Pathogenesis Of Rheumatoid Arthritis Research Articles

Dietary habit and risk of rheumatoid arthritis: a mendelian randomization study identifying protective and risk factors.

Dietary habit significantly contributes to the initiation and progression of rheumatoid arthritis (RA). Dietary choices intersect with a range of clinical and societal factors. The utilization of cross-sectional methodologies in numerous studies poses a challenge in establishing definitive causality for the noted associations. Moreover, within identical food categories, specific items may elicit diverse effects on the pathogenesis of RA, and the correlation between several prevalent food items or beverages and RA remains inadequately explored. We performed a two-sample Mendelian Randomization (MR) study to evaluate the causal impact of 27 distinct dietary habits and RA susceptibility. These dietary-related phenotypes encompass both the relative intake of the four macronutrients (fat, protein, carbohydrates, and sugar) and 23 specific single food intake. Several filtering steps were employed to select eligible genetic instruments strongly associated with each of the traits. The random-effects inverse-variance weighted, weighted median, and MR-Egger methods were employed for MR estimations. Sensitivity analyses and power calculations were executed to ensure the robustness of our study. After rigorous single-nucleotide polymorphism (SNP) filtering procedures, 611 SNPs were included in our ongoing investigations. The consumption of dried fruit, bread, and alcohol emerged as protective factors, while beef, processed meat, and coffee intake were identified as risk factors. The robustness of our study was confirmed through the outcomes of sensitivity analysis and power calculation. The ongoing investigations furnish evidence that accentuates the influence of diet on RA disease activity, underscoring the importance of delineating the optimal nutritional lifestyle for RA patients.

Serum Anti-Aminoacyl-Transfer Ribonucleic Acid Synthetase Antibody Levels Are Involved in Rheumatoid Arthritis Complicated with Interstitial Lung Disease

Objectives: A common complication in patients with rheumatoid arthritis (RA) is interstitial lung disease (ILD). Antibodies (Abs) to anti-aminoacyl-transfer ribonucleic acid synthetase (ARS) are linked to ILD in patients with idiopathic inflammatory myopathies (IIM). There have been limited studies of anti-ARS Abs in RA. In this study, we examined anti-ARS Abs in ILD in patients with RA. Methods: Anti-ARS Abs in serum from patients with RA were measured. Results: There were higher anti-ARS Ab levels in RA patients with ILD (mean ± SDM, 16.3 ± 32.3 vs. 7.4 ± 7.0 (Index), p = 5.58 × 10−12), usual interstitial pneumonia (14.4 ± 24.4 vs. 7.4 ± 7.0 [Index], p = 3.14 × 10−12), and nonspecific interstitial pneumonia (17.9 ± 37.7 vs. 7.4 ± 7.0 (Index), p = 5.07 × 10−5) compared with patients without chronic lung disease. The area under the curve (AUC) of the receiver operating characteristic curve for anti-ARS Ab was too low to allow for discrimination among RA patients with/without chronic lung disease (0.608, 95% confidence interval (CI) 0.560–0.655, p = 8.69 × 10−6). Multiple logistic regression analyses of age, smoking status, anti-ARS Abs, as well as Steinbrocker stage generated an ARS-index with a high AUC value (0.707, 95%CI 0.662–0.752, p = 2.20 × 10−19). Conclusions: Anti-ARS Abs are related to ILD pathogenesis in RA and may be a biomarker for ILD.

A detailed quantitative analysis of circulating T peripheral and follicular helper lymphocytes in patients with rheumatoid arthritis and systemic lupus erythematosus

