Isoaspartylation appears to trigger small cell lung cancer-associated autoimmunity against neuronal protein ELAVL4

J Neuroimmunol. 2016 Oct 15:299:70-78. doi: 10.1016/j.jneuroim.2016.09.002. Epub 2016 Sep 3.

Abstract

Autoantibodies against SCLC-associated neuronal antigen ELAVL4 (HuD) have been linked to smaller tumors and improved survival, but the antigenic epitope and mechanism of autoimmunity have never been solved. We report that recombinant human ELAVL4 protein incubated under physiological conditions acquires isoaspartylation, a type of immunogenic protein damage. Specifically, the N-terminal region of ELAVL4, previously implicated in SCLC-associated autoimmunity, undergoes isoaspartylation in vitro, is recognized by sera from anti-ELAVL4 positive SCLC patients and is highly immunogenic in subcutaneously injected mice and in vitro stimulated human lymphocytes. Our data suggest that isoaspartylated ELAVL4 is the trigger for the SCLC-associated anti-ELAVL4 autoimmune response.

Keywords: Autoimmunity; Isoaspartylation; SCLC; Small cell lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Amino Acid Sequence
  • Animals
  • Autoimmunity / immunology*
  • ELAV-Like Protein 4 / genetics
  • ELAV-Like Protein 4 / immunology*
  • ELAV-Like Protein 4 / metabolism
  • Female
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Neurons / immunology*
  • Neurons / metabolism
  • Rabbits
  • Small Cell Lung Carcinoma / genetics
  • Small Cell Lung Carcinoma / immunology*
  • Small Cell Lung Carcinoma / metabolism

Substances

  • ELAV-Like Protein 4
  • ELAVL4 protein, human