Complement profiling of sural nerves in chronic-inflammatory demyelinating polyneuropathy

Chronic-inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated polyneuropathy causing substantial disability. While both cell-mediated and humoral mechanisms contribute to CIDP, the role of complement remains poorly understood. Considering the rise of complement-targeted treatment, it is crucial to examine the role of complement in CIDP. In this cross-sectional, study, sural nerve biopsies from 55 CIDP patients were analyzed using histopathology, gene- and protein-based techniques, comparing them to two non-diseased controls (NDCs), as well as 8 patients with hereditary neuropathy (HN) and idiopathic axonal neuropathy (IPN). Overall, 94% (n = 52) revealed abnormal and prominent deposition of terminal complement complex C5b-9 on endoneurial capillaries. Patients with significant complement deposition presented with a progressive disease course (n = 52) and the number and distribution of infiltrating CD8 + T cells and CD68 + macrophages, since a basic immunological paradigm holds that those two may form an immunological synapse, correlated with clinical disease severity as measured by inflammatory neuropathy cause and treatment sensory sum (INCAT) score (p < 0.001). Furthermore, changes in abundances of complement proteins as unveiled by untargeted proteomics accord with changes on transcript level as identified by targeted gene expression studies. In contrast, there was no complement deposition in NDC nor DC. This study provides an extensive evaluation of sural nerve specimens of CIDP patients finding a marked involvement of complement supporting the postulated concept of complement mediated demyelination in CIDP. Our results support the approach of targeting the complement system as a new and promising therapeutic strategy-at least in a subgroup of CIDP. Further research is warranted to unravel the functional implications and role of complement in CIDP progression and optimize patient care. Clinical Trial Registration: The study is registered under the German clinical trial registry ( https://www.drks.de ), DRKS0003245.