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Frontiers in Immunology 2024Rheumatoid arthritis (RA) is a systemic disease that attacks the joints and causes a heavy economic burden on humans worldwide. T cells regulate RA progression and are...
Integrated analysis of single-cell RNA-seq, bulk RNA-seq, Mendelian randomization, and eQTL reveals T cell-related nomogram model and subtype classification in rheumatoid arthritis.
OBJECTIVE
Rheumatoid arthritis (RA) is a systemic disease that attacks the joints and causes a heavy economic burden on humans worldwide. T cells regulate RA progression and are considered crucial targets for therapy. Therefore, we aimed to integrate multiple datasets to explore the mechanisms of RA. Moreover, we established a T cell-related diagnostic model to provide a new method for RA immunotherapy.
METHODS
scRNA-seq and bulk-seq datasets for RA were obtained from the Gene Expression Omnibus (GEO) database. Various methods were used to analyze and characterize the T cell heterogeneity of RA. Using Mendelian randomization (MR) and expression quantitative trait loci (eQTL), we screened for potential pathogenic T cell marker genes in RA. Subsequently, we selected an optimal machine learning approach by comparing the nine types of machine learning in predicting RA to identify T cell-related diagnostic features to construct a nomogram model. Patients with RA were divided into different T cell-related clusters using the consensus clustering method. Finally, we performed immune cell infiltration and clinical correlation analyses of T cell-related diagnostic features.
RESULTS
By analyzing the scRNA-seq dataset, we obtained 10,211 cells that were annotated into 7 different subtypes based on specific marker genes. By integrating the eQTL from blood and RA GWAS, combined with XGB machine learning, we identified a total of 8 T cell-related diagnostic features (MIER1, PPP1CB, ICOS, GADD45A, CD3D, SLFN5, PIP4K2A, and IL6ST). Consensus clustering analysis showed that RA could be classified into two different T-cell patterns (Cluster 1 and Cluster 2), with Cluster 2 having a higher T-cell score than Cluster 1. The two clusters involved different pathways and had different immune cell infiltration states. There was no difference in age or sex between the two different T cell patterns. In addition, ICOS and IL6ST were negatively correlated with age in RA patients.
CONCLUSION
Our findings elucidate the heterogeneity of T cells in RA and the communication role of these cells in an RA immune microenvironment. The construction of T cell-related diagnostic models provides a resource for guiding RA immunotherapeutic strategies.
Topics: Humans; Arthritis, Rheumatoid; Quantitative Trait Loci; Single-Cell Analysis; RNA-Seq; Mendelian Randomization Analysis; Nomograms; Machine Learning; T-Lymphocytes; Gene Expression Profiling; Single-Cell Gene Expression Analysis
PubMed: 38962008
DOI: 10.3389/fimmu.2024.1399856 -
Journal of Medical Virology Jul 2024Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a serious and common extra-articular disease manifestation. Patients with RA-ILD experience reduced...
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a serious and common extra-articular disease manifestation. Patients with RA-ILD experience reduced bacterial diversity and gut bacteriome alterations. However, the gut mycobiome and virome in these patients have been largely neglected. In this study, we performed whole-metagenome shotgun sequencing on fecal samples from 30 patients with RA-ILD, and 30 with RA-non-ILD, and 40 matched healthy controls. The gut bacteriome and mycobiome were explored using a reference-based approach, while the gut virome was profiled based on a nonredundant viral operational taxonomic unit (vOTU) catalog. The results revealed significant alterations in the gut microbiomes of both RA-ILD and RA-non-ILD groups compared with healthy controls. These alterations encompassed changes in the relative abundances of 351 bacterial species, 65 fungal species, and 4,367 vOTUs. Bacteria such as Bifidobacterium longum, Dorea formicigenerans, and Collinsella aerofaciens were enriched in both patient groups. Ruminococcus gnavus (RA-ILD), Gemmiger formicilis, and Ruminococcus bromii (RA-non-ILD) were uniquely enriched. Conversely, Faecalibacterium prausnitzii, Bacteroides spp., and Roseburia inulinivorans showed depletion in both patient groups. Mycobiome analysis revealed depletion of certain fungi, including Saccharomyces cerevisiae and Candida albicans, in patients with RA compared with healthy subjects. Notably, gut virome alterations were characterized by an increase in Siphoviridae and a decrease in Myoviridae, Microviridae, and Autographiviridae in both patient groups. Hence, multikingdom gut microbial signatures showed promise as diagnostic indicators for both RA-ILD and RA-non-ILD. Overall, this study provides comprehensive insights into the fecal virome, bacteriome, and mycobiome landscapes of RA-ILD and RA-non-ILD gut microbiota, thereby offering potential biomarkers for further mechanistic and clinical research.
