Background/Purpose: Metabolic processes have a critical role in regulating immune cell function, therefore being relevant to understanding the pathogenesis and progression of autoimmune diseases.  Here we aim to identify unique metabolic mechanisms in SLE immune response, compared to rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D) and healthy controls (CTRL).

Methods: PBMCs isolated from CTRL (n=10), patients with SLE (n=10), MS (n=8), RA (n=14), and T1D 8n=11) were either subject to T-cell-stimulation with anti-CD3/CD28 dynabeads® or vehicle for 24 h. After processing, the cellular metabolome was analyzed using liquid chromatography-high-resolution mass spectrometry. RNA was isolated from PBMCs; then, sequencing by synthesis and Hierarchical Indexing for Spliced Alignment of Transcripts 2 were performed. The obtained data were quality-checked, controlled for extraneous variables, and analyzed to assess changes in metabolite levels and differential gene expression. Finally, pathway and gene/metabolite enrichment analyses were performed using over-representation and overexpression approaches.

Results: In unstimulated PBMCs, SLE versus CTRLs exhibited significantly increased levels of metabolites directly linked to energy metabolism. Pathway analysis revealed that MS, RA and SLE shared overall changes in cell transport mechanisms, central carbon metabolism, protein translation and the metabolism of amino acids and co-factors. Adenosine monophosphate-activated protein kinase (AMPK) signaling pathway showed a greater relevance in SLE compared to other diseases. Specific pathways associated with carbohydrate metabolism, endocrine system and neutrophil extracellular trap were found as significantly altered exclusively in SLE. In T-cell stimulated PBMCs, SLE showed a broader range of affected pathways, displaying unique disturbances in lysine degradation, carbohydrate metabolism, fatty acid degradation and porphyrin metabolism. In addition, when compared to the unstimulated counterparts, SLE T-cell-activated PBMCs exhibited the most singular pathway activity profile. The pathways uniquely disturbed in SLE stimulation mainly belonged to metabolic hubs related to cellular functions, and the processing of environmental and genetic information. Moreover, RNA sequencing revealed the most pronounced gene deregulation in the differential expression analysis for PBMCS from SLE patients compared to other autoimmune diseases.

Conclusion: The conservation of several metabolic alterations across SLE, MS and RA suggests similar underlying mechanisms related to their autoimmune pathophysiology. Compared to MS and RA , AMPK signaling might play a unique function in the metabolic adaptation of T cells in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/comparative-immuno-metabolomics-shows-singular-changes-in-systemic-lupus-erythematosus-metabolic-phenotype-induced-by-t-cell-activation/