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

Sgodzai M, Klöster K, Karakaya H, Didehvar P, Horstkemper L, Rilke N, Demir S, Klimas R, Pedreiturria X, Blusch A, Bohle J, Groß J, Kautzner D, Walke D, Heinzen J, Sarpong B, Toben C, Fisse AL, Grüter T, Faissner A, Motte J, Nitschke L, Hünig T, Gold R, Pitarokoili K (2026)

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Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 149

Pages Range: 502-518

Journal Issue: 2

DOI: 10.1093/brain/awaf304

Abstract

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 antigens 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 demonstrated 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 analysed a cohort of 110 chronic inflammatory demyelinating polyneuropathy patients, identifying significantly elevated soluble PD1, PD-L1 and TIM-3 levels compared with healthy controls. Further, in typical chronic inflammatory demyelinating polyneuropathy, soluble PD1, PD-L1 and LAG-3 revealed 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 with 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 the immunopathogenesis of chronic inflammatory demyelinating polyneuropathy, implicating the PD1-axis as an influential hub within a broader inter-connected immune-checkpoint network.

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How to cite

APA:

Sgodzai, M., Klöster, K., Karakaya, H., Didehvar, P., Horstkemper, L., Rilke, N.,... Pitarokoili, K. (2026). Tipping the balance: the PD1-axis as a modulator in chronic inflammatory demyelinating polyneuropathy. Brain, 149(2), 502-518. https://doi.org/10.1093/brain/awaf304

MLA:

Sgodzai, Melissa, et al. "Tipping the balance: the PD1-axis as a modulator in chronic inflammatory demyelinating polyneuropathy." Brain 149.2 (2026): 502-518.

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