title: A switch in pathogenic mechanism in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in IFN-γ-inducible lysosomal thiol reductase-free mice.
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.
authors.affiliation: Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Bergman
authors.forename: Cecilia B
authors.initials: CB
authors.lastname: Marta
authors.forename: Maja
authors.initials: M
authors.lastname: Maric
authors.forename: Steven E
authors.initials: SE
authors.lastname: Pfeiffer
authors.forename: Peter
authors.initials: P
authors.lastname: Cresswell
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Ruddle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009185:Myelin Proteins / Q000276:immunology* / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D010088:Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010446:Peptide Fragments / Q000276:immunology*; D051381:Rats; D017386:Sequence Homology, Amino Acid
chemical_list: D006023:Glycoproteins; C571326:MOG protein, human; C571327:Mog protein, mouse; C571328:Mog protein, rat; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D010088:Oxidoreductases; C483811:Ifi30 protein, mouse; D050862:Oxidoreductases Acting on Sulfur Group Donors