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Frontiers in Immunology 2024Ankylosing spondylitis (AS) is an autoimmune disease that affects millions of individuals. Immune cells have been recognized as having a crucial role in the pathogenesis...
BACKGROUND
Ankylosing spondylitis (AS) is an autoimmune disease that affects millions of individuals. Immune cells have been recognized as having a crucial role in the pathogenesis of AS. However, their relationship has not been fully explored.
METHODS
We chose to employ Mendelian randomization (MR) to investigate the potential correlation between immune cells and AS. We sourced the data on immune cells from the latest genome-wide association studies (GWASs). We obtained data on AS from the FinnGen consortium. Our comprehensive univariable MR analysis covered 731 immune cells to explore its potential causal relationship with AS. The primary analysis method was inverse-variance weighted (IVW). Additionally, we used Cochran's Q test and the MR-Egger intercept test to assess the presence of pleiotropy and heterogeneity. We examined whether our results could be influenced by individual single-nucleotide polymorphisms (SNPs) using the leave-one-out test. We conducted a bidirectional MR to investigate the reverse relationship. We also applied multivariable MR to decrease the potential influence between the immune cells.
RESULTS
Overall, our univariable MR analysis revealed eight immune cells associated with AS. Among these, four immune cells contributed to an increased risk of AS, while four immune cells were identified as protective factors for AS. However, the Bonferroni test confirmed only one risk factor and one protective factor with a significance level of p < 6.84E-05. CD8 on effector memory CD8 T cell could increase the risk of AS (p: 1.2302E-05, OR: 2.9871, 95%CI: 1.8289-4.8786). HLA DR on CD33 HLA DR CD11b could decrease the risk of AS (p: 1.2301E-06, OR: 0.5446, 95%CI: 0.4260-0.6962). We also identified a bidirectional relationship between CD4 on CD39 activated CD4 regulatory T cells and AS utilizing the bidirectional MR. To address potential confounding among immune cells, we employed multivariable MR analysis, which revealed that only one immune cell had an independent effect on AS. HLA DR on CD33 HLA DR CD11b could decrease the risk of AS (p: 2.113E-06, OR: 0.0.5423, 95%CI: 0.4210-0.6983). Our findings were consistently stable and reliable.
CONCLUSIONS
Our findings indicated a potential link between immune cells and AS, which could provide a new idea for future research. Nevertheless, the specific underlying mechanisms require further exploration.
Topics: Spondylitis, Ankylosing; Humans; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Genome-Wide Association Study; Genetic Predisposition to Disease
PubMed: 38655262
DOI: 10.3389/fimmu.2024.1345416 -
Frontiers in Immunology 2021Genome-wide association studies (GWAS) have identified 113 single nucleotide polymorphisms (SNPs) affecting the risk of developing ankylosing spondylitis (AS), and an... (Review)
Review
Genome-wide association studies (GWAS) have identified 113 single nucleotide polymorphisms (SNPs) affecting the risk of developing ankylosing spondylitis (AS), and an on-going GWAS study will likely identify 100+ new risk loci. The translation of genetic findings to novel disease biology and treatments has been difficult due to the following challenges: (1) difficulties in determining the causal genes regulated by disease-associated SNPs, (2) difficulties in determining the relevant cell-type(s) that causal genes exhibit their function(s), (3) difficulties in determining appropriate cellular contexts to interrogate the functional role of causal genes in disease biology. This review will discuss recent progress and unanswered questions with a focus on these challenges. Additionally, we will review the investigation of biology and the development of drugs related to the IL-23/IL-17 pathway, which has been partially driven by the AS genetics, and discuss what can be learned from these studies for the future functional and translational study of AS-associated genes.
Topics: Animals; Anti-Inflammatory Agents; Drug Discovery; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Interleukin-17; Interleukin-23; Molecular Targeted Therapy; Phenotype; Polymorphism, Single Nucleotide; Signal Transduction; Spondylitis, Ankylosing
PubMed: 33679768
DOI: 10.3389/fimmu.2021.624632 -
BMC Musculoskeletal Disorders May 2023The aim of this study was to search for key genes in ankylosing spondylitis (AS) through comprehensive bioinformatics analysis, thus providing some theoretical support...
OBJECTIVE
The aim of this study was to search for key genes in ankylosing spondylitis (AS) through comprehensive bioinformatics analysis, thus providing some theoretical support for future diagnosis and treatment of AS and further research.