Introduction and objectivePeripheral and follicular helper T lymphocytes (Tph and Tfh, respectively) have an important role in B cell immune responses and the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Although several studies on the number of Tph and Tfh cells in these conditions have been published, different phenotypes have been employed for their analysis. In this study, we assessed the levels and function of Tph and Tfh cells in blood samples from patients with RA and SLE by using an extended immunophenotype. Materials and methodsIn a cross-sectional pilot study, blood samples from twenty-seven patients with RA and fifteen with SLE, and twenty-six healthy controls were studied. The levels of Tph (CD4+PD-1+CXCR5−CD38+CD69+ICOS+) and Tfh (CD4+PD-1+CXCR5+CD38+CD69+ICOS+) cells were analyzed by flow cytometry. In addition, the function of Tph/Tfh cells was estimated by measuring the synthesis of IL-21 by these lymphocytes as well as the number of circulating plasmablasts (CD19+CD27+CD20−CD38hi). ResultsIncreased percentages of Tph and Tfh lymphocytes were detected in patients with RA and SLE. Furthermore, the synthesis of IL-21 tended to be higher in both conditions, and higher levels of plasmablasts were detected in these patients, compared to controls. In patients with SLE, the number of Tph cells was associated with disease activity and with the levels of circulating plasmablasts, whereas in patients with RA a significant correlation between Tph cells and evolution time was observed. Discussion and conclusionsOur data of Tph and Tfh lymphocytes, based in the analysis of an extended phenotype of these cells, provides further evidence on their involvement in the pathogenesis of RA and SLE.

Classical proinflammatory cytokines in patients with rheumatoid arthritis: immunologic and clinical relationships

Relevance. Activation of innate and acquired immunity, accompanied by increased production of classical (interleukin (IL) IL-1β, IL-6, tumor necrosis factor-α (TNF-α) and interferon-γ (INF-γ)) proinflammatory cytokines in synovial fluid and blood serum, plays an important role in the pathogenesis of rheumatoid arthritis (RA).Objective. To determine the concentration of IL-1β, IL-6, TNF-α and INF-γ in RA patients in the advanced stage of the disease, to evaluate the relationship between them, clinical indices of disease activity, the presence of rheumatoid factor (RF), and antibodies to cyclic citrullinated peptide (ACCP).Material and methods. We examined 154 patients with RA (41 men and 113) who were middle-aged (56.0 (50.0; 64.0) years), disease duration (9.4 (3.0; 13.0) years), seropositive 129 (83.8 %) for IgM RF and/or 106 (68.8 %) ACCP with moderate to high (DAS28-ESR — 5.40 (4.65; 6.00)) disease activity. The concentration of IL-1β, IL-6, TNF-α and INF-γ in serum determined by multiplex technology.Results. The concentration of IL-1β was not significantly different between patients with RA and controls. The values of IL-6 and INF-γ were significantly higher, and TNF-α — significantly lower than in donors. IL-6 hyperproduction was detected most frequently (51.6 %), whereas elevated levels of INF-γ (38.96 %), IL-1β (26.62 %) and TNF-α (23.38 %) were less common. Significant positive correlations were observed between the concentrations of all cytokines and their high levels. The strongest correlations were characteristic for IL-1β, TNF-α and INF-γ. No statistically significant differences in cytokine levels were observed between patients with RA who were positive or negative for IgM-RF and ACCP. The concentration of IL-6 alone significantly positively correlated with the values of the indices (DAS28-ESR, CDAI, SDAI) of RA clinical activity (p<0.05).Conclusions. There are differences in the levels and frequencies of proinflammatory cytokines among patients with advanced-stage RA. In the presence of a close relationship between them, there are certain differences in their associations with clinical and laboratory indicators of disease activity.

Inflammatory cytokines, metabolites, and rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint destruction. Although the roles of inflammatory cytokines and metabolites in RA pathogenesis have caught a lot of attention, there is a lack of systematic studies, and their causal relationships remain unclear. We conducted a two-step mendelian randomization analysis utilizing genetic data from genome-wide association studies (GWAS) of inflammatory cytokines, metabolites, and RA. The first step assessed the causal effect of 91 inflammatory cytokines and 1400 metabolites on RA risk using inverse variance weighted method, complemented by MR-Egger, weighted median, simple mode and MR-PRESSO to ensure robustness and assess pleiotropy. The second step evaluated the mediation effects of selected metabolites on the relationship between cytokines and RA. The analysis identified 9 inflammatory cytokines, including IL-1α and IL-10, which significantly increase RA risk, while TNF-β exhibited a protective effect. Additionally, 6 metabolites were associated with increased RA risk, including 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE and arachidonate (20:4n6). Conversely, 5 metabolites, such as docosatrienoate (22:3n3) and Cholesterol, were found to reduce RA risk. The mediation analysis revealed that TNF-β may exerts its protective effect through its influence on specific metabolites, and X-24949, which accounted for a -2.58% mediated effect in the TNF-β-RA causal pathway. This study explores the complex interplay between inflammatory cytokines, metabolites, and RA. The findings suggest potential biomarkers for early diagnosis and novel therapeutic targets, particularly those related to lipid metabolites and specific cytokines like TNF-β. Key message What is already known on this topic Inflammatory factors and metabolites are considered to be related to the onset and progression of RA. What this study adds We conducted a MR analysis to identify all inflammatory factors and metabolites associated with RA and calculated the mediation effect of inflammatory cytokines on RA through metabolites. This study contributes to a comprehensive understanding of the pathophysiological processes of RA. How this study might affect research, practice or policy This has laid the groundwork for developing early diagnosis methods and future treatments.

