Diverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). We set out to ...(1) further define the key microbial characteristics driving disease, and (2) examine the effects of tumour necrosis factor-inhibitor (TNFi) therapy upon the microbiome.
The stools from a case-control cohort of 250 Han-Chinese subjects underwent shotgun metagenomic sequencing. All subjects were genotyped using the Illumina CoreExome SNP microarray.
Previous reports of gut dysbiosis in AS were reconfirmed and several notable bacterial species and functional categories were differentially abundant. TNFi therapy was correlated with a restoration the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of patients with AS, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy largely restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. TNFi therapy of patients with AS was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients.
These findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS and highlight potential therapeutic and/or preventative targets.
2 Then, a follow-up study by Xu et al further identified a strong association between AS and Stat3,3 a transcription factor critical for Th17 cell development, acting downstream of IL-6 and IL-23. An ...single nucleotide polymorphism in the gene RUNX3 was found to affect the microbiome in AS patients, indicating the impact of a non-HLA-B27 host genetic variation on AS through the gut. Identifying the pathways for gene–environment, intra- and inter-gene interactions can provide important clues into its pathogenesis,16 which will ultimately contribute to precision diagnosis and more effective treatment.
Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis affecting the mainly axial joints in both East Asia and Europe. To date, the pathogenesis of AS is still unknown, ...although we know that genetics play a vital role in it. The HLA-B27 allele is found in over 85% of AS patients. However, strong evidence suggests that other major histocompatibility complex (MHC) and non-MHC genes are also involved in the pathogenesis. In addition, current data showed that there were significant differences in both genomics and metagenomics among the different ethnic populations. The investigation of the key role of the microbiome in AS pathogenesis also highlighted the host–microbiome genetic interactions. Here, we systematically review current AS genetic research data and further compare genetic differences, especially between East Asian and European groups, which may highlight the challenge in future genetic studies.
Gut microbiome dysbiosis has been known to be associated with all stages of non-alcoholic fatty liver disease (NAFLD), but questions remain about microbial profiles in progression and homogeneity ...across NAFLD stages. We performed a meta-analysis of three publicly shotgun datasets and built predictive models to determine diagnostic capacity. Here, we found consistently microbiome shifts across NAFLD stages, of which co-occurrence patterns and core sets of new biomarkers significantly correlated with NAFLD progression were identified. Machine learning models that are able to distinguish patients with any NAFLD stage from healthy controls remained predictive when applied to patients with other NAFLD stages, suggesting the homogeneity across stages once again. Focusing on species and metabolic pathways specifically associated with progressive stages, we found that increased toxic metabolites and decreased protection of butyrate and choline contributed to advanced NAFLD. We further built models discriminating one stage from the others with an average of 0.86 of area under the curve. In conclusion, this meta-analysis firmly establishes generalizable microbiome dysbiosis and predictive taxonomic and functional signatures as a basis for future diagnostics across NAFLD stages.
Since the coronavirus disease 2019 (COVID‐19) outbreak, the nosocomial infection rate worldwide has been reported high. It is urgent to figure out an affordable way to monitor and alarm nosocomial ...infection. Carbon dioxide (CO2) concentration can reflect the ventilation performance and crowdedness, so CO2 sensors were placed in Beijing Tsinghua Changgung Hospital's fever clinic and emergency department where the nosocomial infection risk was high. Patients’ medical records were extracted to figure out their timelines and whereabouts. Based on these, site‐specific CO2 concentration thresholds were calculated by the dilution equation and sites’ risk ratios were determined to evaluate ventilation performance. CO2 concentration successfully revealed that the expiratory tracer was poorly diluted in the mechanically ventilated inner spaces, compared to naturally ventilated outer spaces, among all of the monitoring sites that COVID‐19 patients visited. Sufficient ventilation, personal protection, and disinfection measures led to no nosocomial infection in this hospital. The actual outdoor airflow rate per person (Qc) during the COVID‐19 patients’ presence was estimated for reference using equilibrium analysis. During the stay of single COVID‐19 patient wearing a mask, the minimum Qc value was 15–18 L/(s·person). When the patient was given throat swab sampling, the minimum Qc value was 21 L/(s·person). The Qc value reached 36–42 L/(s·person) thanks to window‐inducted natural ventilation, when two COVID‐19 patients wearing masks shared the same space with other patients or healthcare workers. The CO2 concentration monitoring system proved to be effective in assessing nosocomial infection risk by reflecting real‐time dilution of patients’ exhalation.