METHODS
Gene expression profiles were collected from Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/ ) by searching for the term "ankylosing spondylitis". Ultimately, two microarray datasets (GSE73754 and GSE11886) were downloaded from the GEO database. A bioinformatic approach was used to screen differentially expressed genes and perform functional enrichment analysis to obtain biological functions and signalling pathways associated with the disease. Weighted correlation network analysis (WGCNA) was used to further obtain key genes. Immune infiltration analysis was performed using the CIBERSORT algorithm to conduct a correlation analysis of key genes with immune cells. The GWAS data of AS were analysed to identify the pathogenic regions of key genes in AS. Finally, potential therapeutic agents for AS were predicted using these key genes.
RESULTS
A total of 7 potential biomarkers were identified: DYSF, BASP1, PYGL, SPI1, C5AR1, ANPEP and SORL1. ROC curves showed good prediction for each gene. T cell, CD4 naïve cell, and neutrophil levels were significantly higher in the disease group than in the paired normal group, and key gene expression was strongly correlated with immune cells. CMap results showed that the expression profiles of ibuprofen, forskolin, bongkrek-acid, and cimaterol showed the most significant negative correlation with the expression profiles of disease perturbations, suggesting that these drugs may play a role in AS treatment.
CONCLUSION
The potential biomarkers of AS screened in this study are closely related to the level of immune cell infiltration and play an important role in the immune microenvironment. This may provide help in the clinical diagnosis and treatment of AS and provide new ideas for further research.
Topics: Humans; Spondylitis, Ankylosing; Ibuprofen; Algorithms; Biomarkers; Computational Biology; LDL-Receptor Related Proteins; Membrane Transport Proteins
PubMed: 37226132
DOI: 10.1186/s12891-023-06550-3 -
Anaesthesia May 2009Ankylosing spondylitis can present significant challenges to the anaesthetist as a consequence of the potential difficult airway, cardiovascular and respiratory... (Review)
Review
Ankylosing spondylitis can present significant challenges to the anaesthetist as a consequence of the potential difficult airway, cardiovascular and respiratory complications, and the medications used to reduce pain and control the disease. There is also an increased risk of neurological complications in the peri-operative period. Awake fibreoptic intubation is the safest option in those patients with a potentially difficult airway as it allows continuous neurological monitoring while achieving a definitive airway. Neurophysiological monitoring (somatosensory and motor evoked potentials) should be considered in patients undergoing surgery for cervical spine deformity. The medical management of the disease has improved with the use of anti-tumour necrosis factor-alpha agents. There is potential for increased wound infection in patients taking these drugs. This article reviews the anaesthetic issues in patients with ankylosing spondylitis. The challenge to the anaesthetist is in the understanding of these issues so that appropriate management can be planned and undertaken.
Topics: Adult; Anesthesia; Antirheumatic Agents; Female; Humans; Intubation, Intratracheal; Male; Spondylitis, Ankylosing; Tumor Necrosis Factor-alpha; Young Adult
PubMed: 19413825
DOI: 10.1111/j.1365-2044.2008.05794.x -
Current Opinion in Rheumatology Jul 2013To review the optimal criteria and conditions for establishing a clinical registry, as well as detailing their application in a number of ankylosing spondylitis (AS) and... (Review)
Review
PURPOSE OF REVIEW
To review the optimal criteria and conditions for establishing a clinical registry, as well as detailing their application in a number of ankylosing spondylitis (AS) and axial spondyloarthritis (axSpA) Registries already in existence.
RECENT FINDINGS
Recent genetic studies and studies of long-term treatment efficacy and side-effects have underscored the need for large numbers of patients, much larger than would be possible from a single center or consortium. An optimal Registry should have its aims established upfront, with appropriate governance and oversight, and inclusion and exclusion criteria for participating collaborators and subject defined. Collaborators contributing subjects to a Registry should use validated instruments for which they have been previously trained. The numerous cross-sectional and longitudinal Registries on AS and axSpA have been recently established that differ widely depending on the referral and selection issues.
SUMMARY
The challenge of large-scale examinations of genetics, comorbidities, medication usage, and side-effects in spondyloarthritis underscores the need for combining data from well characterized registries of AS patients which require careful planning. There are currently many such registries available internationally, offering promise for collaborations and data pooling that can answer some of the pressing questions facing rheumatology clinicians and researchers.