YTHDC1 Regulates the Migration, Invasion, Proliferation, and Apoptosis of Rheumatoid Fibroblast-Like Synoviocytes.

Rheumatoid arthritis (RA), a chronic autoimmune condition, is characterized by persistent synovial inflammation, bone degradation, and progressive joint deterioration. Despite considerable research efforts, the precise molecular mechanism underlying RA remains elusive. This investigation aims to elucidate the potential role and molecular mechanism of N6-methyladenosine (m6A) methylation regulators in the pathogenesis of RA. In this study, we employed bioinformatics tools to elucidate the association between RA and m6A modifications, aiming to identify potential biological markers. We extracted datasets GSE12021, GSE55235, and GSE55457 from the Gene Expression Omnibus (GEO) database for comprehensive analysis. Utilizing differential expression analysis, protein-protein interaction (PPI) analysis, and single-cell sequencing techniques, we identified pivotal hub genes implicated in the pathogenesis of RA. Subsequently, we assessed the correlation between these hub genes and the pathogenesis of RA using Gene Set Enrichment Analysis (GSEA). Both in vivo and in vitro experiments were performed to confirm the expression and functional roles of the identified key hub gene in RA. Differential expression analysis, PPI analysis, and single-cell analysis identified three key hub genes (YTHDC1, YTHDC2, and YTHDF2) associated with RA. GSEA results further revealed that these genes are enriched in pathways associated with inflammatory responses. Subsequent correlation analysis demonstrated a significant negative correlation between YTHDC1 expression and CD8+ T cell levels. Notably, the gene and protein expression levels of YTHDC1 and YTHDF2 were significantly reduced in the synovial tissue of RA patients. Furthermore, silencing YTHDC1 in fibroblast-like synoviocytes (FLSs) significantly inhibited their migration, invasion, proliferation, and induced apoptosis. YTHDC1 may potentially be involved in the pathogenesis of RA through its regulation of migration, invasion, proliferation, and apoptosis in FLSs.

Noncoding RNAs in rheumatoid arthritis: modulators of the NF-κB signaling pathway and therapeutic implications.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint inflammation and gradual tissue destruction. New research has shown how important noncoding RNAs (ncRNAs) are for changing immune and inflammatory pathways, such as the WNT signaling pathway, which is important for activating synovial fibroblasts and osteoblasts to work. This article examines the current understanding of several ncRNAs, such as miRNAs, lncRNAs, and circRNAs, that influence NF-κB signaling in the pathogenesis of RA. We investigate how these ncRNAs impact NF-κB signaling components, altering cell proliferation, differentiation, and death in joint tissues. The paper also looks at how ncRNAs can be used as potential early detection markers and therapeutic targets in RA because they can change important pathogenic pathways. This study highlights the therapeutic potential of targeting ncRNAs in RA therapy techniques, with the goal of reducing inflammation and stopping disease progression. This thorough analysis opens up new possibilities for understanding the molecular foundations of RA and designing novel ncRNA-based treatments.

