Some encephalitides and seizure disorders previously thought to be idiopathic now appear to be immune mediated. The antigens are cell surface or synaptic receptors that have critical roles in neuronal transmission and plasticity, such as the excitatory glutamate receptors, NMDAR and AMPAR, and the inhibitory GABAB receptor. The spectrum of associated symptoms varies according to the target antigen and their recognition is important because they can affect children and young adults, may occur with and without tumor association, and respond to immunotherapy. For example, anti-NMDAR encephalitis results in a characteristic syndrome that is now widely recognized in children and adults. Symptoms of this disorder include, psychosis, alterations of memory, behavior and cognition, seizures, dyskinesias, and autonomic and breathing instability. In contrast, antibodies to AMPAR and GABAB receptors associate more frequently with cancer and result in a classical picture of limbic encephalitis or prominent psychiatric manifestations. Immunologically these disorders are characterized by four features: 1) the epitopes are extracellular, 2) the antibody binding is directly visible in cells expressing the receptor, 3) patients’ antibodies alter the structure or function of the target receptor; for example, NMDAR antibodies crosslink and internalize the receptors resulting in a decrease of synaptic NMDAR cluster density and NMDAR-mediated currents, and 4) the clinical features of these disorders resemble pharmacologic or genetic models in which the corresponding receptors are disrupted. Given that the syndromes attributed to voltage-gated potassium channels (VGKC) did not fulfill these criteria, we recently conducted experiments to clarify the identity of the antigen. These studies resulted in the isolation of LGI1, an epilepsy related gene that encodes a secreted neuronal protein, as the main antigen of limbic encephalitis previously ascribed to VGKC. We also identified CASPR2 as the antigen of a form of encephalitis with seizures, some cases of Morvan’s syndrome, and infrequent cases of neuromyotonia. Thus, our studies have revealed an expanding group of disorders of memory, behavior and cognition that appear to be directly mediated by antibodies against receptors and neuronal cell surface proteins. Future studies should focus in the mechanisms whereby antibodies affect the structure, function, and trafficking of the targeted synaptic proteins.


Friday, November 4, 2011, 12:00. Blue Lecture Room

Hosted by Prof. Melike Lakadamyali