Frontiers in immunology · 2026
Case Report: Schwann cell reprogramming and PDGF-driven nerve hypertrophy in an NF1 patient with CIDP-like autoimmunity.
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Wang Fei, Cao Wenqian, Lu Jiaye, Huang Run, Bai Yuhan, Zhang Yining, Wang Zilan, Chen Zhouqing, Wang Zhong
Аннотация
BACKGROUND AND AIMS: Differentiating neoplastic proliferation from inflammatory fibrosis in peripheral nerve hypertrophy is critical. We report a patient with a neurofibromatosis type 1 (NF1) deletion exhibiting extreme diffuse nerve enlargement and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like autoimmunity. This study aims to elucidate the underlying endoneurial fibrotic mechanism, specifically focusing on the signaling networks between Schwann cells (SCs) and fibroblasts.
METHODS: Single-cell RNA sequencing was performed on a biopsied sural nerve to profile the cellular and transcriptomic landscape. Intercellular interactome and pseudotime trajectory analyses were utilized to map molecular evolution and signaling crosstalk.
RESULTS: Transcriptomic profiling revealed that SCs-which normally maintain myelin around axons and support peripheral nerve function-were pathologically entrapped in a dedifferentiated state. Serving as a genetic primer, the NF1 deletion lowered the threshold for SC reprogramming, a vulnerability that was subsequently unleashed by a severe autoimmune infiltrate consisting of macrophages and T cells. These reprogrammed SCs abandoned myelin-maintaining genes, such as MPZ, to acquire a pro-fibrotic phenotype. Through a coordinated platelet-derived growth factor (PDGF) dual-axis network involving PDGFC-PDGFRA and PDGFD-PDGFRB, the entrapped SCs exclusively secreted PDGF ligands that potently activated endoneurial fibroblasts and vascular mural cells. This persistent paracrine signaling orchestrated excessive extracellular matrix deposition, driving a massive expansion of the endoneurial interstitium and the formation of classic "onion bulbs".
INTERPRETATION: Our data suggest that the macroscopic hypertrophic changes observed in this specific clinical presentation may reflect an aberrant, immune-triggered fibrotic cascade-where autoimmune leukocyte infiltration continuously drives stromal overgrowth-complementing rather than entirely precluding the classical RAS/MAPK-driven neoplastic SC hyperproliferation. Furthermore, within the limitations of this pilot evaluation, characterizing this potential SC-fibroblast crosstalk indicates that the PDGF signaling pathway may warrant further investigation as a candidate translational therapeutic target for refractory hypertrophic neuropathies.
METHODS: Single-cell RNA sequencing was performed on a biopsied sural nerve to profile the cellular and transcriptomic landscape. Intercellular interactome and pseudotime trajectory analyses were utilized to map molecular evolution and signaling crosstalk.
RESULTS: Transcriptomic profiling revealed that SCs-which normally maintain myelin around axons and support peripheral nerve function-were pathologically entrapped in a dedifferentiated state. Serving as a genetic primer, the NF1 deletion lowered the threshold for SC reprogramming, a vulnerability that was subsequently unleashed by a severe autoimmune infiltrate consisting of macrophages and T cells. These reprogrammed SCs abandoned myelin-maintaining genes, such as MPZ, to acquire a pro-fibrotic phenotype. Through a coordinated platelet-derived growth factor (PDGF) dual-axis network involving PDGFC-PDGFRA and PDGFD-PDGFRB, the entrapped SCs exclusively secreted PDGF ligands that potently activated endoneurial fibroblasts and vascular mural cells. This persistent paracrine signaling orchestrated excessive extracellular matrix deposition, driving a massive expansion of the endoneurial interstitium and the formation of classic "onion bulbs".
INTERPRETATION: Our data suggest that the macroscopic hypertrophic changes observed in this specific clinical presentation may reflect an aberrant, immune-triggered fibrotic cascade-where autoimmune leukocyte infiltration continuously drives stromal overgrowth-complementing rather than entirely precluding the classical RAS/MAPK-driven neoplastic SC hyperproliferation. Furthermore, within the limitations of this pilot evaluation, characterizing this potential SC-fibroblast crosstalk indicates that the PDGF signaling pathway may warrant further investigation as a candidate translational therapeutic target for refractory hypertrophic neuropathies.