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

Braendle, Simone M.; Cerina, Manuela; Weber, Susanne; Held, Kathrin; Menke, Amelie F.; Alcala, Carmen; Gebert, David; Herrmann, Alexander M.; Pellkofer, Hannah; Gerdes, Lisa Ann; Bittner, Stefan; Leypoldt, Frank; Teegen, Bianca; Komorowski, Lars; Kuempfel, Tania; Hohlfeld, Reinhard; Meuth, Sven G.; Casanova, Bonaventura; Melzer, Nico; Beltran, Eduardo und Dornmair, Klaus (2021): Cross-reactivity of a pathogenic autoantibody to a tumor antigen in GABA(A) receptor encephalitis. In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 118, No. 9, e1916337118

Abstract

Encephalitis associated with antibodies against the neuronal gamma-aminobutyric acid A receptor (GABA(A)-R) is a rare form of autoimmune encephalitis. The pathogenesis is still unknown but autoimmune mechanisms were surmised. Here we identified a strongly expanded B cell clone in the cerebrospinal fluid of a patient with GABA(A)-R encephalitis. We expressed the antibody produced by it and showed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry that it recognizes the GABA(A)-R. Patch-clamp recordings revealed that it tones down inhibitory synaptic transmission and causes increased excitability of hippocampal CA1 pyramidal neurons. Thus, the antibody likely contributed to clinical disease symptoms. Hybridization to a protein array revealed the cross-reactive protein LIM-domain-only protein 5 (LMO5), which is related to cell-cycle regulation and tumor growth. We confirmed LMO5 recognition by immunoprecipitation and ELISA and showed that cerebrospinal fluid samples from two other patients with GABA(A)-R encephalitis also recognized LMO5. This suggests that cross-reactivity between GABA(A)-R and LMO5 is frequent in GABA(A)-R encephalitis and supports the hypothesis of a paraneoplastic etiology.

• Item Type: Journal article
• Faculties: Medicine; Medicine > Munich Cluster for Systems Neurology (SyNergy)
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0027-8424
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198