Identification and Experimental Verification of PDK4 as a Potential Biomarker for Diagnosis and Treatment in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by sustained joint inflammation, with an etiology that remains elusive. Achieving an early and precise diagnosis poses significant challenges. This study aims to elucidate the molecular pathways involved in RA pathogenesis by screening genes associated with its occurrence, analyzing the related molecular activities, and ultimately developing more effective molecular-level treatments for RA. Microarray expression profiling datasets GSE1919, GSE10500, GSE15573, GSE77298, GSE206848, and GSE236924 were sourced from the Gene Expression Omnibus (GEO) database. Samples were divided into experimental (RA) and control (normal) groups. Differentially expressed genes (DEGs) were identified using R software packages such as limma, glmnet, e1071 as well as randomForest. Cross-validation of DEGs was conducted using lasso regression and the random forest (RF) algorithm in R software to pinpoint intersecting genes that met the criteria. Among these, one gene was selected as the target for correlation analysis to identify DEGs related to the target gene. Enrichment analysis utilized the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway databases and Gene Ontology (GO) data. Gene Set Enrichment Analysis (GSEA) was performed to compare the expression levels of the target gene (PDK4) across various biological pathways and functions in groups with high and low expression. The relationship between target gene expression levels and cellular immune function was assessed using the immune function score technique. The discrepancy in immune cell distribution between the control and experimental groups, as well as their correlation with target gene expression levels, was elucidated using CIBERSORT. The relationships between mRNA, lncRNA, and miRNA were depicted in the ceRNA regulation network. The expression levels of the target gene were validated using Western blot and qRT-PCR. In this study, six intersecting genes meeting the criteria were identified through cross-validation, and PDK4 was chosen as the target gene for further investigation. Functional analysis using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) revealed that PDK4-associated DEGs are primarily enriched in the PPAR signaling pathway, thereby regulating synovial cell proliferation and migration, ultimately influencing the onset and progression of rheumatoid arthritis (RA). Immune infiltration analysis suggested that eosinophil quantity may influence the progression of RA. Experimental results from PCR and Western blot confirmed the downregulation of PDK4 in the RA group. The significant downregulation of PDK4 expression in patients diagnosed with rheumatoid arthritis (RA) was confirmed. PDK4 may function as a novel regulatory factor in the onset and progression of RA, with potential applications as a diagnostic biomarker for the condition.

Associations between Gut Microbiota and Microbial Metabolites in Adjuvant- induced Arthritis Rats with Moist Heat Arthralgia Spasm Syndrome.

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease. According to Traditional Chinese Medicine (TCM) syndromes theory, moist heat arthralgia spasm syndrome is the most prevalent syndrome of RA patients in the active period. However, the mechanism of alteration of gut microbiota in RA with moist heat arthralgia spasm syndrome has not been reported until now. This study focused on the alteration of gut microbiota in adjuvant-induced arthritis rats with moist heat arthralgia spasm syndrome, elaborated its regulation mechanism, and analyzed the associations between gut microbiota and microbial metabolites. The disease-syndrome combination rat model of RA with moist heat arthralgia spasm syndrome was constructed with Adjuvant-Induced Arthritis (AIA) under damp-heat stimulating. Enzyme-Linked Immunosorbent Assay (ELISA) was used to measure serum biochemical indicators. Damages of ankle joints were observed using hematoxylin and eosin (H&E). 16 small ribosomal subunit RNA (16S rRNA) gene sequencing was conducted to assess the gut microbiota composition and function on feces from rats. Alterations in fecal metabolites profiling were evaluated by fecal metabolomics through Liquid Chromatography-Mass Spectrometry (LC-MS) and Gas Chromatography-Mass Spectrometry (GC-MS). Pearson correlation analysis was performed to explore the associations of altered gut microbiota and microbial metabolites in Model rats. The imbalance of gut microbiota in Model rats was accompanied by metabolic disorders. Lactobacillus, Prevotellaceae_NK3B31_group, Allobaculum, Prevotellaceae_UCG_001, Alloprevotella, and Dubosiella were found to be dominant genera in Model rats. In total, 357 metabolites were significantly altered in Model rats and predominantly enriched into fatty acid degradation and glycerophospholipid metabolism. Pearson correlation analysis showed that TNF-α and IL-1β were associated with Prevotellaceae_Ga6A1_group and 3R-hydroxy-docosan-5S-olide, alpha-N-(3-hydroxy-14-methyl-pentadecanoyl)-ornithine, 17-methyl-trans-4,5- methylenenona-decanoic acid, Semiplenamide F. The key differential microbiota genera and differential microbial metabolites may become important targets for the treatment of RA and provide the theoretical basis for exploring the pathogenesis of RA.

