Background/Purpose: Recently, many reports on immune metabolism have been accumulated and metabolic changes are now considered to be a key factor for controlling immune cell differentiation, proliferation and function. Although precise mechanism of tuning metabolic status in immune cells has been clarified, these results have mainly come from the mice experiments and metabolomics analysis on human autoimmune diseases gets underway. The aim of this study is to get some insights on metabolomic regulation in SLE by comprehensively measuring plasma metabolites.

Methods: We collected plasma samples from patients with SLE (n=41) who met the 1997 American College of Rheumatology criteria for SLE and had the history of lupus nephritis. Gender- and age-matched healthy controls (HCs) (n=30) were recruited. For comparison, plasma from 19 rheumatoid arthritis (RA) patients were also collected. Metabolic profiles were analyzed with capillary electrophoresis (CE)- and liquid chromatography (LC)- time of flight mass spectrometry (TOFMS) in conjunction with multivariate statistical analysis. Transcriptome data of SLE patients were obtained from our RNA-sequencing data of each immune cell subset (total 20 subsets).

Results: About 180 peaks were detected from CE-TOFMS including absolutely quantified 110 metabolites and about 160 peaks were detected from LC-TOFMS. Random Forest, one of the machine learning algorithms, revealed the importance of histidine (His) to classify SLE patients from HCs. Partial least squares discriminant analysis (PLS-DA) also showed the significance of His, whose plasma level was lower in SLE patients. In addition, we divided SLE patients into two groups by using transcriptome data; interferon (IFN)-signature high and low. Interestingly, we found some amino acids were associated with IFN-signature level. In addition, inverse correlation between His level and titer of ds-DNA was detected. His level was also decreased in RA patients compared to HCs and was inversely correlated with DAS28-ESR and CRP in RA. Weighted gene co-expression network analysis (WGCNA), one of network analysis, showed positive correlation between mitochondria-related module and plasma His level in B cells.

Conclusion: Plasma metabolic changes in autoimmune diseases might not only reflect the chronic activated immune-status but also associate with their pathogenesis themselves. His may be an important factor for SLE pathogenesis especially in B cells independently from IFN signal. SLC15A4, a transporter of His on lysosome, is one of the SLE GWAS SNPs and has been reported to play an important role in IFN production in B cells through regulation of TLR7/9 activation. Low plasma level of His could be a useful marker of SLE activity and maintenance of His homeostasis could become a novel treatment target for SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/plasma-metabolomic-analysis-combined-with-transcriptome-data-has-revealed-the-importance-of-amino-acids-homeostasis-in-sle-pathogenesis/