To enhance the pathophysiological understanding of the different subtypes of seropositive Autoimmune Encephalitis (spAE) and facilitate the detection of novel disease biomarkers and therapeutic approaches.

AE is an immune-mediated, non-infectious disorder, whose exact, in particular subtype-specific, mechanisms have not been fully understood. Even though diagnostic opportunities and therapeutic approaches are extending, diagnosis and treatment of AE is still delayed in some cases and deficits may persist and cause live-long disability including intractable epilepsy and prolonged cognitive impairment in some patients. Thus, a concise understanding of the pathophysiological mechanisms as well as novel diagnostic and prognostic biomarkers are needed to support early diagnosis and optimize treatment.

We applied an unsupervised proteomic approach to analyze the CSF protein profile of AE patients with autoantibodies against NMDA receptor (n = 9), LGI1 (n = 9), and GAD65 (n = 8) compared to 9 patients with relapsing-remitting Multiple Sclerosis, as inflammatory controls, and 10 non-inflammatory controls.

We found a dysregulation of the complement system, a disbalance between pro-inflammatory and anti-inflammatory proteins on the one hand, and dysregulation of proteins involved in synaptic transmission, synaptogenesis, brain connectivity, and neurodegeneration on the other hand to a different extent in all AE subtypes compared to non-inflammatory controls. Moreover, higher levels of several proteases and reduction in protease inhibitors could be detected in all AE subtypes compared to non-inflammatory controls. Furthermore, the different AE subtypes showed distinct protein profiles compared to each other and inflammatory controls.

CSF proteomics dissected the complex mechanisms underlying the pathophysiology of spAE, including immune dysregulation, neuronal dysfunction, neurodegeneration, and altered protease function. These observations might be valuable to gain an extensive understanding of the pathophysiology of spAE, which could facilitate the development of novel comprehensive therapeutic regimen and the identification of potential disease-specific biomarkers.