Gut microbiota dysbiosis in rheumatoid arthritis: a systematic review and meta-analysis

Background: Rheumatoid arthritis (RA) is an autoimmune joint disease with systemic manifestations. Emerging evidence implicates the gut microbiota in the pathophysiology of RA. However, the specific changes in the gut microbiota in RA patients remain poorly understood. Methods: We conducted a comprehensive search of PubMed, EMBASE, Web of Science, Cochrane Library, MEDLINE, Wanfang, VIP, CBM, and CNKI from the time the databases were created until October, 2023. To evaluate changes in α-diversity and the abundance of certain microbiota families in RA, standardized mean difference (SMD) and 95% confidence interval (CI) calculations were made. Results: Firstly, we evaluated the changes in α-diversity of gut microbes in patients with RA compared to healthy controls. Our analysis of 18 studies revealed a significant decrease in richness and evenness among RA patients. Importantly, the subgroup analysis suggested the decrease in α-diversity was more significant in treatment naïve patients rather than those who received anti-rheumatic medication. Additionally, in the subgroup analysis of 316 patients stratified by baseline disease activity, no significant differences in α-diversity were detected between groups. Discussion: Our analysis further evidence of altered α-diversity and the relative abundance of specific bacteria in RA. These findings contribute to our understanding of the role of gut microbiota dysbiosis in the pathogenesis of RA. Further research is warranted to elucidate the underlying mechanisms and explore the potential therapeutic implications of targeting the gut microbiota in RA management.

Relationship Between Serum Interleukin-6 Levels, Systemic Immune-Inflammation Index, and Other Biomarkers Across Different Rheumatoid Arthritis Severity Levels.

Background Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by joint inflammation, pain, and progressive disability. Identifying biomarkers that accurately reflect disease severity is crucial for effective management. Interleukin-6 (IL-6) is a pro-inflammatory cytokine involved in the pathogenesis of RA, and the systemic immune-inflammation index (SII) is emerging as a useful marker of systemic inflammation. This study aims to explore the relationship between serum IL-6 levels, SII, and various biomarkers to better predict disease severity in RA patients. Objective To determine the relationship between serum IL-6 levels and the SII, along with various biomarkers, across different severity levels for predicting the severity of RA in patients. Methods This cross-sectional, observational study was conducted at the Mardan Medical Complex from January 2024 to August 2024, involving 67 RA patients.Clinical assessments included demographic data, disease activity (DAS28), pain (VAS), joint damage (Larsen score), and functional status (HAQ-DI). Serum IL-6 levels, along with other biomarkers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and the SII, were measured through fasting blood samples. Statistical analyses, including density plots, scatter plots, boxplots with ANOVA, and random forest models, were performed to explore associations between IL-6 and all other variables. Significance was set at p < 0.05. Results The study included 67 RA patients (mean age: 41.79 ± 10.51 years, 53.73% male). Elevated IL-6 levels (mean: 80.28 ± 35.27 pg/mL) were strongly associated with disease severity. Patients with DAS28 > 5.5 had IL-6 levels over 100 pg/mL, while those in remission had around 40 pg/mL. IL-6 levels correlated with joint damage (100 pg/mL in severe cases) and pain (over 120 pg/mL for severe pain). Patients with metabolic and cardiovascular comorbidities had the highest IL-6 levels, particularly with diabetes and hypertension (98.6 pg/mL) or cardiovascular disease (119.3 pg/mL). IL-6 correlated strongly with CRP (r = 0.65), ESR (r = 0.51), and SII (r = 0.62). Regression confirmed IL-6 as an independent predictor of severity (p < 0.001), with comorbidities being key predictors. Conclusion Elevated IL-6 and SII levels serve as critical markers for predicting the severity of RA. Addressing these markers may lead to more targeted and effective therapeutic strategies for managing disease progression.

Butyrate: a bridge between intestinal flora and rheumatoid arthritis.

