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The Journal of Clinical Investigation Nov 2023Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights...
Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed single-cell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patient subtypes based on their underlying disrupted cellular programs as well as associated biomarkers or clinical features. Among twelve independently identified subtypes, this analysis uncovered what we believe to be a novel complement and interferon activation program identified in SJIA-LD monocytes. Extending these analyses to adult and pediatric lupus patients found new but also shared disease programs with SJIA, including interferon and complement activation. Finally, supervised comparison of these programs in a compiled single-cell pan-immune atlas of over 1,000 healthy donors found a handful of normal healthy donors with evidence of early inflammatory activation in subsets of monocytes and platelets, nominating possible biomarkers for early disease detection. Thus, integrative pan-immune single-cell analysis resolved what we believe to be new conserved gene programs underlying inflammatory disease pathogenesis and associated complications.
Topics: Adult; Humans; Child; Arthritis, Juvenile; Biomarkers; Lung Diseases; Interferons; Genomics
PubMed: 37733441
DOI: 10.1172/JCI166741 -
Arthritis Research & Therapy Oct 2023N6-methyladenosine (m6A) methylation modification is involved in the regulation of various biological processes, including inflammation, antitumor, and antiviral... (Review)
Review
BACKGROUND
N6-methyladenosine (m6A) methylation modification is involved in the regulation of various biological processes, including inflammation, antitumor, and antiviral immunity. However, the role of m6A modification in the pathogenesis of autoimmune diseases has been rarely reported.
METHODS
Based on a description of m6A modification and the corresponding research methods, this review systematically summarizes current insights into the mechanism of m6A methylation modification in autoimmune diseases, especially its contribution to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).
RESULTS
By regulating different biological processes, m6A methylation is involved in the pathogenesis of autoimmune diseases and provides a promising biomarker for the diagnosis and treatment of such diseases. Notably, m6A methylation modification is involved in regulating a variety of immune cells and mitochondrial energy metabolism. In addition, m6A methylation modification plays a role in the pathological processes of RA, and m6A methylation-related genes can be used as potential targets in RA therapy.
CONCLUSIONS
M6A methylation modification plays an important role in autoimmune pathological processes such as RA and SLE and represents a promising new target for clinical diagnosis and treatment, providing new ideas for the treatment of autoimmune diseases by targeting m6A modification-related pathways.
Topics: Humans; Methylation; Autoimmune Diseases; Arthritis, Rheumatoid; Lupus Erythematosus, Systemic; Epigenesis, Genetic
PubMed: 37784134
DOI: 10.1186/s13075-023-03149-w -
Clinical and Experimental Rheumatology May 2024The relationship between intestinal microbiota and arthritis has garnered significant attention, with emerging evidence suggesting a potential association between... (Review)
Review
The relationship between intestinal microbiota and arthritis has garnered significant attention, with emerging evidence suggesting a potential association between dysbiosis and various forms of inflammatory arthropathies. While observational studies have provided valuable insights into microbiota alterations in patients with arthritis, establishing causality remains challenging. Observational data, influenced by multiple confounders such as environmental factors, medication effects, and dietary habits, are insufficient to conclusively determine whether microbiota changes are somehow causally linked to arthritis. The heterogeneity of results across independent studies further complicates interpretation. To further support this hypothesis, interventional randomised trials are deemed necessary, yet their implementation in this area presents significant technical limitations. Experimental animal models offer insights into potential pathogenic mechanisms linking dysbiosis to arthritis, including compromised intestinal barrier function, the role of microbiota-derived metabolites and molecular mimicry. However, conflicting findings underscore the complexity of hostmicrobiota interactions and the challenges in establishing causality.Efforts to modulate the microbiota for arthritis treatment or prevention have shown promise, yet efficacy and applicability remains uncertain. Antibacterial drugs, dietary interventions, probiotics, and faecal microbiota transplantation have been explored, but their clinical utility awaits further validation. In conclusion, while the association between intestinal microbiota and arthritis is increasingly recognised, establishing causality remains elusive.
Topics: Humans; Gastrointestinal Microbiome; Dysbiosis; Animals; Probiotics; Arthritis; Fecal Microbiota Transplantation; Host-Pathogen Interactions; Risk Factors
PubMed: 38743445
DOI: 10.55563/clinexprheumatol/f6q4dc -
Frontiers in Immunology 2023Although previous sporadic studies have reported the associations between a few autoimmune diseases and nasal polyps, these studies have limitations such as conflicting...
