Integrated peripheral immune profiling reveals B-cell dysregulation and CD8 effector signatures in chronic...

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated peripheral neuropathy with heterogeneous and often incomplete responses to current immunotherapies, but the underlying immune basis remains poorly defined. Although CIDP shares features of immune-mediated demyelination with multiple sclerosis (MS), the two diseases affect distinct anatomical compartments and exhibit divergent therapeutic responses, suggesting fundamentally different underlying immune programs. Here, we address this gap by defining the peripheral immune architecture of CIDP using an integrated, multi-modal approach.

Peripheral blood was obtained from 20 patients with CIDP and 20 age- and sex-matched healthy controls. Single-cell RNA sequencing was performed in a discovery subset and integrated with publicly available MS peripheral blood datasets to provide a cross-disease reference framework. The single-cell analysis was designed as an exploratory discovery step to identify candidate immune signatures. Transcriptomic, pathway, and ligand-receptor analyses were complemented by cytokine profiling and flow-cytometric validation in the full cohort.

CIDP exhibited broad inflammatory activation with preferential enrichment of type I interferon and inflammasome-related programs compared with MS. Despite reduced B-cell frequencies, CIDP showed transcriptional enrichment of germinal center-associated programs, indicating a dissociation between cell number and activation state. In parallel, CD8 effector T cells demonstrated enhanced cytotoxicity and cytoskeletal remodeling programs, supported by increased expression of actin-regulatory genes and strengthened intercellular signaling interactions. In contrast, MS showed greater enrichment of integrin-talin-vinculin signaling pathways in B cells and CD4 T-cell subsets, consistent with trafficking-related immune mechanisms. Together, these findings indicate a coordinated immune axis linking B-cell dysregulation and cytotoxic CD8 T-cell activation in CIDP.

Integrated peripheral immune profiling identified candidate CIDP-associated immune signatures including dysregulated B-cell activation despite numerical reduction and a prominent cytotoxic CD8 T-cell program within a type I interferon- and inflammasome-skewed inflammatory milieu. These findings provide an exploratory framework for understanding peripheral immune dysregulation in CIDP and warrant further translational studies in larger, treatment-stratified cohorts.