Phenotypic and Metabolic Signatures in Chronic Autoimmune Inflammation 2308477

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by systemic chronic inflammation that can lead to heterogeneous clinical manifestations, from mild cutaneous disease to multi-organ damage and failure. Understanding how immune cell composition, their activation status, and metabolic changes contribute to disease is important to identify new biomarkers and therapeutic targets. In this study, we combined spectral flow cytometry and CITE-Seq to profile immune cell subsets and metabolic changes at the single-cell level. Peripheral white blood cells from SLE patients, psoriatic arthritis (PsA) patients, and healthy donors were analyzed using a 50-marker panel that evaluated immune subsets, activation and exhaustion markers, including metabolic dependencies by using SCENITH. The same antibody panel was used in CITE-Seq to validate flow cytometric findings and explore additional metabolic and inflammation pathways. High-dimensional computational analysis was used to identify immune subpopulations with specific metabolic signatures that distinguished SLE from PsA and healthy individuals. Across 44 immune cell populations, we observed significant immunophenotypic and immunometabolic changes in both diseases. B cell analysis revealed altered frequencies, different translational activity, and metabolic dependence in early developmental and antigen-experienced cell subsets. SCENITH profiling showed distinct metabolic signatures in CD4+ and CD8+ T cells, with more pronounced differences in naive and memory subsets. In fact, in SLE, T cells exhibited strong dependence on OXPHOS and limited sensitivity to glycolytic inhibition. Finally, PsA patients presented increased NKT-cell frequencies, indicating an involvement of lipid antigens. Overall, these findings describe several immune and metabolic dysregulations in SLE and PsA patients, which could be used as potential biomarkers for disease progression and therapeutic intervention. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project 321115009 (GRK 2336/3) Basic Autoimmunity (BA)