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 MOG35–55 peptide would induce EAE, but that MOG protein would not. GILT−/− mice were relatively resistant to MOG35–55-induced EAE but slightly more susceptible to rat MOG protein-induced EAE than wild-type (WT) mice. Even though MOG35–55 was immunogenic in GILT−/− mice, GILT APCs could not generate MOG35–55 from MOG protein in vitro, suggesting that the endogenous MOG protein was not processed to the MOG35–55 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 MOG35–55. In contrast to WT rat MOG-immunized mice, rat MOG-immunized GILT−/− mice generated Abs that transferred EAE to MOG35–55-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.