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 identication of the synaptic vesicle-associated protein Synapsin as a novel autoantigen in a patient with LE.Methods: Methods included indirect immunouorescence, 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 decits, and left hippocampal hyper-intensities on T2-weighted magnetic resonance imaging. Cerebrospinaluid (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 immunouorescence on murine brain sections showed prominent staining of the mossybre 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 identied the neuron-specific synaptic vesicle-associated protein Synapsin as the anti-genic target. Knockout studies and cell-based assays un-ambiguously conrmed 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.