Topics: Humans; Gastrointestinal Microbiome; Lung Diseases, Interstitial; Arthritis, Rheumatoid; Feces; Female; Male; Middle Aged; Bacteria; Aged; Virome; Mycobiome; Adult; Viruses; Fungi
PubMed: 38961767
DOI: 10.1002/jmv.29781 -
Arthritis & Rheumatology (Hoboken, N.J.) Jul 2024Notch ligands and receptors, including JAG1/2, DLL1/4, and Notch1/3, are enriched on macrophages (MΦs), fibroblast-like synoviocytes (FLS), and/or endothelial cells in... (Review)
Review
Notch ligands and receptors, including JAG1/2, DLL1/4, and Notch1/3, are enriched on macrophages (MΦs), fibroblast-like synoviocytes (FLS), and/or endothelial cells in rheumatoid arthritis (RA) compared to normal synovial tissues (ST). Power Doppler ultrasound-guided ST studies reveal that the Notch family is highly involved in early active RA, especially during neovascularization. In contrast, the Notch family is not implicated during the erosive stage, evidenced by their lack of correlation with radiographic damage in RA STs. TLRs and TNF are the common inducers of Notch expression in RA MΦs, FLS, and endothelial cells. Among Notch ligands, JAG1 and/or DLL4 are most inducible by inflammatory responses in RA MΦs or endothelial cells and trans-activate their receptors on RA FLS. TNF plays a central role on Notch ligands, as anti-TNF good responders display JAG1/2 and DLL1/4 transcriptional downregulation in RA ST myeloid cells. In in vitro studies, TNF increases Notch3 expression in MΦs, which is further amplified by RA FLS addition. Specific disease-modifying anti-rheumatic drugs (DMARDs) reduced JAG1 and Notch3 expression in MΦ and RA FLS cocultures. Organoids containing FLS and endothelial cells have increased expression of JAG1 and Notch3. Nonetheless, Methotrexate, IL-6R antibodies, and B cell blockers are mostly ineffective at decreasing Notch family expression. NF-κB, MAPK, and AKT pathways are involved in Notch signaling, whereas JAK/STATs are not. Although Notch blockade has been effective in RA preclinical studies, its small molecule inhibitors have failed in phase I and II studies, suggesting that alternative strategies may be required to intercept their function.
PubMed: 38961731
DOI: 10.1002/art.42937 -
Journal of Cellular and Molecular... Jul 2024There is a close relationship between immune-mediated inflammation and cancer, and there is still controversy over whether rheumatoid arthritis (RA) increases the risk... (Meta-Analysis)
Meta-Analysis
There is a close relationship between immune-mediated inflammation and cancer, and there is still controversy over whether rheumatoid arthritis (RA) increases the risk of malignancy. We first used Mendelian randomization (MR) analysis to explore the potential causal relationship between RA and pan-cancer. And verify the effect of immune-mediated inflammation on cancer through intermediate MR analysis. Then we extracted the standardized incidence rate of malignancy in RA patients relative to the general population through large-scale meta-analysis. Finally, we performed pan-cancer analysis on the RA related genes obtained from MR analysis. And perform immune related analysis on key genes to reveal the association between RA and malignancy. The MR analysis demonstrated a negative correlation between RA and pan-cancer (p = 0.008). Autoimmune traits were the main mediating variable for the causal relationship between RA and pan-cancer. Based on the results of the meta-analysis, we validated that RA reduces the risk of developing colorectal cancer (SIR = 0.69, 95% CI 0.53-0.85). Pan-cancer analysis also showed that high expression of RA related genes was negatively correlated with colon adenocarcinoma. IL6R was the gene with the highest correlation among them, and its correlation with immune cells was higher in colorectal cancer than in other malignancy. Our MR study provides evidence that RA was associated with reduced risk of colorectal cancer. This effect is caused by immune-mediated inflammation, with IL6R being a key regulatory gene.