BACKGROUND
Although previous sporadic studies have reported the associations between a few autoimmune diseases and nasal polyps, these studies have limitations such as conflicting results, small sample sizes, and low levels of evidence.
METHODS
Several autoimmune diseases were selected as exposures while the nasal polyps were selected as outcomes. Bidirectional univariable Mendelian randomization and multivariable Mendelian randomization analyses were performed after rigorous screening of instrumental variables. Then mediation analyses were conducted to further investigate the underlying mechanisms.
RESULTS
For the first time, we investigated the causal relationships between nine autoimmune diseases and nasal polyps in different genders and found: (1) there was a causal association between adult-onset Still's disease and nasal polyps; (2) sarcoidosis, ulcerative colitis, type 1 diabetes, and Crohn's disease had no significant associations with nasal polyps; (3) celiac disease showed a suggestive positive association with female nasal polyps, whereas juvenile arthritis and multiple sclerosis showed suggestive positive associations with male nasal polyps. By contrast, arthropathic psoriasis showed a suggestive negative association with nasal polyps. In addition to these nine diseases, previous controversial issues were further investigated: (1) there was a causal relationship between rheumatoid arthritis and nasal polyps, which was partially mediated by "BAFF-R for IgD+ B cells"; (2) ankylosing spondylitis showed suggestive positive associations with the female but not the male nasal polyps. Besides, we validated that there was no causal effect of autoimmune hyperthyroidism on nasal polyps.
CONCLUSION
Specific conclusions regarding the causal effects of multiple autoimmune diseases on nasal polyps are the same as above. By comparing results between different genders, we have initially observed the sex bimodality in the causal effects between autoimmune diseases and nasal polyps, with those on male nasal polyps being stronger than those on female nasal polyps. Our study lays a solid foundation for further research in the future, not only helping identify individuals susceptible to nasal polyps early but also improving our understanding of the immunopathogenesis of these heterogeneous diseases.
Topics: Adult; Female; Male; Humans; Nasal Polyps; Arthritis, Rheumatoid; Diabetes Mellitus, Type 1; Multiple Sclerosis; Arthritis, Juvenile
PubMed: 37691921
DOI: 10.3389/fimmu.2023.1228226 -
Frontiers in Immunology 2024Autoimmune inflammation is caused by the loss of tolerance to specific self-antigens and can result in organ-specific or systemic disorders. Systemic autoimmune diseases... (Review)
Review
Autoimmune inflammation is caused by the loss of tolerance to specific self-antigens and can result in organ-specific or systemic disorders. Systemic autoimmune diseases affect a significant portion of the population with an increasing rate of incidence, which means that is essential to have effective therapies to control these chronic disorders. Unfortunately, several patients with systemic autoimmune diseases do not respond at all or just partially respond to available conventional synthetic disease-modifying antirheumatic drugs and targeted therapies. However, during the past few years, some new medications have been approved and can be used in real-life clinical settings. Meanwhile, several new candidates appeared and can offer promising novel treatment options in the future. Here, we summarize the newly available medications and the most encouraging drug candidates in the treatment of systemic lupus erythematosus, rheumatoid arthritis, Sjögren's disease, systemic sclerosis, systemic vasculitis, and autoimmune myositis.
Topics: Humans; Autoimmune Diseases; Sjogren's Syndrome; Arthritis, Rheumatoid; Lupus Erythematosus, Systemic; Myositis
PubMed: 38558805
DOI: 10.3389/fimmu.2024.1249500 -
Free Radical Biology & Medicine Oct 2023Rheumatoid arthritis is a systemic autoimmune disease with pain and functional disorder of joints. Multiple strategies toward treatment of the rheumatoid arthritis are...
Rheumatoid arthritis is a systemic autoimmune disease with pain and functional disorder of joints. Multiple strategies toward treatment of the rheumatoid arthritis are operating, while there are concerns of serious adverse effects of the therapeutic drugs. Here, we show that activation of Nrf2 (Nuclear factor erythroid 2-related factor 2) efficiently improves arthritis of SKG mice, which develop T cell-mediated autoimmune arthritis by zymosan A injection. We found that genetic Nrf2 activation by knockdown of Keap1 (Kelch-like ECH-associated protein 1), a negative regulator of Nrf2, repressed arthritis by inhibiting the expression of pro-inflammatory cytokines and inducing the expression of antioxidant enzymes in SKG mice. In addition, oral administration of CDDO-Im, a representative chemical inducer of Nrf2, had effects of both prevention and treatment toward arthritis of SKG mice in an Nrf2-dependent manner. We also found that Nrf2 activation through myeloid-cell lineage-specific Keap1 disruption did not achieve significant improvement in the arthritis of SKG mice. In contrast, expressions of pro-inflammatory cytokine genes were decreased, and those of antioxidant enzyme genes were increased in fibroblast-like synoviocytes (FLS) isolated from SKG mouse. Our results thus demonstrate that Nrf2 activation exerts marked anti-arthritis effects in the SKG experimental rheumatoid arthritis model mice, supporting the contention that the Nrf2 activation is a new therapeutic strategy for the rheumatoid arthritis.