In patients with rheumatoid arthritis (RA), intestinal flora imbalance and butyrate metabolism disorders precede clinical arthritis and are associated with the pathogenesis of RA. This imbalance can alter the immunology and intestinal permeability of the intestinal mucosa, leading to damage to the intestinal barrier. In this context, bacteria and their metabolites can enter the bloodstream and reach the distant target tissues of the host, resulting in local inflammation and aggravating arthritis. Additionally, arthritis is also exacerbated by bone destruction and immune tolerance due to disturbed differentiation of osteoclasts and adaptive immune cells. Of note, butyrate is a metabolite of intestinal flora, which not only locally inhibits intestinal immunity and targets zonulin and tight junction proteins to alleviate intestinal barrier-mediated arthritis but also inhibits osteoclasts and autoantibodies and balances the immune responses of T and B lymphocytes throughout the body to repress bone erosion and inflammation. Therefore, butyrate is a key intermediate linking intestinal flora to the host. As a result, restoring the butyrate-producing capacity of intestinal flora and using exogenous butyrate are potential therapeutic strategies for RA in the future.

Environmental pollution impact on the severity of some rheumatic diseases: a comparative analytical study on inflammatory and non-inflammatory samples

ObjectiveEnvironmental pollution of heavy metals is increasingly a problem and has become of great concern due to the adverse effects it causes worldwide. Heavy metal exposure has been implicated in health problems, including fibromyalgia and rheumatoid arthritis. We aim to evaluate the rule of chronic heavy metals toxicity on the induction of vitamin D3 (VD) deficiency and parathyroid hormone (PTH) disturbances in an inflammatory disease like rheumatoid arthritis (RA) and non-inflammatory disease like fibromyalgia syndrome (FMS).MethodsThis comparative analytical study was conducted on sixty adults (age ≥ 18 years). Participants were divided into three groups. Group I: twenty patients diagnosed with RA according to the specific ACR/EULAR criteria for RA. Group II: twenty patients diagnosed with FMS according to the specific 2010 (ACR) criteria for FMS. Group III: twenty healthy adults. All patients and controls were subjected to routine laboratory tests as well as the measurement of PTH, VD and estimation of serum levels of lead, cadmium, and chromium.ResultsVD was significantly inversely correlated to PTH, lead, cadmium, chromium, and activity scores in the RA and FMS groups. Lead, Cadmium and Chromium had a significant independent risk on the VD level in RA patients, while lead had a significant independent risk on the VD level in FMS patients.ConclusionHeavy metals may affect VD synthesis, leading to hypovitaminosis D and secondary hyperparathyroidism in RA and FMS patients. Heavy metals play a key role in the pathogenesis of RA, FMS, and their disease activity.

Rheumatoid Arthritis: What Inflammation Do We Face?

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by symmetrical joint inflammation, cartilage degradation, and bone erosion. This review explores the multifaceted aspects of RA pathogenesis, focusing on the dynamic interplay between innate and adaptive immune responses, genetic predisposition, and environmental triggers. The development of RA involves genetic susceptibility and trigger events such as infections, trauma, smoking, obesity, and microbiome alterations, fostering autoimmune reactions and tissue/organ destruction. The innate immune response, including toll-like receptor activation and synovial fibroblasts’ roles, contributes to the acceleration of inflammatory processes in joint tissues. Monocytes and macrophages organize and sustain chronic joint inflammation, leading to tissue damage and bone resorption, while highlighting the significance of CD14 and CD16 subsets in RA pathogenesis. In the adaptive immune response, aberrant activation and proliferation of CD4+ T cells and the role of regulatory T cells in maintaining immune tolerance are discussed. Target cytokines like TNF-α, IL-6, IL-1, IL-17, and BAFF, as well as chemokines such as CCL2, CXCL10, CCL5, and CXCL12, have emerged as critical components in managing chronic inflammation and joint damage in RA. This comprehensive overview provides insights into the pathophysiology of RA and potential therapeutic avenues, emphasizing the importance of understanding these complex immunological and genetic mechanisms for developing more effective treatment strategies.

The role of lactylation in plasma cells and its impact on rheumatoid arthritis pathogenesis: insights from single-cell RNA sequencing and machine learning.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovitis, systemic inflammation, and autoantibody production. This study aims to explore the role of lactylation in plasma cells and its impact on RA pathogenesis. We utilized single-cell RNA sequencing (scRNA-seq) data and applied bioinformatics and machine learning techniques. A total of 10,163 cells were retained for analysis after quality control. Clustering analysis identified 13 cell clusters, with plasma cells displaying the highest lactylation scores. We performed pathway enrichment analysis to examine metabolic activity, such as oxidative phosphorylation and glycolysis, in highly lactylated plasma cells. Additionally, we employed 134 machine learning algorithms to identify seven core lactylation-promoting genes and constructed a diagnostic model with an average AUC of 0.918. The RA lactylation score (RAlac_score) was significantly elevated in RA patients and positively correlated with immune cell infiltration and immune checkpoint molecule expression. Differential expression analysis between two plasma cell clusters revealed distinct metabolic and immunological profiles, with cluster 2 demonstrating increased immune activity and extracellular matrix interactions. qRT-PCR validation confirmed that NDUFB3, NGLY1, and SLC25A4 are highly expressed in RA. This study highlights the critical role of lactylation in plasma cells for RA pathogenesis and identifies potential biomarkers and therapeutic targets, which may offer insights for future therapeutic strategies.