Topics: Humans; Arthritis, Rheumatoid; Colorectal Neoplasms; Inflammation; Mendelian Randomization Analysis; Risk Factors; Genetic Predisposition to Disease; Receptors, Interleukin-6
PubMed: 38961677
DOI: 10.1111/jcmm.18515 -
Human Vaccines & Immunotherapeutics Dec 2024The present study aimed at investigating whether the hydroxychloroquine (HCQ) treatment would impact the neutralizing antibody production, viremia levels and the...
The present study aimed at investigating whether the hydroxychloroquine (HCQ) treatment would impact the neutralizing antibody production, viremia levels and the kinetics of serum soluble mediators upon planned 17DD-Yellow Fever (YF) primovaccination (Bio-Manguinhos-FIOCRUZ) of primary Sjögren's syndrome (pSS). A total of 34 pSS patients and 23 healthy controls (HC) were enrolled. The pSS group was further categorized according to the use of HCQ (HCQ and Non-HCQ). The YF-plaque reduction neutralization test (PRNT ≥1:50), YF viremia (RNAnemia) and serum biomarkers analyses were performed at baseline and subsequent time-points (Day0/Day3-4/Day5-6/Day7/Day14-D28). The pSS group showed PRNT titers and seropositivity rates similar to those observed for HC (GeoMean = 238 440, = .11; 82% 96%, = .13). However, the HCQ subgroup exhibited lower seroconversion rates as compared to HC (GeoMean = 161 440, = .04; 69% 96%, = .02) and Non-HQC (GeoMean = 161 337, = .582; 69% 94%, = .049). No differences in YF viremia were observed amongst subgroups. Serum biomarkers analyses demonstrated that HCQ subgroup exhibited increased levels of CCL2, CXL10, IL-6, IFN-γ, IL1-Ra, IL-9, IL-10, and IL-2 at baseline and displayed a consistent increase of several biomarkers along the kinetics timeline up to D14-28. These results indicated that HCQ subgroup exhibited a deficiency in assembling YF-specific immune response elicited by 17DD-YF primovaccination as compared to Non-HCQ subgroup. Our findings suggested that hydroxychloroquine is associated with a decrease in the humoral immune response after 17DD-YF primovaccination.
Topics: Humans; Hydroxychloroquine; Sjogren's Syndrome; Female; Middle Aged; Male; Seroconversion; Adult; Yellow Fever; Antibodies, Viral; Antibodies, Neutralizing; Yellow Fever Vaccine; Aged; Viremia; Yellow fever virus; Cytokines; Biomarkers
PubMed: 38961639
DOI: 10.1080/21645515.2024.2318814 -
Journal of Cannabis Research Jul 2024The belief that cannabis has analgesic and anti-inflammatory properties continues to attract patients with chronic musculoskeletal (MSK) pain towards its use. However,...
BACKGROUND
The belief that cannabis has analgesic and anti-inflammatory properties continues to attract patients with chronic musculoskeletal (MSK) pain towards its use. However, the role that cannabis will play in the management of chronic MSK pain remains to be determined. This study examined 1) the rate, patterns of use, and self-reported efficacy of cannabis use among patients with chronic MSK pain and 2) the interest and potential barriers to cannabis use among patients with chronic MSK pain not currently using cannabis.
METHODS
Self-reported cannabis use and perceived efficacy were prospectively collected from chronic MSK pain patients presenting to the Orthopaedic Clinic at the University Health Network, Toronto, Canada. The primary dependent variable was current or past use of cannabis to manage chronic MSK pain; bivariate and multivariable logistic regression were used to identify patient characteristics independently associated with this outcome. Secondary outcomes were summarized descriptively, including self-perceived efficacy among cannabis users, and interest as well as barriers to cannabis use among cannabis non-users.
RESULTS
The sample included 629 patients presenting with chronic MSK pain (mean age: 56±15.7 years; 56% female). Overall, 144 (23%) reported past or present cannabis use to manage their MSK pain, with 63.7% perceiving cannabis as very or somewhat effective and 26.6% considering it as slightly effective. The strongest predictor of cannabis use in this study population was a history of recreational cannabis use (OR 12.7, p<0.001). Among cannabis non-users (N=489), 65% expressed interest in using cannabis to manage their chronic MSK pain, but common barriers to use included lack of knowledge regarding access, use and evidence, and stigma.
