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

Automated summary

Encephalitis associated with antibodies against the neuronal GABA(A)-R is a rare form of autoimmune encephalitis. A study found a significantly expanded B cell clone in the cerebrospinal fluid of a patient with GABA(A)-R encephalitis, producing antibodies that likely contribute to clinical disease symptoms. Additionally, cross-reactivity between GABA(A)-R and the protein LMO5 was identified, supporting the hypothesis of a paraneoplastic etiology in GABA(A)-R encephalitis.