Plasma Proteomics Reveals IL-6 and Complement as Key Drivers of LGI-1 Autoimmune Encephalitis

LGI-1 autoimmune encephalitis (LGI-1 AE) is the most common form of autoimmune encephalitis in adults, characterized by limbic inflammation, seizures, cognitive impairment, and psychiatric symptoms. While many patients respond to immunotherapy, persistent cognitive dysfunction is common and the underlying peripheral immune mechanisms remain incompletely understood. This study sought to comprehensively characterize the circulating proteome and monocyte transcriptome across acute (untreated) and chronic (treated) disease phases.

Researchers recruited nine acute-phase and 27 chronic-phase LGI-1 AE patients through the Australian Autoimmune Encephalitis Consortium, alongside 16 age- and sex-matched healthy controls. High-throughput plasma proteomics was performed using the SomaLogic 11k panel, measuring thousands of proteins simultaneously. Differential protein expression was analyzed using voom/limma with false discovery rate correction. Additionally, bulk RNA sequencing was performed on isolated monocytes from ten chronic LGI-1 AE participants and 28 controls, with pathway analysis via gene set enrichment analysis (GSEA) against Gene Ontology Biological Processes.

In the acute phase, 215 proteins were overexpressed and 1,015 were suppressed relative to healthy controls. Upregulated proteins and pathways encompassed innate immune activation, myeloid cell chemoattractants, terminal complement cascade components, and lymphocyte signaling and activation molecules — consistent with broad systemic immune engagement during active disease. Notably, pathways related to autophagy were significantly downregulated, a finding not previously reported in LGI-1 AE and potentially relevant to how neurons and immune cells clear pathological substrates. No significant protein differences were detected between acute and chronic patients, or between chronic patients and healthy controls, suggesting that immunotherapy partially normalizes the plasma proteome but that the chronic phase may harbor more subtle residual changes.

Monocyte transcriptomics in the chronic phase revealed 18 upregulated and 170 downregulated genes, with IL-6 and its downstream signaling cascade emerging as the most prominently dysregulated pathway. IL-6 is a pleiotropic cytokine with established roles in B-cell differentiation, antibody production, and neuroinflammation — all highly relevant to LGI-1 AE pathophysiology. These findings align with prior ELISA-based studies showing elevated IL-6 in LGI-1 AE CSF and serum, and raise the possibility that IL-6 receptor blockade (e.g., tocilizumab) could be therapeutically beneficial.

The identification of terminal complement cascade activation in the acute proteome is also clinically significant, as complement inhibitors (e.g., eculizumab, ravulizumab) are already approved for other antibody-mediated neurological diseases. The suppression of autophagy-related pathways represents a potentially novel and underappreciated mechanism — autophagy dysregulation could impair neuronal homeostasis and contribute to the persistent cognitive deficits seen even in treated patients. Together, these findings provide a rich molecular framework for understanding LGI-1 AE and suggest specific, actionable therapeutic targets for clinical investigation.