Mutated cancer autoantigen implicated cause of paraneoplastic myasthenia gravis

Anastasia Zekeridou, Guy E. Griesmann, Vanda A Lennon

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Introduction: Antitumor immune responses are postulated to initiate paraneoplastic neurological disorders when proteins that are normally restricted to neural cells are expressed as oncoproteins. Mutated oncopeptides could bypass self-tolerant T cells to activate cytotoxic effector T lymphocytes and requisite helper T lymphocytes to stimulate autoantibody production by B lymphocytes. Methods: We investigated muscle-type nicotinic acetylcholine receptor (AChR) antigen expression at transcriptional and protein levels in a small-cell lung cancer line (SCLC) established from a patient with AChR-immunoglobulin G (IgG)-positive myasthenia gravis. Results: We identified messenger RNA transcripts encoding the 2 AChR α1-subunit isoforms and 7 alternative-splicing products, 3 of which yielded premature stop codons. Despite detecting native muscle-type AChR pentamers in the tumor, we did not identify mutant α1-peptides. However, we found α1-subunit-derived peptides bound to tumor major histocompatibility complex (MHC)1-protein. In a control SCLC from an antineuronal nuclear autoantibody, type 1 (anti-Hu)-IgG-positive patient, we identified MHC1-complexed Hu protein-derived peptides but not AChR peptides. Discussion: Our findings support onconeural protein products as pertinent immunogens initiating paraneoplastic neurological autoimmunity. Muscle Nerve, 2018.

Original languageEnglish (US)
JournalMuscle and Nerve
DOIs
StateAccepted/In press - Jan 1 2018

Keywords

  • cancer neoantigen
  • lung cancer
  • muscle acetylcholine receptor autoantibody
  • onconeural antigens
  • paraneoplastic autoimmunity
  • sensory neuronopathy

ASJC Scopus subject areas

  • Physiology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Physiology (medical)

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