Sera from Rheumatoid Arthritis Patients Induce Oxidative Stress and Pro-Angiogenic and Profibrotic Phenotypes in Human Endothelial Cells.

Background: Rheumatoid arthritis (RA) is a long-term autoimmune condition marked by persistent inflammation of the joints and various systemic complications, including endothelial dysfunction, atherosclerosis, and pulmonary fibrosis. Oxidative stress is a key contributor to the pathogenesis of RA, potentially exacerbating vascular damage and promoting pro-angiogenic and profibrotic processes. Objective: This study aims to investigate the effects of sera from RA patients on human umbilical vein endothelial cells (HUVECs), focusing on the induction of oxidative stress, endothelial cell proliferation, migration, and collagen type I synthesis. Methods: Twenty-eight serum samples were collected from RA patients and healthy donors (HDs). HUVECs were exposed to these sera, and intracellular reactive oxygen species (ROS) levels were fluorescently detected using H2DCF-DA. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell migration was evaluated through a scratch wound assay, and collagen type I synthesis was measured using a lentiviral vector expressing the green fluorescent protein (GFP) under the control of the human COL1A1 gene promoter. Results: Exposure to RA sera resulted in a significant increase in intracellular ROS levels in HUVECs compared to HD sera, indicating an elevated state of oxidative stress. RA sera also promoted endothelial cell proliferation and migration, suggesting a pro-angiogenic stimulus. Additionally, RA sera significantly increased collagen type I synthesis in HUVECs, implicating a potential role in profibrotic processes associated with RA. Conclusion: The results of this study emphasize the importance of circulating factors in RA sera in promoting oxidative stress, endothelial dysfunction, and pro-angiogenic and profibrotic phenotypes in endothelial cells. These processes may contribute to the vascular and fibrotic complications observed in RA, highlighting the necessity for additional research into focused therapeutic approaches to alleviate these effects.

TLR2 reprograms glucose metabolism in CD4+ T cells of rheumatoid arthritis patients to mediate cell hyperactivation and TNF-α secretion.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which activated CD4+ T cells participate in the disease process by inducing inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) on CD4+ T cells in RA patients, and to elucidate the underlying mechanisms by which TLR2 contributes to the pathogenesis of RA. Serum samples were collected from RA patients and healthy controls. Soluble TLR2 levels were quantified using an enzyme-linked immunosorbent assay (ELISA). Flow cytometry was employed to assess the TLR2 expression level, activation status, cytokine production, reactive oxygen species (ROS) levels, and glucose uptake capacity of CD4+ T cells. Quantitative polymerase chain reaction (qPCR) was used to measure the expression of enzymes associated with glucose and lipid metabolism. The concentration of lactic acid in the culture supernatant was determined using a dedicated detection kit. RA patients had higher levels of TLR2 in their serum, which positively correlated with C-reactive protein and rheumatoid factor. The expression level of TLR2 in CD4+ T cells of RA patients was increased, and TLR2+ cells showed higher activation levels than TLR2- cells. Activation of TLR2 in CD4+ T cells of RA patients promoted their activation, TNF-α secretion, and increased production of ROS. Furthermore, TLR2 activation led to changes in enzymes related to glucose metabolism, causing a shift in glucose metabolism towards the pentose phosphate pathway. Blocking oxidative phosphorylation and the pentose phosphate pathway had varying effects on CD4+ T cell function. TLR2 reprograms the glucose metabolism of CD4+ T cells in RA patients, contributing to the development of RA through ROS-mediated cell hyperactivation and TNF-α secretion. Key Points • TLR2 is upregulated in CD4+ T cells of RA patients and correlates with disease severity markers such as CRP and RF. • Activation of TLR2 in CD4+ T cells promotes cell activation, TNF-α secretion, and increased ROS production, contributing to the pathogenesis of RA. • TLR2 activates glucose metabolism in CD4+ T cells, shifting towards the pentose phosphate pathway, which may be a novel therapeutic target for RA treatment. • Blocking glucose metabolism and ROS production can reduce CD4 + T cell hyperactivation and TNF-α secretion, indicating potential therapeutic strategies for RA management.

