A Stage-Dependent Translational Signature in Peripheral Blood Mononuclear Cells from Clinically Isolated Syndrome to...

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by inflammatory demyelination, neurodegeneration, and progressive disability. Clinically isolated syndrome (CIS) often represents the first overt presentation of MS. We performed an exploratory cross-sectional transcriptomic investigation of peripheral blood mononuclear cells (PBMCs) from healthy controls (HC, n = 40), CIS patients (n = 49), and Relapsing-Remitting MS (RRMS, n = 53) patients using the ArrayExpress dataset E-MTAB-11415. Differential expression analysis was performed using limma, adjusting for age and sex. Functional enrichment and network analyses were conducted using clusterProfiler, STRING, and Cytoscape. Although Principal Component Analysis (PCA) showed partial overlap among groups, pathway-level analyses revealed coherent alterations in translation, ribosome biology, mitochondrial protein synthesis, and stress-response regulation. In CIS compared with HC, cytoplasmic and mitochondrial ribosomal genes were predominantly downregulated, suggesting reduced translational capacity in PBMCs. This was accompanied by altered expression of translation-initiation and transcriptional regulators, whereas genes involved in stress-adaptive translational control, including GCN1, YARS1, QARS1, and SIL1, were selectively upregulated. Conversely, RRMS compared with CIS showed upregulation of ribosome-related and biosynthetic programs. Overall, these findings suggest that CIS may be characterized by peripheral translational restraint and adaptive stress response activation, whereas RRMS progression is associated with biosynthetic reactivation.