Tipping the balance: the PD1-axis as modulator in chronic inflammatory demyelinating polyneuropathy

Collapse of self-tolerance toward peripheral nervous system antigens initiates chronic inflammatory demyelinating polyneuropathy. This breakdown likely recurs, driving disease onset and flare-ups, providing a window to predict progression before symptoms worsen, yet the mechanisms behind self-tolerance maintenance or disruption remain underexplored. Using a transgenic mouse model with Schwann cell-restricted ovalbumin expression and adoptive transfer of ovalbumin reactive CD8 T-cells, we demonstrate that maintenance of immune tolerance to peripheral nervous system antigen is linked to PD1-axis activity. This is characterized by PD1-axis induction, exhaustion, abortive proliferation and deletional tolerance of the transferred cells within the lymph node environment. Complementary in vitro co-culture demonstrate that lymph node stromal cells ectopically present ovalbumin, as evidenced by proliferation of ovalbumin-reactive CD8 T-cells, pointing to cooperation of antigen presentation and PD1-axis activity to maintain peripheral nervous system self-tolerance. To assess whether PD1-axis involvement in peripheral nervous system tolerance extends to human autoimmunity, we analyzed a cohort of 110 chronic inflammatory demyelinating polyneuropathy patients, identifying significantly elevated soluble PD1, PD-L1, and TIM-3 levels compared to healthy controls. Further, in typical chronic inflammatory demyelinating polyneuropathy, soluble PD1, PD-L1 and LAG-3 showed consistent low-to-moderate negative correlations (|r| ≈ 0.3-0.5, p < 0.05) with disease severity. Atypical chronic inflammatory demyelinating polyneuropathy patients displayed no significant associations, likely reflecting cohort heterogeneity and limited sensitivity of clinical measures rather than a lack of biological relevance. Exploratory correlation network analyses reveal increased numbers of immune-checkpoints forming inter-correlated networks in chronic inflammatory demyelinating polyneuropathy compared to healthy controls, suggesting engagement of a broader immune- checkpoint regulatory axis. Through this multilayered translational approach - from early immune decision-making in a mouse model to patient data - we offer a fresh perspective on chronic inflammatory demyelinating polyneuropathy immunopathogenesis, implicating the PD1-axis as an influential hub within a broader inter-connected immune-checkpoint-network.