The role of non-coding RNAs in fibroblast-like synoviocytes in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by synovial hyperplasia, and fibroblast-like synoviocytes (FLSs) constitute the majority of cells in the synovial tissue, playing a crucial role in the onset of RA. Dysregulation of FLSs function is a critical strategy in treating joint damage associated with RA. Non-coding RNAs, a class of RNA molecules that do not encode proteins, participate in the development of various diseases. This article aims to review the progress in the study of long non-coding RNAs, microRNAs, and circular RNAs in FLSs. Non-coding RNAs are involved in the pathogenesis of RA, directly or indirectly regulating FLSs' proliferation, migration, invasion, apoptosis, and inflammatory responses. Furthermore, non-coding RNAs also influence DNA methylation and osteogenic differentiation in FLSs. Therefore, non-coding RNAs hold promise as biomarkers for diagnosing RA. Targeting non-coding RNAs in FLSs locally represents a potential strategy for future therapies in RA.

Study of the mechanism of fibroblast-like synoviocytes-derived exosomes inducing macrophages M1 polarization and CD8+T cells immune regulation ferroptosis and autophagy in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the joints. The pathogenesis of RA is complex, involving membrane lipid antioxidant systems, oxidative stress, and lipid peroxidation. In this study, it was found that cysteine dioxygenase 1 (CDO1) is significantly upregulated in RA fibroblast-like synoviocytes (RA-FLS) and that exosomes derived from these RA-FLS deliver CDO1 to promote M1 polarization of macrophages, thus facilitating RA progression. In the immune microenvironment, CD8+T cells play a role in immune regulation by producing cytokines such as interferon gamma (IFNγ) in various diseases. The results of this study suggested that in RA-FLS, CD8+T cells deliver IFNγ, which not only inhibits the viability of RA-FLS but also affects glutathione (GSH) through CDO1, regulating the GPX4 antioxidant signaling pathway to promote ferroptosis and autophagy in cells. It was also discovered that IFNγ enhances the expression of TRI69, ubiquitinates and degrades FSP1, thereby forming a cooperative regulation process of GPX4 and FSP1 in ferroptosis. These findings provide a new direction for the treatment of RA.

Physiological and hormonal changes between postmenopausal rheumatoid arthritis and systemic lupus erythematosus in women

It is thought that sex hormones are playing an actual role in the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The purpose of this study was to determine the differences of some hematological, hormonal and immunological parameters between the postmenopausal women with rheumatoid arthritis and systemic lupus erythematosus. This study contained 75 postmenopausal women (52-65 years old). They included 25 women diagnosed with rheumatoid arthritis, 25 diagnosed with systemic lupus erythematosus and 25 normal controls. Blood was collected and used to determine complete blood count (CBC) and erythrocyte sedimentation rate (ESR) tests. Serum was separated and used to determine Follicle-stimulating hormone (FSH), Luteinizing Hormone (LH), Prolactin, cortisol, Estrogen, progesterone, testosterone, rheumatoid factor (RF) and Immunoglobulin E (IgE). The results indicated that both patients’ groups had anemia. However, the RA group had leukocytosis, but the SLE group had leukopenia. Moreover, thrombopenia occurred only in SLE patients. Although the levels of FSH and cortisol were significantly higher, the levels of LH, Estrogen and testosterone had significantly dropped in both patient groups. Interestingly, the level of progesterone was higher in the SLE and lower in the RA group. Moreover, the levels of RF, ESR and IgE were significantly increased in both patients’ groups. In conclusion, there were many differences in hematological and hormonal levels between postmenopausal women with rheumatoid arthritis and systemic lupus erythematosus. Such findings need future work to find out the reasons for these differences and how they could be used in future treatment strategies.