CONCLUSIONS
One in five patients presenting to an orthopaedic surgeon with chronic MSK pain are using or have used cannabis with the specific intent to manage their pain, and most report it to be effective. Among non-users, two-thirds reported an interest in using cannabis to manage their MSK pain, but common barriers to use existed. Future double-blind placebo-controlled trials are required to understand if this reported efficacy is accurate, and what role, if any, cannabis may play in the management of chronic MSK pain.
PubMed: 38961506
DOI: 10.1186/s42238-024-00231-1 -
Arthritis Research & Therapy Jul 2024Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) with poor treatment outcomes. The role and underlying mechanisms of ferroptosis in LN...
BACKGROUND
Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) with poor treatment outcomes. The role and underlying mechanisms of ferroptosis in LN remain largely unknown. We aimed to explore ferroptosis-related molecular subtypes and assess their prognostic value in LN patients.
METHODS
Molecular subtypes were classified on the basis of differentially expressed ferroptosis-related genes (FRGs) via the Consensus ClusterPlus package. The enriched functions and pathways, immune infiltrating levels, immune scores, and immune checkpoints were compared between the subgroups. A scoring algorithm based on the subtype-specific feature genes identified by artificial neural network machine learning, referred to as the NeuraLN, was established, and its immunological features, clinical value, and predictive value were evaluated in patients with LN. Finally, immunohistochemical analysis was performed to validate the expression and role of feature genes in glomerular tissues from LN patients and controls.
RESULTS
A total of 10 differentially expressed FRGs were identified, most of which showed significant correlation. Based on the 10 FRGs, LN patients were classified into two ferroptosis subtypes, which exhibited significant differences in immune cell abundances, immune scores, and immune checkpoint expression. A NeuraLN-related protective model was established based on nine subtype-specific genes, and it exhibited a robustly predictive value in LN. The nomogram and calibration curves demonstrated the clinical benefits of the protective model. The high-NeuraLN group was closely associated with immune activation. Clinical specimens demonstrated the alterations of ALB, BHMT, GAMT, GSTA1, and HAO2 were in accordance with bioinformatics analysis results, GSTA1 and BHMT were negatively correlated with the severity of LN.
CONCLUSION
The classification of ferroptosis subtypes and the establishment of a protective model may form a foundation for the personalized treatment of LN patients.
Topics: Humans; Ferroptosis; Lupus Nephritis; Neural Networks, Computer; Female; Male; Adult; Machine Learning; Prognosis; Middle Aged
PubMed: 38961491
DOI: 10.1186/s13075-024-03356-z -
BMC Musculoskeletal Disorders Jul 2024Decreased strength and increased stiffness of the quadriceps have been associated with a higher risk of developing knee osteoarthritis (OA) in elders. Dynamic joint...
Associations amongst dynamic knee stiffness during gait, quadriceps stiffness, and the incidence of knee osteoarthritis over 24 months: a cohort study with a mediation analysis.
BACKGROUND
Decreased strength and increased stiffness of the quadriceps have been associated with a higher risk of developing knee osteoarthritis (OA) in elders. Dynamic joint stiffness (DJS) represents collective resistance from active and passive knee structures for dynamic knee motions. Elevated sagittal knee DJS has been associated with worsening of cartilage loss in knee OA patients. Altered quadriceps properties may affect DJS, which could be a mediator for associations between quadriceps properties and knee OA. Hence, this study aimed to examine whether DJS and quadriceps properties would be associated with the development of clinical knee OA over 24 months, and to explore the mediation role of DJS in associations between quadriceps properties and knee OA.
METHODS
This was a prospective cohort study with 162 healthy community-dwelling elders. Gait analysis was conducted to compute DJS during the loading response phase. Quadriceps strength and stiffness were evaluated using a Cybex dynamometer and shear-wave ultrasound elastography, respectively. Knee OA was defined based on clinical criteria 24 months later. Logistic regression with generalized estimating equations was used to examine the association between quadriceps properties and DJS and incident knee OA. Mediation analysis was performed to explore the mediation role of DJS in associations between quadriceps properties and the incidence of knee OA.
