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

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.