Topics: Animals; Mice; Antioxidants; Arthritis, Experimental; Arthritis, Rheumatoid; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2
PubMed: 37494986
DOI: 10.1016/j.freeradbiomed.2023.07.016 -
BMC Musculoskeletal Disorders Jul 2023The weight-adjusted-waist Index (WWI), an innovative metric for assessing obesity, exhibits superior efficacy in appraising lean muscle and adipose tissue mass relative...
INTRODUCTION
The weight-adjusted-waist Index (WWI), an innovative metric for assessing obesity, exhibits superior efficacy in appraising lean muscle and adipose tissue mass relative to both the Body Mass Index (BMI) and Waist Circumference (WC). The objective of this research paper is to investigate the correlation between WWI and the incidence of Rheumatoid Arthritis (RA) and Osteoarthritis (OA).
METHODS
In this population-based study, we collected data from adult participants aged 20-80 years using the National Health and Nutrition Examination Survey (NHANES) conducted between 2011 and 2020 to analyze the association between WWI and the occurrence of RA and OA. NHANES, a nationally representative cross-sectional survey, is designed to evaluate the health and nutritional status of the U.S.
POPULATION
The current research incorporates an extensive, nationally representative sample of U.S. adults, utilizing weighted multivariate linear regression and smoothed curve fitting techniques to examine linear and non-linear relationships. Threshold effects were determined through a two-part linear regression model. Additionally, subgroup analyses and interaction tests were conducted to explore the connection between WWI and the incidence of RA and OA.
RESULTS
Our findings reveal a linear positive correlation between WWI and OA prevalence, indicating that an increase in WWI is linked to a heightened risk of OA. Conversely, a non-linear relationship was observed between WWI and RA prevalence, exhibiting a significant threshold effect with a saturation value of 11.21 cm/√kg. A positive association was detected to the left of the saturation point, while no significant association was present between the two variables to the right of the saturation point, suggesting a complex non-linear relationship between RA prevalence and WWI.
CONCLUSIONS
This investigation demonstrates a positive linear association between WWI and OA prevalence, as well as a complex non-linear relationship with RA prevalence in U.S. adults aged 20-80 years.
Topics: Adult; Humans; Nutrition Surveys; Prevalence; Cross-Sectional Studies; Osteoarthritis; Arthritis, Rheumatoid; Body Mass Index
PubMed: 37474953
DOI: 10.1186/s12891-023-06717-y -
Frontiers in Immunology 2023The NLRP3 inflammasome, which belongs to the pyrin domain containing 3 family of NOD-like receptors, has a significant impact on both the innate and adaptive immune... (Review)
Review
The NLRP3 inflammasome, which belongs to the pyrin domain containing 3 family of NOD-like receptors, has a significant impact on both the innate and adaptive immune responses. Regulating host immune function and protecting against microbial invasion and cell damage, the NLRP3 inflammasome plays a crucial role. By triggering caspase-1, it facilitates the development of the inflammatory cytokines IL-1β and IL-18, and triggers cell pyroptosis, resulting in cell lysis and demise. Common sterile arthritis includes osteoarthritis (OA), rheumatoid arthritis (RA) and gouty arthritis (GA), all of which manifest as bone destruction and synovial inflammation in a complex inflammatory state, placing a significant medical burden on the families of patients and government agencies. In the past few years, there has been a growing interest in investigating the impact of cell pyroptosis on arthritis development, particularly the widespread occurrence of pyroptosis mediated by the NLRP3 inflammasome. The NLRP3 inflammasome's biological properties are briefly described in this review, along with the presentation of the fundamental processes of pyroptosis resulting from its activation. Furthermore, we provide a summary of the advancements made in studying the NLRP3 inflammasome in various forms of arthritis and enumerate the intervention approaches that target the NLRP3-mediated pyroptosis, either directly or indirectly. These discoveries lay the groundwork for future investigations on medications for arthritis, offering fresh approaches for the clinical identification and treatment of this condition.
