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

Abstract

Significance Antibodies recognizing the neuronal gamma-aminobutyric acid A receptor (GABAA-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 GABAA-R encephalitis we cloned a highly expressed antibody and showed that it binds the GABAA-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 GABAA-R patients, suggesting that such cross-reactivity is presumably a key event in the pathogenesis of GABAA-R encephalitis. 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.