Defining and treating leucine-rich glioma inactivated 1 antibody associated autoimmunity

Abstract

The identification of subtypes of autoimmune encephalitis, associated with autoantibodies to cell surface components of CNS ion channels and related proteins, has had great impact on the practice of clinical neurology in the last decade. The new classifications based on mechanism-related autoantibodies herald a new era which bridges neurology, psychiatry, immunology and synaptic biology. Leucine-rich glioma-inactivated (LGI) proteins 1–4 have roles in synaptic transmission and myelination (Kegel et al. , 2013), and LGI1 is one of the novel autoantigens in autoimmune encephalitis. The LGI1 gene on chromosome 10 was identified in high grade gliomas in 1998 and found to be mutated in autosomal dominant partial epilepsy with auditory features (ADPEAF) in 2002. LGI1 protein is notable for being secreted, and contains a leucine-rich (LRR) domain and an epilepsy-associated or epitempin (EPTP) domain. LGI1 may regulate synaptic strength at excitatory synapses through interaction with postsynaptic ADAM22, PSD95 and presynaptic ADAM23; and LGI +/− and LGI −/− mice are proving to be useful animal models of focal epilepsy (Chabrol et al. , 2010). One type of autoimmune encephalitis, notable for variable combinations of seizures, amnesia, psychosis, hyponatraemia, low prevalence of remote tumour and high response rate to immunotherapy was identified in 2001 by Angela Vincent and colleagues. The cases had serum autoantibodies directed to voltage gated potassium channel complexes (VGKC) measured by radioimmunoprecipitation assay of whole rabbit-brain homogenates using 125I-labelled dendrotoxin (Vincent et al. , 2004). These are the same circulating antibodies, though at higher levels, as those studied by the late John Newsom-Davis and the late Ian Hart in peripheral nerve hyperexcitability and Morvan’s syndrome (Hart et al. , 2002). VGKC-complex antibodies are probably pathogenic. They tick a few of the boxes to satisfy Witebsky’s postulates of autoimmune disease: the antibodies are highly specific, though …