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Cross-reactivity of a pathogenic autoantibody to a tumor antigen in GABAA receptor encephalitis.

Proc Natl Acad Sci U S A. 2021 Mar 2;118(9):e1916337118. doi: 10.1073/pnas.1916337118. PMID: 33619082.

Authors/Editors: Brändle SM, Cerina M, Weber S, Held K, Menke AF, Alcalá C, Gebert D, Herrmann AM, Pellkofer H, Gerdes LA, Bittner S, Leypoldt F, Teegen B, Komorowski L, Kümpfel T, Hohlfeld R, Meuth SG, Casanova B, Melzer N, Beltrán E, Dornmair K.
Publication Date: 2021

Abstract

Encephalitis associated with antibodies against the neuronal gamma-aminobutyric acid A receptor (GABAA-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 GABAA-R encephalitis. We expressed the antibody produced by it and showed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry that it recognizes the GABAA-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 GABAA-R encephalitis also recognized LMO5. This suggests that cross-reactivity between GABAA-R and LMO5 is frequent in GABAA-R encephalitis and supports the hypothesis of a paraneoplastic etiology.

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