Clinical and immunological characterization of antibody-mediated autoimmune encephalitis

January 29, 2018
Versione stampabile

Venue: Edificio Povo 2, via Sommarive nr. 9, Povo (Tn) - Room B102
Hour: 3.00 p.m.

  • Marianna Spatola - IDIBAPS (August Pi i Sunyer Biomedical Research Institute) Neuroimmunology laboratory - BARCELONA (Spain)

Autoimmune encephalitis associated with neuronal cell surface antibodies: a paradigm shift 
The term encephalitis refers to an inflammation of the brain, which can manifest with alteration of behavior, memory deficits, decreased level of consciousness and seizures. Despite an extensive diagnostic work-up, in up to half of the cases the etiology remains undetermined. In the last 10 years, the identification of a group of autoimmune encephalitis (AE) associated with neuronal cell surface antibodies has determined a paradigm shift, since several forms of encephalitis, that were previously considered “idiopathic” are now known to be immune-mediated. Since the first description in 2007 of anti-NMDAR encephalitis, an increasing number of antibodies against neuronal proteins including synaptic receptors (such as NMDAR, AMPAR, GABAAR, GABABR, and mGluR5) or transynaptic proteins (LGI-1, CASPR2) have been identified. AE are clinically relevant because they affect both children and adults, they can have severe manifestations often requiring intensive care support, potentially leading to neurological sequelae and death if not promtly diagnosed, and they respond to immunotherapy. The reasons why these neuronal antibodies are produced is largely unknown.  In some cases, an underlying tumor might represent the trigger for an autoimmune response (paraneoplastic origin). Moreover, recently, the observation that autoantibodies may develop after herpes simplex virus encephalitis has provided new fascinating hypothesis on the role of neurotropic viruses in triggering brain autoimmunity.
Pathogenic mechanisms of autoimmune encephalitis 
For some of these AE there is evidence that the antibodies are pathogenic. The best-characterized autoantibodies are those that target the ionotropic glutamate receptor NMDAR. Anti-NMDAR antibodies have direct functional effects on cultured neurons, causing a decrease in the number of membrane receptors and these effects have been also demonstrated in an animal model using intraventricular infusion of the antibodies. These effects are reversible upon removal of the antibodies, representing a clinical correlate of the response of neurological symptoms to immunotherapy. 
Novel findings in autoimmune encephalitis with mGluR5 antibodies 
Few patients have been reported with autoimmune encephalitis and Hodgkin’s lymphoma associated with antibodies to the metabotropic glutamate receptor 5 (mGluR5). Thus, the clinical spectrum and long-term outcome are largely unknown. We characterized the main clinical features of 11 patients with anti-mGluR5 encephalitis, and found that this AE mostly affect children and young adults, manifests with a complex neuropsychiatric syndrome, and can occur without tumor. Patients respond to immunotherapy and cancer treatment but can experience neurological relapses. The antibodies have pathogenic effects on cultures of rat hippocampal neurons by altering the levels of cell surface mGluR5, and induce changes in memory and behavior in mice infused intrathecally with patients’ antibodies.