GABA_A Receptor Antibodies from a Pediatric Encephalitis Patient Cause Autoimmune Epileptic Seizures

Background/Purpose: Since the first description of NMDA receptor encephalitis in 2007, an increasing number of antineuronal antibodies have been identified in patients with various neurological symptoms, commonly with an age peak in adolescence or early adulthood. The broad availability of antibody testing and increasing numbers of positive test results demonstrate the high clinical need for studies investigating the functional relevance of single antineuronal autoantibodies.

Antibodies targeting the GABA_A receptor (GABA_AR) hallmark an autoimmune encephalitis presenting with frequent seizures and psychomotor abnormalities. Their pathogenic role is still not well-defined, given the common overlap with further autoantibodies and the lack of patient derived monoclonal antibodies (mAbs).

Methods: We cloned and recombinantly produced 68 mAbs from cerebrospinal fluid cells of a pediatric index patient and examined their binding properties on tissue sections and cell-based assays. Using molecular biology and electrophysiology in functional assays we characterized identified GABA_AR-mAbs in vitro and in vivo.

Results: Five affinity-maturated GABA_AR IgG1 mAbs bound to various epitopes involving α1 and γ2 receptor subunits, with variable binding strength and partial competition. mAbs selectively reduced GABAergic currents in neuronal cultures without causing receptor internalization. Cerebroventricular infusion of GABA_AR mAbs and Fab fragments into rodents induced a severe phenotype with catatonia, seizures and increased mortality, reminiscent of encephalitis patients’ symptoms.

Conclusion: Our results prove direct functional effects of autoantibodies on GABA_ARs and provide an animal model for GABA_AR encephalitis. They further provide the scientific rationale for clinical treatments using antibody depletion and pave the way for future antibody-selective immunotherapies.

Publication History

Article published online:
28 October 2021