Cross-reactivity of a pathogenic autoantibody to a tumor antigen in GABA A receptor encephalitis

• DOI: 10.1073/pnas.1916337118
• Publication Date: 2021-02-22T21:25:25Z
• Authors: Simone M. Brändle; Manuela Cerina; Susanne Weber; Kathrin Held; Amélie F. Menke; Carmen Alcalá; David Gebert; Alexander M. Herr...; Hannah Pellkofer; Lisa Ann Gerdes; Stefan Bittner; Frank Leypoldt; Bianca Teegen; Lars Komorowski; Tania Kümpfel; Reinhard Hohlfeld; Sven G. Meuth; Bonaventura Casanova; Nico Melzer; Eduardo Beltrán; Klaus Dornmair
• Keywords: B-Lymphocytes; Pyramidal Cells; GABA-A-receptor encephalitis, autoantibody, autoimmune encephalitis, epilepsy, paraneoplastic encephalitis; Autoimmunity; Cross Reactions; Receptors, GABA-A; Autoantigens; 3. Good health; 03 medical and health sciences; Autoimmune Diseases of the Nervous System; 0302 clinical medicine; Antigens, Neoplasm; Encephalitis; Humans; Disease Susceptibility; Biomarkers; Autoantibodies

Significance

Antibodies recognizing the neuronal gamma-aminobutyric acid A receptor (GABA A -R) cause severe encephalitis by triggering internalization of the antibody–receptor complexes in inhibitory synapses, which leads to hyperexcitability and dysfunction of neuronal networks. From the cerebrospinal fluid of a patient with GABA A -R encephalitis we cloned a highly expressed antibody and showed that it binds the GABA A -R and influences signal transduction in neurons, explaining clinical symptoms. Using several experimental techniques, we confirmed that the antibody cross-reacts to an oncoprotein which is known to be involved in several malignancies. We showed that cross-reactivity to this oncoprotein may also be detected in two other GABA A -R patients, suggesting that such cross-reactivity is presumably a key event in the pathogenesis of GABA A -R encephalitis.