Topics: Humans; International Cooperation; Prevalence; Registries; Spondylitis, Ankylosing; Treatment Outcome
PubMed: 23656716
DOI: 10.1097/BOR.0b013e3283620e1d -
Current Opinion in Rheumatology Sep 2010To summarize recent advances in the classification of preradiographic axial spondyloarthritis (SpA). (Review)
Review
PURPOSE OF REVIEW
To summarize recent advances in the classification of preradiographic axial spondyloarthritis (SpA).
RECENT FINDINGS
Inflammation in the sacroiliac joints precedes radiographic damage that is necessary to establish a diagnosis of ankylosing spondylitis (AS). Preradiographic axial SpA refers to patients with SpA who exhibit signs and symptoms of axial involvement, but lack criteria for AS. Patients with axial SpA can have remarkably similar clinical features and disease activity as those with early AS. MRI is a sensitive method for detecting sacroiliac joint inflammation, which is useful in predicting the development of AS. Whole-body MRI has emerged as a means to visualize additional areas of involvement. However, it may be less sensitive than conventional MRI, and thus its added value will need to be further assessed. The incorporation of MRI evaluation of the sacroiliac joints and HLA-B27 testing into criteria for identifying individuals with preradiographic axial disease has led to the development of criteria for classifying axial SpA.
SUMMARY
The development of classification criteria for axial SpA will aid in the identification of patients suitable for clinical trials testing whether early intervention will slow the development and/or progression of structural changes in that lead to AS.
Topics: Diagnosis, Differential; Disease Progression; Early Diagnosis; Humans; Radiography; Spondylitis, Ankylosing
PubMed: 20592602
DOI: 10.1097/BOR.0b013e32833c7255 -
Scientific Reports Sep 2023Methazolamide is a carbonic anhydrase (CA) inhibitor with satisfactory safety. Our previous studies have demonstrated the elevation of CA1 expression and the therapeutic...
Methazolamide is a carbonic anhydrase (CA) inhibitor with satisfactory safety. Our previous studies have demonstrated the elevation of CA1 expression and the therapeutic effect of Methazolamide in Ankylosing spondylitis (AS). In this study, we explored the pathogenic role of CA1 and the pharmacological mechanism of Methazolamide in AS through Gene Set Enrichment Analysis (GSEA) and network pharmacology. Seven out of twelve CA1 related gene sets were enriched in AS group. CA1 was core enriched in above seven gene sets involving zinc ion binding, arylesterase activity and one carbon metabolic process. Functional analysis of the candidate target genes obtained from the intersection of AS associated genes and Methazolamide target genes indicated that Methazolamide exerts therapeutic effects on AS mainly through inflammatory pathways which regulate the production of tumor necrosis factor, IL-6 and nitric oxide. PTGS2, ESR1, GSK3β, JAK2, NOS2 and CA1 were selected as therapeutic targets of Methazolamide in AS. Molecular docking and molecular dynamics simulations were performed successfully. In addition, we innovatively obtained the intersection of Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and GSEA results, and found that 18 GO terms and 5 KEGG terms were indicated in the pharmacological mechanism of Methazolamide in AS, involving bone mineralization, angiogenesis, inflammation, and chemokine signaling pathways. Nevertheless, validation for these mechanisms is needed in vivo/vitro experiments.
Topics: Humans; Methazolamide; Spondylitis, Ankylosing; Network Pharmacology; Molecular Docking Simulation; Carbonic Anhydrase Inhibitors
PubMed: 37717047
DOI: 10.1038/s41598-023-42721-x -
Frontiers in Immunology 2021Ankylosing spondylitis (AS) is a type of spondyloarthropathies, the diagnosis of which is often delayed. The lack of early diagnosis tools often delays the institution...
Ankylosing spondylitis (AS) is a type of spondyloarthropathies, the diagnosis of which is often delayed. The lack of early diagnosis tools often delays the institution of appropriate therapy. This study aimed to investigate the systemic metabolic shifts associated with AS and TNF inhibitors treatment. Additionally, we aimed to define reliable serum biomarkers for the diagnosis. We employed an untargeted technique, ultra-performance liquid chromatography-mass spectroscopy (LC-MS), to analyze the serum metabolome of 32 AS individuals before and after 24-week TNF inhibitors treatment, as well as 40 health controls (HCs). Multivariate and univariate statistical analyses were used to profile the differential metabolites associated with AS and TNF inhibitors. A diagnostic panel was established with the least absolute shrinkage and selection operator (LASSO). The pathway analysis was also conducted. A total of 55 significantly differential metabolites were detected. We generated a diagnostic panel comprising five metabolites (L-glutamate, arachidonic acid, L-phenylalanine, PC (18:1(9Z)/18:1(9Z)), 1-palmitoylglycerol), capable of distinguishing HCs from AS with a high AUC of 0.998, (95%CI: 0.992-1.000). TNF inhibitors treatment could restore the equilibrium of 21 metabolites. The most involved pathways in AS were amino acid biosynthesis, glycolysis, glutaminolysis, fatty acids biosynthesis and choline metabolism. This study characterized the serum metabolomics signatures of AS and TNF inhibitor therapy. We developed a five-metabolites-based panel serving as a diagnostic tool to separate patients from HCs. This serum metabolomics study yielded new knowledge about the AS pathogenesis and the systemic effects of TNF inhibitors.
