A switch in pathogenic mechanism in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in IFN-γ-inducible lysosomal thiol reductase-free mice

J Immunol. 2012 Jun 15;188(12):6001-9. doi: 10.4049/jimmunol.1101898. Epub 2012 May 14.

Abstract

IFN-γ-inducible lysosomal thiol reductase (GILT) is an enzyme located in the Lamp-2-positive compartments of APC. GILT(-/-) mice are phenotypically normal, but their T cells exhibit reduced proliferation to several exogenously administered Ags that include cysteine residues and disulfide bonds. We undertook the present studies to determine if GILT(-/-) mice would process exogenously administered myelin oligodendrocyte glycoprotein (MOG), which contains disulfide bonds, to generate experimental autoimmune encephalomyelitis (EAE) to the endogenous protein. One possibility was that MOG(35-55) peptide would induce EAE, but that MOG protein would not. GILT(-/-) mice were relatively resistant to MOG(35-55)-induced EAE but slightly more susceptible to rat MOG protein-induced EAE than wild-type (WT) mice. Even though MOG(35-55) was immunogenic in GILT(-/-) mice, GILT APCs could not generate MOG(35-55) from MOG protein in vitro, suggesting that the endogenous MOG protein was not processed to the MOG(35-55) peptide in vivo. Immunization of GILT(-/-) mice with rat MOG protein resulted in a switch in pathogenic mechanism from that seen in WT mice; the CNS infiltrate included large numbers of plasma cells; and GILT(-/-) T cells proliferated to peptides other than MOG(35-55). In contrast to WT rat MOG-immunized mice, rat MOG-immunized GILT(-/-) mice generated Abs that transferred EAE to MOG(35-55)-primed GILT(-/-) mice, and these Abs bound to oligodendrocytes. These studies, demonstrating the key role of a processing enzyme in autoimmunity, indicate that subtle phenotypic changes have profound influences on pathogenic mechanisms and are directly applicable to the outbred human population.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigen-Presenting Cells / immunology
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Fluorescent Antibody Technique
  • Glycoproteins / immunology*
  • Humans
  • Immunoblotting
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Myelin Proteins / immunology*
  • Myelin Proteins / metabolism
  • Myelin-Oligodendrocyte Glycoprotein
  • Oxidoreductases / deficiency
  • Oxidoreductases / genetics
  • Oxidoreductases / immunology*
  • Oxidoreductases Acting on Sulfur Group Donors
  • Peptide Fragments / immunology*
  • Rats
  • Sequence Homology, Amino Acid

Substances

  • Glycoproteins
  • MOG protein, human
  • Mog protein, mouse
  • Mog protein, rat
  • Myelin Proteins
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • myelin oligodendrocyte glycoprotein (35-55)
  • Oxidoreductases
  • Ifi30 protein, mouse
  • Oxidoreductases Acting on Sulfur Group Donors