Myelin oligodendrocyte glycoprotein peptide-induced experimental allergic encephalomyelitis and T cell responses are unaffected by immunoproteasome deficiency

Abstract

The inoculation of MOG peptides into C57BL/6 mice induces CD4 + and CD8 + T cells, and recent work has shown that adoptive transfer of the latter population, after extensive in vitro stimulation, can cause EAE in naïve recipient mice. Herein, we have evaluated the incidence and severity of EAE, and the induction of CD4 + and CD8 + T cells, following MOG peptide inoculation of wt mice and of LMP-2KO mice that lack an intact immunoproteasome, a cytoplasmic organelle that is induced by chronic inflammation and that may be important for the presentation of MHC class I epitopes to CD8 + T cells. We report that EAE, evaluated by both clinical and histological criteria, is similar in LMP-2KO mice and wildtype C57B/6 mice (wt) in response to immunization with MOG peptides MOG 35-55 and MOG [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] , suggesting that the immunoproteasome does not play a key role in the development of demyelinating disease. Furthermore, and consistent with previous reports, peptidespecific CD8 + T cells were barely detectable in the CNS of peptide-immunized mice, although peptide-specific CD4 + T cells were abundant. Therefore, we used a new technique to look for autoreactive CD8 + T cells in MOG peptide-immunized mice, and we report the identification of CD4 + and CD8 + T cells that, as late as 19 days after peptide injection, are actively producing IFNγ in vivo, in response to in vivo antigen contact.

Immuno- and Constitutive Proteasomes Do Not Differ in Their Abilities to Degrade Ubiquitinated Proteins

“…No significant difference in disease scores was observed between LMP7 −/− and wild-type mice (Figure 5), in clear contrast to the results reported by Seifert et al. (2010) but consistent with the study by Frausto et al. (2007), who found no effect of LMP2 deficiency on the course of EAE.…”

Inhibition of the immunoproteasome ameliorates experimental autoimmune encephalomyelitis

“…Interestingly, we found that mice genetically deficient in any of the immunoproteasome active site subunits developed EAE following MOG 35–55 immunization that was indistinguishable from wild type C57BL/6 mice (Fig ). Similar results using LMP2 −/− mice have been reported by Frausto et al () while Seifert et al have reported that MOG 35–55 immunization of LMP7 −/− mice results in more severe inflammation compared to wild type mice (Seifert et al , ), which could not be confirmed by others (Nathan et al , ). Although a precise reason for these disparate results is not known, it appears that the clinical severity reported by Seifert et al (approximately 0.75) was much lower than we report here.…”

Proteomic Identification of Immunoproteasome Accumulation in Formalin-Fixed Rodent Spinal Cords with Experimental Autoimmune Encephalomyelitis

“…For example, a 60HH variant of the IP-specific LMP2 gene has been correlated with altered MBP epitope generation and reduced risk of multiple sclerosis development in HLA-A*02 + Italian females 61 . However, in LMP2 knockout mice, MOG peptide-induced EAE symptoms were not significantly different compared to wild type animals 68 .…”