Topics: Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Arthritis, Rheumatoid; Osteoarthritis; Arthritis, Gouty
PubMed: 37954594
DOI: 10.3389/fimmu.2023.1273174 -
Journal of Immunology Research 2023The aim of the study was to investigate the landscape of B-cell-related gene expression profiling in rheumatoid arthritis (RA) synovium and explore the biological and...
BACKGROUND
The aim of the study was to investigate the landscape of B-cell-related gene expression profiling in rheumatoid arthritis (RA) synovium and explore the biological and clinical significance of these genes in RA.
METHODS
Expression profiling of synovial biopsies from subjects with 152 RA patients, 22 osteoarthritis (OA) patients, and 28 healthy controls was downloaded from the Gene Expression Omnibus database. Single-sample gene set enrichment analysis (ssGSEA) was performed to evaluate the abundance of infiltrated immune cells, and the results were validated using immunohistochemical staining. GSEA was employed to decipher differences in B-cell-related biological pathways. B-cell-related differential expression genes (BRDEGs) were screened, and BRDEGs-based model was developed by machine learning algorithms and evaluated by an external validation set and clinical RA cohort, then biological functions were further analyzed.
RESULTS
High levels of immune cell infiltration and B-cell-related pathway activation were revealed in RA synovium. BRDEGs were screened, and three key molecular markers consisting of FAS, GPR183, and TFRC were identified. The diagnosis model was established, and these gene markers have good discriminative ability for RA. Molecular pathological evaluation confirmed RA patients with high-risk scores presented higher levels of B-cell activation and RA characteristics. In addition, a competitive endogenous RNA network was established to elucidate the molecular mechanisms of the posttranscriptional network.
CONCLUSIONS
We described the B-cell-related molecular landscape of RA synovium and constructed a molecular diagnostic model in RA. The three genes FAS, GPR183, and TFRC may be potential targets for clinical diagnosis and immunoregulatory therapy of RA.
Topics: Humans; Arthritis, Rheumatoid; Synovial Membrane; Osteoarthritis; Biomarkers
PubMed: 38046263
DOI: 10.1155/2023/9422990 -
Autoimmunity Reviews Sep 2023Psoriatic arthritis (PsA) is an inflammatory complex condition. Posttranslational modifications influence almost all aspects of normal cell biology and pathogenesis. The... (Review)
Review
BACKGROUND AND AIMS
Psoriatic arthritis (PsA) is an inflammatory complex condition. Posttranslational modifications influence almost all aspects of normal cell biology and pathogenesis. The aim of this systematic review was to collect all published evidence regarding posttranslational modifications in PsA, and the main outcome was to evaluate an association between disease outcomes and specific posttranslational modifications in PsA.
METHODS
A systematic electronic search was performed in Medline, PubMed, Cochrane, Virtual Health Library, and Embase databases. A total of 587 articles were identified; 59 were evaluated after removing duplicates and scanning, of which 47 were included. A descriptive analysis was conducted, with results grouped according to the type of posttranslational modification evaluated. The protocol was registered at the PROSPERO database.
RESULTS
Seven posttranslational modifications were identified: citrullination, carbamylation, phosphorylation, glycosylation, acetylation, methylation, and oxidative stress. Anti-citrullinated peptide and anti-carbamylated protein have been evaluated in rheumatoid arthritis. There is now information suggesting that these antibodies may be helpful in improving the diagnosis of PsA and that they may demonstrate a correlation with worse disease progression (erosions, polyarticular involvement, and poor treatment response). Glycosylation was associated with increased inflammation and phosphorylation products related to the expression of SIRT2 and pSTAT3 or the presence of Th17 and cytokine interleukin-22, suggesting a possible therapeutic target.
CONCLUSIONS
Posttranslational modifications often play a key role in modulating protein function in PsA and correlate with disease outcomes. Citrullination, carbamylation, phosphorylation, glycosylation, acetylation, methylation, and oxidative stress were identified as associated with diagnosis and prognosis.
Topics: Humans; Arthritis, Psoriatic; Protein Processing, Post-Translational; Citrullination; Glycosylation; Arthritis, Rheumatoid
PubMed: 37487969
DOI: 10.1016/j.autrev.2023.103393