developed nf-core/airrflow, an end-to-end bulk and single-cell AIRR-seq processing workflow which integrates the Immcantation Framework following BCR and TCR sequencing data analysis best practices. The Immcantation Framework is a comprehensive toolset, which allows the processing of bulk and single-cell AIRR-seq data from raw read processing to clonal inference. nf-core/airrflow is written in Nextflow and is part of the nf-core project, which collects community contributed and curated Nextflow workflows for a wide variety of analysis tasks. We assessed the performance of nf-core/airrflow on simulated sequencing data with sequencing errors and show example results with real datasets. To demonstrate the applicability of nf-core/airrflow to the high-throughput processing of large AIRR-seq datasets, we validated and extended previously reported findings of convergent antibody responses to SARS-CoV-2 by analyzing 97 COVID-19 infected individuals and 99 healthy controls, including a mixture of bulk and single-cell sequencing datasets. Using this dataset, we extended the convergence findings to 20 additional subjects, highlighting the applicability of nf-core/airrflow to validate findings in small in-house cohorts with reanalysis of large publicly available AIRR datasets. Author summary: We have created nf-core/airrflow, a workflow to help researchers study the immune system in healthy and disease states, such as infections, autoimmunity, and cancer. The adaptive immune system is responsible for the third line of defense responses, specific to each particular threat, after physical barriers have been compromised and the nonspecific innate immune response has failed to clear the danger. Two types of white blood cells are central players in the adaptive response, namely B cells and T cells. These cells have surface receptors that recognize suspicious elements (antigens). Learning what receptors bind to which antigens is of utmost interest to understand immune responses. Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) is a technique that allows to determine the genetic sequence of these receptors. The amount of data generated in these experiments is large, and the analysis complex. nf-core/airrflow simplifies running a comprehensive analysis connecting tools from Immcantation, a specialized software project to analyze AIRR-seq data. The workflow can efficiently process large datasets on multiple computing platforms. We analyzed immune responses to COVID-19 in 97 infected individuals and 99 healthy people, and confirmed previous findings and provided new insights, demonstrating the workflow's applicability to reanalyzing large publicly available datasets. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) is a chemical modification of RNA and has become a widely discussed topic among scientific researchers in recent years. It is distributed in various organisms, including eukaryotes and bacteria. It has been found that m6A is composed of writers, erasers and readers and is involved in biological functions such as splicing, transport and translation of RNA. The balance of the human immune microenvironment is important for human health abnormalities. Increasing studies have found that m6A affects the development of immune diseases such as inflammatory enteritis and systemic lupus erythematosus (SLE) by participating in the homeostatic regulation of the immune microenvironment in vivo. In this manuscript, we introduce the composition, biological function, regulation of m6A in the immune microenvironment and its progression in various immune diseases, providing new targets and directions for the treatment of immune diseases in clinical practice. [ABSTRACT FROM AUTHOR]