Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis

Abstract

We describe here the paradoxical development of spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell antigen receptor (TCR) in the absence of MOG. We report that in Mog-deficient mice (Mog-/-), the autoimmune response by transgenic T cells is redirected to a neuronal cytoskeletal self antigen, neurofilament-M (NF-M). Although components of radically different protein classes, the cross-reacting major histocompatibility complex I-Ab-restricted epitope sequences of MOG35-55 and NF-M18-30 share essential TCR contact positions. This pattern of cross-reaction is not specific to the transgenic TCR but is also commonly seen in MOG35-55-I-Ab-reactive T cells. We propose that in the C57BL/6 mouse, MOG and NF-M response components add up to overcome the general resistance of this strain to experimental induction of autoimmunity. Similar cumulative responses against more than one autoantigen may have a role in spontaneously developing human autoimmune diseases.

Exploring the origins of grey matter damage in multiple sclerosis

“…These include the possible expression or relative overabundance of a target autoantigen for adaptive (T cell-and antibody-mediated) immune mechanisms 53 or the involvement of a T cell with specificity for both a myelin-and neuronal antigen 54 . An alternative hypothesis suggests that the presence of inflammatory infiltrates in the meningeal space and/or in the adjacent perivascular spaces might lead to the release of cytotoxic inflammatory mediators into the grey matter 17,38,55 .…”

T Cell Apoptosis and Induction of Foxp3+ Regulatory T Cells Underlie the Therapeutic Efficacy of CD4 Blockade in Experimental Autoimmune Encephalomyelitis

“…To this end, we passively induced EAE in C57BL/6 mice by adoptively transferring 14 3 10 6 MOG-specific 2D2 cells that were primed in vitro under Th1 polarization conditions (Fig. 4A) (55). Treating the recipient mice on days 0, 2, and 4 after Th1 transfer with anti-CD4 mAbs prevented the onset of disease in all treated mice (Fig.…”

Fragile privileges: autoimmunity in brain and eye

“…A detailed proteomic investigation revealed that the MOG-specific TCR co-recognized a particular epitope on the middle neurofilament (NF-M18-30), a component of the axonal cytoskeleton. Transfer studies confirmed that MOG/NF-M double reactive T cells transferred to MOG-deficient mice induced EAE with a delayed onset compared to wildtype, MOG sufficient recipients, whereas double knock-out mice lacking both MOG and NF-M remained completely resistant [29] .…”