Topics: Adult; Female; Humans; Male; Metabolomics; Spondylitis, Ankylosing; Tumor Necrosis Factor Inhibitors; Young Adult
PubMed: 33679777
DOI: 10.3389/fimmu.2021.630791 -
Immunity, Inflammation and Disease Aug 2022Osteoporosis is related to lncRNA-neighboring enhancer of FOXA2 (NEF) and inversely correlated to ankylosing spondylitis (AS), implying that lncRNA-NEF might also relate...
INTRODUCTION
Osteoporosis is related to lncRNA-neighboring enhancer of FOXA2 (NEF) and inversely correlated to ankylosing spondylitis (AS), implying that lncRNA-NEF might also relate to AS. Thus, the study was carried out to investigate the involvement of lncRNA-NEF in AS.
METHODS
The study included 60 AS patients and 60 healthy controls. LncRNA-NEF expression in synovial fluid samples was analyzed by reverse transcription quantitative real-time polymerase chain reaction. Disease activity of the 60 AS patients was determined using the Ankylosing Spondylitis Disease Activity Score (ASDAS) 1-4 and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Western blot was carried out to investigate the effects of lncRNA-NEF on inflammatory factors in human fibroblast-like synovial (HFLS) cells. A 3-year follow-up was performed to analyze the role of lncRNA-NEF in the prediction of the recurrence of AS.
RESULTS
Our study observed that lncRNA-NEF expression was upregulated in synovial fluid of AS patients and significantly correlated with the ASDAS 1-4, BASDAI, erythrocyte sedimentation rate (ESR), and C-reactive protein level (p < .05). Treatment with nonsteroidal anti-inflammatory drugs significantly downregulated lncRNA-NEF expression (p < .01). A 3-year follow-up showed that patients with high lncRNA-NEF levels had a high recurrence rate (hazard ratio = 2.266). In addition, lncRNA-NEF was found to regulate the expression of inflammatory factors in HFLS cells.
CONCLUSIONS
Therefore, lncRNA-NEF upregulation can predict recurrence and poor treatment outcomes of AS and has a great potential to serve as a predictive biomarker factor for the recurrent AS.
Topics: Blood Sedimentation; Humans; RNA, Long Noncoding; Severity of Illness Index; Spondylitis, Ankylosing; Treatment Outcome; nef Gene Products, Human Immunodeficiency Virus
PubMed: 35894706
DOI: 10.1002/iid3.627 -
Expert Review of Clinical Immunology Feb 2019Secukinumab, an interleukin-17A (IL-17A) antagonist, is the first non-TNF alpha inhibitor agent licensed for ankylosing spondylitis (AS), which opens up a new era of... (Review)
Review
Secukinumab, an interleukin-17A (IL-17A) antagonist, is the first non-TNF alpha inhibitor agent licensed for ankylosing spondylitis (AS), which opens up a new era of alternative cytokine targets beyond TNF. Areas covered: This review explores the pathophysiology and scientific evidence behind the use of this new mode of action and discusses the basis for its efficacy and clinical utility in the management of AS. In particular, how the emergent data points towards the efficacy of secukinumab and ixekizumab, a second emergent IL-17A blocker, in AS has helped focus research into the IL-23/17 axis in entheseal driven disease in man and how IL-17A inhibition may be linked to the presence of innate and adaptive immune cell populations capable of IL-17A elaboration in these target tissues. Expert commentary: Collectively these emergent data point towards an efficacious role of IL-17A inhibition strategies targeting AS pathogenesis in a fundamental way whilst carrying a good safety profile.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Humans; Interleukin-17; Interleukin-23; Spondylitis, Ankylosing
PubMed: 30576610
DOI: 10.1080/1744666X.2019.1561281