Differences in innate immune cell populations distinguish autoimmune from herpesvirus-associated encephalitis

Autoimmune encephalitis (AIE) is a disabling inflammatory condition of the brain deemed to be due to a dysregulated immune response. Viral infections and malignancies together with certain genetic polymorphisms are thought to contribute to the pathogenesis of AIE, yet the exact mechanisms remain insufficiently understood. Diagnosis of AIE currently relies on clinical consensus criteria. However, diagnostic workup can be challenging in some cases, potentially delaying treatment initiation associated with poor clinical outcomes. This study aims to investigate the systemic and intrathecal immune cell profiles of AIE in comparison to viral meningoencephalitis (VME) as a clinically relevant differential diagnosis and evaluate its diagnostic and therapeutic potential.

97 mainly treatment-naïve AIE patients, 47 patients with VME, and 109 somatic symptom disorder (SD) controls were included. Analysis of peripheral blood (PB) and cerebrospinal fluid (CSF) immune cell profiles was performed using multidimensional flow cytometry (mFC) in combination with novel computational approaches.

We were able to identify alterations in the adaptive B and T cell-mediated immune response in AIE compared to SD controls which correspond to respective changes in the brain parenchyma. AIE and VME exhibit similar patterns of adaptive B and T cell responses and differ in pattern of innate immunity especially NK cells. MFC together with routine CSF parameters can differentiate AIE from VME and SD controls implying diagnostic potential.

AIE is characterized by a B and T cell-mediated systemic and intrathecal immune-cell signature which corresponds to changes reported in the brain parenchyma providing insights into immunopathogenesis. Differences between AIE and VME were most prominent for the innate immune response indicating a potential role of NK cells in the pathogenesis of autoimmunity. Our data provides evidence that mFC could be a novel complementary approach to the diagnosis of AIE with diagnostic, therapeutic, and prognostic implications.