Project description:Guillain-Barré syndrome (GBS) is an autoimmune disorder that causes sensory loss, motor deficits, autonomic dysfunction, and chronic neuropathic pain. The most common GBS variant, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), primarily results from immune attack against myelin surrounding cranial and peripheral axons and associated Schwann cells. Pathogenic peripheral myelin-specific antibodies are hypothesized to contribute to pathogenesis; however, the specific immune mediators responsible for driving autoimmune injury in early disease stages 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 transcript and signaling pathway alterations and predict interactions between pathogenic leukocytes and peripheral nervous system cells that could drive disease. Bulk transcriptomics showed a type I and II interferon- and JAK/STAT-driven proinflammatory signature in myeloid cells, while CD8+ T-cells were highly proliferative and expressed axon guidance genes. Single-cell transcriptomics revealed dysregulation of regulatory and CD4+ effector memory T-cells indicative of poorly controlled type 1 and type 17 immune response. A subset of intermediate CD14+CD16+ intermediate monocytes with a highly activated phenotype uniquely upregulated genes related to angiogenesis and the interleukin (IL)-6 family cytokine 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. These included epiregulin, interferon-beta, adrenomedullin, clusterin, IL-6, and IL-15. Activated intermediate monocytes participated in a CCL4 to CCR1/CCR5 interaction toward both sensory neurons and Schwann cells. These results unearth specific molecular interactions by which specific leukocyte populations in AIDP-variant GBS may induce peripheral nerve injury and drive associated neuropathic pain.

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Longitudinal single-cell RNA sequencing of PBMCs from a Guillain–Barré syndrome patient before and after IVIg treatment

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