The corneal neuroimmune junction: dendritic cell maturity and proximity to small nerve fibres in painful and painless type 1 diabetic neuropathy
Aims: To determine whether corneal dendritic cell (DC) density, maturity, and spatial relationship to corneal nerves differ according to type 1 diabetes (T1DM), diabetic peripheral neuropathy (DPN), and neuropathic pain status.
Methods: This post hoc cross-sectional analysis included 73 participants: T1DM with painful DPN (n=19), T1DM with painless DPN (n=15), T1DM without DPN (n=19), and healthy controls (HC) (n=20). DPN was defined using Toronto consensus criteria supported by vibration perception threshold testing (≥25V) with painful DPN defined by a Douleur Neuropathique 4 Questions (DN4) score of ≥4. Corneal confocal microscopy was performed and images analysed using CCMetrics. DCs were classified as mature or immature based on morphological criteria and categorised as near or distant based on direct contact with a corneal nerve fibre. Non-parametric comparisons were performed using Kruskal–Wallis and Mann–Whitney U tests.
Results: Total DC density did not differ between groups (p=0.343). However, DC subtype distribution varied by DPN subtype. Immature DCs distant from nerves differed overall (p=0.009) and were higher in painful DPN and painless DPN than in T1DM without DPN. Immature DCs near nerves did not differ significantly (p=0.082), and neither did mature DCs distant from nerves (p=0.344). In contrast, mature DCs near nerves differed overall (p=0.045) and were lower in painful DPN than in painless DPN and T1DM without DPN.
Conclusions: Corneal DC maturity and proximity to small nerve fibres differ across neuropathy subgroups in T1DM, suggesting that neuroimmune alterations may influence whether DPN presents with or without pain despite similar overall DC density.
Comments: This study adds a spatial immune dimension to corneal neuropathy assessments using confocal microscopy in people with T1DM, distinguishing DC maturity and proximity to small nerve fibres, potentially complementing established corneal nerve metrics such as length, fibre density, and branch density. The cohort was well characterised, and image selection was blinded, which strengthens internal validity. However, this was a post hoc, cross-sectional analysis using available data, and the imaging protocol was originally designed for nerve fibre assessment rather than immune cell quantification, which limits mechanistic and translational inference. The findings are therefore hypothesis-generating, but they support further work on neuroimmune signatures in painful and painless DPN. Longitudinal corneal confocal microscopy to assess Langerhans cell migration before the emergence of painful or painless phenotypes, combined with tissue-based immunophenotyping to define Langerhans cell-specific neuroimmune signalling, would be of particular interest in future.
Jamie Burgess
Reference. Moussa F, Taleb S, Borbjerg MK, Croosu SS, Mørch CD, Frøkjær JB, Hansen TM, Ejskjaer N, Røikjer J. Corneal Immune Cells and Their Relation to Diabetic Peripheral Neuropathy and Neuropathic Pain. Muscle Nerve. 2026 Jan;73(1):72-78. doi: 10.1002/mus.70061. Epub 2025 Nov 17. PMID: 41246983.
