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RA-MAP: mapping the molecular immunological landscape in early rheumatoid arthritis with vaccine controls

ABSTRACT:

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.

INSTRUMENT(S): Nuclear Magnetic Resonance (NMR)

PROVIDER: MTBLS1497 | MetaboLights | 2021-06-16

REPOSITORIES: MetaboLights

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Project description:Neutrophils are key immune components in rheumatoid arthritis (RA), but the role of ALKBH5 in neutrophil function and RA progression remains unclear. METTL3, METTL14, WTAP, ALKBH5, FTO, YTHDF2, autophagy related gene were investigated by RT-qPCR. Autophagy, LC3B were respectively detected by flow cytometry analysis, Western blotting. Correlation analyses between ALKBH5 levels and RA disease activity, autophagy were performed, and receiver operating characteristic (ROC) curves were constructed to evaluate its predictive value. Univariate analysis and multivariate regression analysis were used to analyze the risk factors and construct predictive model. Sh-ALKBH5 lentiviral vectors was constructed and used to infect HL-60 cell line. The role of ALKBH5 in autophagy regulation was explored using RNA immunoprecipitation with next generation sequencing (RIP-Seq), m6A RNA Methylation Analysis, m6A immunocoprecipitation-quantitative polymerase chain reaction (MeRIP-qPCR) and Actinomycin D treatment. Results showed significantly reduced ALKBH5 levels in RA neutrophils compared to healthy controls (HC) and ankylosing spondylitis (AS) patients, correlating with RA disease activity. A novel predictive model incorporating ALKBH5, hemoglobin (HGB), and lymphocyte percentage (L%) exhibited enhanced efficacy in distinguishing RA patients from HC (AUC = 0.937) and AS patients (AUC = 0.943), and could reflect RA severity and activity. Additionally, autophagy levels in neutrophils were highest in RA synovial fluid, followed by RA peripheral blood, and lowest in HC peripheral blood, with ALKBH5 expression showing the opposite trend. Moreover, ALKBH5 negatively correlated with neutrophil autophagy and the silencing of ALKBH5 in HL-60 enhanced the autophagy. Silencing ALKBH5 increased m6A level of ATG7 mRNA and ATG7 mRNA stability. Mechanistically, ALKBH5 inhibited neutrophil autophagy through mediating m6A modification of the ATG7 mRNA. In conclusion, these findings demonstrate that ALKBH5 regulates neutrophil autophagy in RA, and the ALKBH5-HGB-L% model holds potential as a diagnostic and disease activity indicator for RA.

			Action	DRS
	TACERA-6m-sera-1.zip	Other
	TACERA-6m-sera-10.zip	Other
	TACERA-6m-sera-100.zip	Other
	TACERA-6m-sera-101.zip	Other
	TACERA-6m-sera-102.zip	Other

Dataset Information

RA-MAP: mapping the molecular immunological landscape in early rheumatoid arthritis with vaccine controls

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