Limbic encephalitis and intrathecal immunoglobulin A and G antibodies to Synapsin, a neuron-specific synaptic vesicle-associated protein

Background: Limbic encephalitis (LE) is characterized by memory dysfunction, seizures, behaviour changes, and mesiotemporal involvement on imaging studies, and is as-sociated with antibodies to neuronal autoantigens. Here we report the identication of the synaptic vesicle-associated protein Synapsin as a novel autoantigen in a patient with LE.Methods: Methods included indirect immunouorescence, immunoprecipitation, mass spectrometry, cell-based assays with Synapsins Ia, Ib, and IIa plasmids, and immunoblots of wild-type and Synapsin I/II/III null mice.Results: A 70-year-old patient presented with seizures, short-term memory decits, and left hippocampal hyper-intensities on T2-weighted magnetic resonance imaging. Cerebrospinal uid (CSF) studies revealed a strong intrat-hecal synthesis of immunoglobulin (Ig)A and IgG. Except for low-titre IgG antibodies to voltage-gated potassium channels in CSF, testing for known neuronal autoantibo-dies was negative. However, indirect immunouorescence on murine brain sections showed prominent staining of the mossy bre tract, amygdala, and the cerebellar molecular and granular layer by IgA antibodies in the patient’s CSF and serum. Immunoprecipitation with CSF IgA and sub-sequent mass spectrometry identied the neuron-specific synaptic vesicle-associated protein Synapsin as the anti-genic target. Knockout studies and cell-based assays un-ambiguously conrmed Synapsin Ia/Ib and Synapsin IIa as autoantigens detected by intrathecally synthesized IgA and IgG antibodies.Conclusion: Synapsin is a novel autoantigen in LE. Re-markably, in addition to IgG, Synapsin is targeted by intrat-hecally produced IgA, suggesting that also IgA antibodies could play a role in antineuronal autoimmunity. Future stu-dies should clarify the prevalence and pathogenic relevance of IgA and IgG antibodies to Synapsin in patients with LE.Disclosure: Nothing to disclose