Neuronal pSTAT1 hallmarks synaptic pathology in autoimmune encephalitis against intracellular antigens
©DiLiberto/UNIGE.
Summary
Autoimmune encephalitis (AE) is an inflammatory syndrome of the central nervous system (CNS) triggered by aberrant immune responses against neuronal intracellular (IC-AE) or surface (NS-AE) autoantigens. The resulting neuronal alterations and clinical trajectories differ, with IC-AE often leading to fatal outcomes. Unfortunately, the scarce availability of tissue from AE cases has hampered systematic analyses that would allow an understanding of the pathogenesis underlying neuronal alterations in T cell-mediated AE syndromes. Here, the authors assembled a cohort comprising both NS-AE (n = 8) and IC-AE (n = 12) from multiple institutions to delineate key histopathological features that distinguish neuronal pathology between IC-AE and NS-AE. In contrast to NS-AE, IC-AE lesions present a prominent neuronal pSTAT1 signature, accompanied by a high proportion of brain-resident memory CD8 + T cells and neurodegenerative GPNMB + phagocytes which show synaptic engulfment with little C3-complement deposition. Their findings highlight distinct histopathological features of IC-AE compared to NS-AE, providing actionable biomarkers for diagnostics and treatment strategies.
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Why is this important?
Autoimmune encephalitis (AE) is an inflammatory syndrome of the central nervous system (CNS). This study sheds light on why some cases of AE are more difficult to treat. Researchers examined brain tissue from patients and found that in cases where the immune response targets intracellular antigens, neurons activated a specific immune signal, pSTAT1, which was not found in cases where the immune response targets neuronal surface antigens. This signal is linked to brain-resident T cells and reactive immune cells that attack synapses, the vital connections between neurons. These changes likely cause the severe symptoms, such as memory loss, confusion, and seizures, seen in these patients. The findings could help identify these aggressive forms earlier and guide clinicians toward more effective treatments beyond standard immune therapies.
Funding:
This work was supported by the Swiss National Science Foundation, the European Research Council, the Novartis Foundation for Biomedical Research, the French National Research Agency (ANR), the National MS Society, the Fondation Pierre Mercier pour la Science, the Propatient Foundation, the Goldschmidt Jacobson Foundation, the Gottfried and Julia Bangerter Rhyner Foundation, and ERA-NET NEURON.