Cell-specific proteome profiling reveals altered peripheral immune cell communication in early multiple sclerosis

Multiple sclerosis (MS) is characterized by immune dysregulation, yet the molecular alterations present at disease onset remain incompletely understood. We sought to characterize immune cell-specific proteomic changes before treatment initiation in early MS and assess their impact on immune cell communication. We performed high-resolution proteomic profiling of four major peripheral immune cell populations, CD4+ and CD8+ T cells, CD19+ B cells, and CD14+ monocytes, from newly diagnosed, treatment-naïve individuals with MS and matched healthy controls. Differential protein expression, pathway enrichment, genetic overlap, and ligand–receptor analyses were performed. All four immune cell populations exhibit distinct proteomic alterations that discriminate individuals with MS from healthy controls. Differentially expressed proteins are enriched in pathways related to coagulation, antigen processing, vesicle trafficking, oxidative phosphorylation, and cellular stress responses. Disease-associated proteins overlap with established MS susceptibility genes, with the strongest enrichments observed in CD14⁺ monocytes and CD19⁺ B cells. Integration of proteomic and ligand–receptor analyses revealed remodeling of adhesion- and immune-regulatory signaling pathways. CD14⁺ monocytes exhibited the strongest predicted outgoing interaction activity, consistent with a prominent role in altered intracellular immune communication. CD19⁺ B cells occupied a central position within the inferred immune interaction network and were enriched for B-cell differentiation, cell adhesion, and immune signaling. These findings demonstrate coordinated, cell type-specific proteomic alterations at the earliest stages of MS. The identified proteomic changes highlight distinct immune processes across cell types, including altered interacellular communication involving CD14⁺ monocytes and B-cell differentiation, adhesion, and signaling in CD19⁺ B cells, providing insight into immune mechanisms that may contribute to disease initiation and early pathogenesis. Multiple sclerosis (MS) is a chronic neurological disorder in which the immune system mistakenly attacks and damages the brain and spinal cord. To better understand the earliest stages of the disease, we analyzed the protein profiles of four major immune cell types from people with newly diagnosed, untreated MS and compared them with those from healthy individuals. We found changes in all four cell types, with the most prominent protein alterations in monocytes and B cells. We also found evidence that communication between different immune cell populations is altered early in the disease. Although B cells are known to play an important role in MS, the role of monocytes is less understood. These findings identify monocytes as an important contributor to early disease processes, provide new insights into how clinical onset begins, and suggest new directions for future research and treatment development. Shams et al. use high-resolution proteomics to profile sorted peripheral immune cell populations from individuals with newly diagnosed, treatment-naïve multiple sclerosis. They identify prominent monocyte-associated inflammatory signaling and altered immune cell communication, revealing coordinated immune dysregulation at disease onset.