RESULTS
A total of 125 participants (65.6 ± 4.0 years, 58.4% females) completed the 24-month follow-up, with 36 out of 250 knees identified as clinical knee OA. Higher DJS (OR = 1.86, 95%CI: 1.33-2.62), lower quadriceps strength (1.85, 1.05-3.23), and greater quadriceps stiffness (1.56, 1.10-2.21) were significantly associated with a higher risk of clinical knee OA. Mediation analysis showed that the DJS was not a significant mediator for the associations between quadriceps properties and knee OA.
CONCLUSIONS
Higher sagittal knee dynamic joint stiffness, lower quadriceps strength, and greater quadriceps stiffness are potential risk factors for developing clinical knee OA in asymptomatic elders. Associations between quadriceps properties and knee OA may not be mediated by dynamic joint stiffness. Interventions for reducing increased passive properties of the quadriceps and knee joint stiffness may be beneficial for maintaining healthy knees in the aging population.
Topics: Humans; Osteoarthritis, Knee; Female; Male; Quadriceps Muscle; Aged; Prospective Studies; Incidence; Gait; Muscle Strength; Mediation Analysis; Knee Joint; Middle Aged; Cohort Studies; Elasticity Imaging Techniques
PubMed: 38961407
DOI: 10.1186/s12891-024-07618-4 -
Scientific Reports Jul 2024Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical...
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. In a longitudinal study, disability status and associated clinical features in 58 MS patients were tracked over 4.2 ± 0.98 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 41 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia, Lachnospiraceae, and Oscillospiraceae, with an expansion of Alloprevotella, Prevotella-9, and Rhodospirillales. Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K production (linked to Akkermansia), and a depletion in SCFA metabolism (linked to Oscillospiraceae). Further, as a proof of principle, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. These results demonstrate a proof of principle for the utility of the gut microbiome for predicting disease progression in MS in a small well-defined cohort. Further, analysis of the inferred metagenome suggested that oxidative stress, vitamin K, and SCFAs are associated with progression, warranting future functional validation and mechanistic study.
Topics: Humans; Gastrointestinal Microbiome; Multiple Sclerosis; Disease Progression; Male; Female; Adult; Longitudinal Studies; Feces; Middle Aged; Severity of Illness Index; RNA, Ribosomal, 16S
PubMed: 38961134
DOI: 10.1038/s41598-024-64369-x -
Communications Biology Jul 2024Oral administration of harmless antigens can induce suppression of reactive immune responses, a process that capitalises on the ability of the gastrointestinal tract to...
Oral administration of harmless antigens can induce suppression of reactive immune responses, a process that capitalises on the ability of the gastrointestinal tract to tolerate exposure to food and commensal microbiome without triggering inflammatory responses. Repeating exposure to type II collagen induces oral tolerance and inhibits induction of arthritis, a chronic inflammatory joint condition. Although some mechanisms underlying oral tolerance are described, how dysregulation of gut immune networks impacts on inflammation of distant tissues like the joints is unclear. We used undenatured type II collagen in a prophylactic regime -7.33 mg/kg three times/week- to describe the mechanisms associated with protective oral immune-therapy (OIT) in gut and joint during experimental Collagen-Induced Arthritis (CIA). OIT reduced disease incidence to 50%, with reduced expression of IL-17 and IL-22 in the joints of asymptomatic mice. Moreover, whilst the gut tissue of arthritic mice shows substantial damage and activation of tissue-specific immune networks, oral administration of undenatured type II collagen protects against gut pathology in all mice, symptomatic and asymptomatic, rewiring IL-17/IL-22 networks. Furthermore, gut fucosylation and microbiome composition were also modulated. These results corroborate the relevance of the gut-joint axis in arthritis, showing novel regulatory mechanisms linked to therapeutic OIT in joint disease.
Topics: Animals; Arthritis, Experimental; Collagen Type II; Mice; Gastrointestinal Microbiome; Homeostasis; Male; Joints; Mice, Inbred DBA; Interleukin-17; Interleukin-22; Administration, Oral
PubMed: 38961129
DOI: 10.1038/s42003-024-06476-z