Neural synaptic vesicle autoimmunity following aerosolized porcine neural tissue exposure: insights into autoimmune inflammatory polyradiculoneuropathy

Abstract

Background: Between 2006 and 2008, cases of occupational inflammatory polyradiculoneuropathy (OIPN) were identified among U.S. swine abattoir workers exposed to aerosolized porcine neural tissue. While the clinical features of this occupational polyradiculoneuropathy/polyradiculopathy have been described, its immunologic basis remained unclear.

Methods: The archived sera of 20 previously reported OIPN cases were evaluated for putative autoantigens by phage immunoprecipitation sequencing (PhIP-Seq). Healthy and diseased controls and cases of other inflammatory neuropathies, including chronic inflammatory polyradiculoneuropathy (CIDP), Guillain-Barré Syndrome (GBS), and axonal/mixed axonal-demyelinating inflammatory polyradiculoneuropathies (IPN, not meeting CIDP/GBS criteria), were also evaluated using by ELISA and CBA.

Findings: PhIP-Seq data identified synaptophysin and growth-associated protein 43 (GAP43) as dominant autoantigens. Confirmation by enzyme linked immunosorbent assay (ELISA) and cell-based assay (CBA) showed that 11 patients with OIPN sera were positive for both synaptophysin-IgG and GAP43-IgG, four were positive only for synaptophysin-IgG, and one was positive only for GAP43-IgG. Thirteen of 15 (87%) synaptophysin-IgG positive patients had neuropathic pain. Electrodiagnostic features in 12 of 15 (80%) patients with OIPN were of a demyelinating or mixed axonal and demyelinating polyradiculoneuropathy. 12 out of 223 (5%) IPN patients tested positive for synaptophysin-IgG. 67% had demyelinating/mixed axonal-demyelinating electrophysiology, and all except one patient experienced neuropathic pain. Seven synaptophysin-IgG positive cases of spontaneous IPN among nine (78%) who received immunotherapy or cancer-directed therapy showed improvement.

Interpretation: Our identification of synaptophysin-IgG and GAP43-IgG as biomarkers of an immunotherapy-responsive idiopathic inflammatory polyradiculoneuropathy has diagnostic and therapeutic implications.

Funding: This research was supported by the Department of Defence under Award # HT9425-23-1-0100.

Keywords: GAP-43; Inflammatory polyradiculopathy; Inhalational autoimmunity; Porcine neural tissue; Synaptophysin.