Peripheral nerve-targeting and pain-promoting transcriptomic signatures in early Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an autoimmune disorder that causes weakness, sensory loss, autonomic dysfunction, and chronic neuropathic pain. The mediators responsible for driving early autoimmune injury in the most common GBS variant, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), remain incompletely understood. We performed bulk and single-cell RNA sequencing on peripheral blood mononuclear cells collected from early untreated AIDP-variant GBS patients and healthy controls to comprehensively deduce leukocyte transcriptome alterations and predict disease-driving interactions between pathogenic leukocytes and peripheral nervous system cells. Bulk transcriptomics showed interferon- and JAK/STAT-driven proinflammatory signatures in myeloid cells. CD8+ T-cells were highly proliferative and expressed axon guidance genes. Single-cell transcriptomics revealed dysregulation of CD4+FOXP3+ regulatory and CD4+ effector memory T-cells indicative of poorly controlled type 1 and type 17 immune responses. Highly activated intermediate monocytes upregulated genes related to angiogenesis and oncostatin M. Interactome analysis between GBS leukocytes, Schwann cells, and sensory neurons predicted increased engagement of ligand-receptor pairs with nerve integrity and pain functions, including epiregulin, interferon-beta, adrenomedullin, clusterin, IL-6, IL-15, and CCL4. Functional validation demonstrated that CCL4 sensitizes human sensory neurons in vitro. These results unearth molecular interactions by which specific leukocyte populations in AIDP-variant GBS may induce peripheral nerve injury and drive neuropathic pain.