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

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

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.

Keywords: GABA-A-receptor encephalitis; autoantibody; autoimmune encephalitis; epilepsy; paraneoplastic encephalitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / immunology*
  • Autoantibodies / immunology*
  • Autoantigens / immunology
  • Autoimmune Diseases of the Nervous System / etiology
  • Autoimmune Diseases of the Nervous System / metabolism
  • Autoimmunity
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Biomarkers
  • Cross Reactions / immunology*
  • Disease Susceptibility* / immunology
  • Encephalitis / etiology*
  • Encephalitis / metabolism
  • Encephalitis / pathology
  • Humans
  • Pyramidal Cells / immunology
  • Pyramidal Cells / metabolism
  • Receptors, GABA-A / immunology*

Substances

  • Antigens, Neoplasm
  • Autoantibodies
  • Autoantigens
  • Biomarkers
  • Receptors, GABA-A