| First Author | Bergman CM | Year | 2012 |
| Journal | J Immunol | Volume | 188 |
| Issue | 12 | Pages | 6001-9 |
| PubMed ID | 22586035 | Mgi Jnum | J:188870 |
| Mgi Id | MGI:5442477 | Doi | 10.4049/jimmunol.1101898 |
| Citation | Bergman CM, et al. (2012) A switch in pathogenic mechanism in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in IFN-gamma-inducible lysosomal thiol reductase-free mice. J Immunol 188(12):6001-9 |
| abstractText | IFN-gamma-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. |
