Immunopathology and synaptopathy in human brain tissue and novel animal models of LGI1 encephalitis

Autoimmune encephalitis with autoantibodies to the neuronal secreted protein LGI1 induces a characteristic clinical syndrome of limbic encephalitis and prototypical faciobrachial dystonic seizures followed by progressive hippocampal atrophy resulting in irreversible memory dysfunction. Antibodies are thought to induce defective synaptic signalling by interfering with LGI1 function. Furthermore, LGI encephalitis is featured by special immunological hallmarks, e.g. by autoantibodies of the IgG 4 subclass and by prominent systemic but also intrathecal production of pathogenic autoantibodies. Here, we aim at elucidating the underlying mechanisms of antineuronal autoimmunity leading to hippocampal atrophy and synaptic pathology in LGI1 encephalitis. Therefore, we will determine immune cell infiltration, effector activation, existence of local germinal centres, neuronal loss, and synaptic pathology in human brain autopsy specimens of patients with LGI1 encephalitis and in cats affected by feline complex partial seizures with orofacial involvement (FEPSO), which represents a natural animal model of limbic encephalitis with LGI1 antibodies. Knowledge about how anti-neuronal autoimmunity is initiated and driven in LGI1 encephalitis will help to better understand the pathophysiology in this enigmatic and frequent type of autoimmune encephalitis and it may allow us to develop and test novel treatment strategies.

Autoimmune encephalitis with autoantibodies to the neuronal surface antibodies are characterized by specific clinical syndromes of limbic encephalitis or diffuse encephalitis often with seizures. Most patients show good response to immunotherapy but some develop progressive hippocampal atrophy resulting in irreversible memory dysfunction. Antibodies are thought to induce defective synaptic signalling by interfering with the targeted antigen function. Furthermore, autoimmune encephalitis is featured by special immunological hallmarks, e.g. by autoantibodies of the IgG4 subclass and by prominent intrathecal but in specific cases also systemic production of pathogenic autoantibodies. In our study, we aim at elucidating the underlying mechanisms of antineuronal autoimmunity leading to hippocampal and cerebellar atrophy and synaptic pathology in different forms of idiopathic and paraneoplastic autoimmune encephalitis. Therefore, we determined immune cell infiltration, effector activation, neuronal loss, and synaptic pathology in human brain autopsy specimens of patients with anti-NMDAR and anti-AMPAR-encephalitis and revealed that synaptic dysfunction in anti-NMDAR encephalitis is antibody-mediated and reversible. We found that the topographic distribution of inflammation in patients with NMDAR-encephalitis reflects the clinical symptoms This is in contrast to paraneoplastic anti-AMPAR-encephalitis that presents a partly T cell-mediated pathology contributing to irreversible neuronal damage. In addition we identified global amnesia as so-far unknown clinical presentation of AMPAR-encephalitis, which will help in the diagnostic work-up of patients with this syndrome. Co-occurring pathologies such as tumors or demyelinating lesions influence the anatomic distribution, composition, and intensity of inflammation, which may modify patients' clinical presentation and outcome. Moreover we compared the pathogenetic mechanisms of paraneoplastic cerebellar degeneration (PCD) associated with intracellular anti-Yo antibodies (abs) to those with surface anti-P/Q-type VGCC abs. Both diseases present an irreversible Purkinje cell loss, which is T cell-mediated in anti-Yo-ab associated PCD but antibody-mediated in anti-P/Q-type VGCC ab-associated PCD. This indicates that anti-P/Q-VGCC-PCD patients could benefit from early oncologic and immunologic therapies. Immune mechanisms in anti-LGI1-encephalitis resemble those we describe in anti-AMPAR encephalitis and show a combination of antibody- and T cell mediated effects that result in hippocampal sclerosis in advanced disease stages. Knowledge about how anti-neuronal autoimmunity is initiated and driven in autoimmune encephalitis will help to better understand the pathophysiology in this enigmatic and frequent type of disease and it may allow us to develop and test novel treatment strategies.