As the methodology of genetic detection has developed rapidly in recent years, through techniques such as genome-wide association studies (GWAS) and the secondary generation of sequencing, we are ...able to view the genomic landscape more clearly. It is well known that genes have a vital role in the pathogenesis of immune-mediated diseases (IMDs), which could provide important insight into new clinical therapeutic targets. Here, we review the genomic landscape of IMDs and analyse overlapping loci between diseases. There may be a need for more epigenetics studies to aid in the understanding of the transition from genotype to phenotype.
Ectopic ossification is an important cause of disability in patients with ankylosing spondylitis (AS). Whether fibroblasts can transdifferentiate into osteoblasts and contribute to ossification ...remains unknown. This study aims to investigate the role of stem cell transcription factors (POU5F1, SOX2, KLF4, MYC, etc.) of fibroblasts in ectopic ossification in patients with AS.
Primary fibroblasts were isolated from the ligaments of patients with AS or osteoarthritis (OA). In an in vitro study, primary fibroblasts were cultured in osteogenic differentiation medium (ODM) to induce ossification. The level of mineralization was assessed by mineralization assay. The mRNA and protein levels of stem cell transcription factors were measured by real-time quantitative PCR (q-PCR) and western blotting. MYC was knocked down by infecting primary fibroblasts with lentivirus. The interactions between stem cell transcription factors and osteogenic genes were analysed by chromatin immunoprecipitation (ChIP). Recombinant human cytokines were added to the osteogenic model in vitro to evaluate their role in ossification.
We found that MYC was elevated significantly in the process of inducing primary fibroblasts to differentiate into osteoblasts. In addition, the level of MYC was remarkably higher in AS ligaments than in OA ligaments. When MYC was knocked down, the expression of the osteogenic genes alkaline phosphatase (ALP) and bone morphogenic protein 2 (BMP2) was decreased, and the level of mineralization was reduced significantly. In addition, the ALP and BMP2 were confirmed to be the direct target genes of MYC. Furthermore, interferon-γ (IFN-γ), which showed high expression in AS ligaments, was found to promote the expression of MYC in fibroblasts in the process of ossification in vitro.
This study demonstrates the role of MYC in ectopic ossification. MYC may act as the critical bridge that links inflammation with ossification in AS, thus providing new insights into the molecular mechanisms of ectopic ossification in AS.
This study aimed to investigate the reliability and validity of serum matrix metalloproteinase-3 (MMP-3) levels and articular ultrasound (US) scores in assessing disease activity and therapeutic ...response in rheumatoid arthritis (RA) patients.
A total of 151 RA patients were enrolled, of whom 22 were treated with certolizumab pegol (Cimzia, CZP). The RA patients were divided into the following four subgroups according to their disease activity score in 28 joints (DAS28): stable, mild activity, moderate activity, and high activity. Forty-three healthy controls were simultaneously studied. The serum MMP-3 levels and 7-joint US (US7) scores of all subjects were determined. The patients who were treated with CZP were subsequently followed for 6 months.
The serum MMP-3 levels of all the RA patients were significantly higher than those of healthy controls, and those of patients with moderate and severe RA were significantly higher than those of patients with stable RA. The US7 scores of patients with severe RA were significantly higher than those of patients in other groups. Using the DAS28 as a reference standard, the corresponding cutoff value of MMP-3 was 70.5 ng/ml. After CZP treatment, the MMP-3 levels and US7 scores were significantly decreased at week 2, and the mean changes in US7 scores at weeks 12 and 24 were significantly higher in both groups with American College of Rheumatology 50% positive response (ACR50) and ACR 70% positive response (ACR70) than in the negative groups.
Serum MMP-3 and the US7 scores could both effectively reflect disease activity and therapeutic responses in patients with moderate to severe RA.
CTR20140405 (RA0044), CTR20140405: A phase 3, Multicenter, Double-blind, Placebo Controlled, Parallel Group, Randomized, 24-Week Study to Evaluate the Safety and Efficacy of Certolizumab Pegol as Additional Medication to Methotrexate in Chinese Subjects With Active Rheumatoid Arthritis Who Have an Incomplete Response to Methotrexate, Registered on 13 June 2014. CTR20140412 (RA0078), CTR20140412: A phase 3, Multicenter, Open-label Extension Study to Assess the Safety and Efficacy of Certolizumab Pegol as Additional Medication to Methotrexate in Chinese Subjects With Active Rheumatoid Arthritis Who Participated in RA0044, Registered on 02 July 2014.
With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between environmental and genetic factors. In a ...nutshell, etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage. In recent years, population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity, providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways. In this review, we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics. An overview of the genetic basis of autoimmunity is followed by 3 chapters detailing susceptibility genes involved in innate immunity, adaptive immunity and inflammatory cell death processes respectively. With such attempts, we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the 'usual suspects' of a limited subset of validated therapeutic targets.
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