Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler's virus-infected mice

J Clin Invest. 1999 Sep;104(5):599-610. doi: 10.1172/JCI7292.

Abstract

The mechanisms underlying the initiation of virus-induced autoimmune disease are not well understood. Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a mouse model of multiple sclerosis, is initiated by TMEV-specific CD4(+) T cells targeting virally infected central nervous system-resident (CNS-resident) antigen-presenting cells (APCs), leading to chronic activation of myelin epitope-specific CD4(+) T cells via epitope spreading. Here we show that F4/80(+), I-A(s+), CD45(+) macrophages/microglia isolated from the CNS of TMEV-infected SJL mice have the ability to endogenously process and present virus epitopes at both acute and chronic stages of the disease. Relevant to the initiation of virus-induced autoimmune disease, only CNS APCs isolated from TMEV-infected mice with preexisting myelin damage, not those isolated from naive mice or mice with acute disease, were able to endogenously present a variety of proteolipid protein epitopes to specific Th1 lines. These results offer a mechanism by which localized virus-induced, T cell-mediated inflammatory myelin destruction leads to the recruitment/activation of CNS-resident APCs that can process and present endogenous self epitopes to autoantigen-specific T cells, and thus provide a mechanistic basis by which epitope spreading occurs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigen Presentation*
  • Autoimmune Diseases / etiology
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / pathology
  • Autoimmune Diseases / virology
  • CD4-Positive T-Lymphocytes / immunology
  • Cardiovirus Infections / complications
  • Cardiovirus Infections / immunology*
  • Cells, Cultured
  • Central Nervous System / immunology*
  • Central Nervous System / pathology
  • Demyelinating Diseases / etiology
  • Demyelinating Diseases / immunology*
  • Demyelinating Diseases / pathology
  • Demyelinating Diseases / virology
  • Disease Models, Animal*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Encephalomyelitis, Autoimmune, Experimental / virology
  • Epitopes / immunology*
  • Female
  • Macrophages / immunology
  • Mice
  • Mice, Inbred Strains
  • Microglia / immunology
  • Molecular Sequence Data
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / virology
  • Myelin Proteolipid Protein / immunology*
  • Peptide Fragments / immunology
  • Spinal Cord / pathology
  • Th1 Cells / immunology
  • Theilovirus*

Substances

  • Epitopes
  • Myelin Proteolipid Protein
  • Peptide Fragments