MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration

Nat Commun. 2014 Apr 16;5:3633. doi: 10.1038/ncomms4633.

Abstract

Subsets of rodent neurons are reported to express major histocompatibility complex class I (MHC-I), but such expression has not been reported in normal adult human neurons. Here we provide evidence from immunolabel, RNA expression and mass spectrometry analysis of postmortem samples that human catecholaminergic substantia nigra and locus coeruleus neurons express MHC-I, and that this molecule is inducible in human stem cell-derived dopamine (DA) neurons. Catecholamine murine cultured neurons are more responsive to induction of MHC-I by gamma-interferon than other neuronal populations. Neuronal MHC-I is also induced by factors released from microglia activated by neuromelanin or alpha-synuclein, or high cytosolic DA and/or oxidative stress. DA neurons internalize foreign ovalbumin and display antigen derived from this protein by MHC-I, which triggers DA neuronal death in the presence of appropriate cytotoxic T cells. Thus, neuronal MHC-I can trigger antigenic response, and catecholamine neurons may be particularly susceptible to T-cell-mediated cytotoxic attack.

Publication types

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

MeSH terms

  • Adrenergic Neurons / drug effects
  • Adrenergic Neurons / metabolism*
  • Aged
  • Aged, 80 and over
  • Animals
  • Cell Survival
  • Dopamine / metabolism
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism*
  • Female
  • Gene Expression Profiling
  • Genes, MHC Class I*
  • Histocompatibility Antigens Class I / drug effects
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Interferon-gamma / pharmacology
  • Locus Coeruleus / metabolism*
  • Male
  • Melanins / metabolism
  • Mice
  • Microglia / metabolism*
  • Middle Aged
  • Oxidative Stress
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism*
  • Substantia Nigra / metabolism*
  • T-Lymphocytes, Cytotoxic
  • alpha-Synuclein / metabolism

Substances

  • Histocompatibility Antigens Class I
  • Melanins
  • RNA, Messenger
  • alpha-Synuclein
  • neuromelanin
  • Interferon-gamma
  • Dopamine