Experimental Allergic Encephalomyelitis

Experimental allergic (or autoimmune) encephalomyeli-tis (EAE) has been a central model of inflammatory demyelinating disease since Rivers and Schwentker induced myelin destruction in monkeys immunized with brain tissue in 1935 (Rivers and Schwentker, 1935). Since that time, it has become clear that EAE can be induced in essentially all mammals, from rodents to humans (Lassmann and Wekerle, 1998; Raine and Bornstein, 1970) (Fig. 8). CNS protein-reactive T-cells are required for induction of EAE, and adoptive transfer of T-cells from immunized animals into naïve animals can elicit autoimmune-mediated inflammation. In contrast to Theiler's virus-mediated demyelination, EAE-related encephalitogenic T-cells are almost entirely CD4+, recognizing CNS antigens only within the context of MHC class II (Swanborg, 2001). While some evidence suggests that CD8+ and yS-T cells may play a regulatory role in EAE (Segal, 2003), CD4+ T-cells are considered to be the primary mediators of autoimmune-mediated demyelination. This is an important distinction, as well as an important difference between human MS and EAE in animals.

Figure 7 Evidence of demyelination and axon loss in the Theiler's virus model of MS. (A) Appearance of normal white matter in an uninfected SJL/J mouse. Ultrathin sections of araldite-embedded spinal cord were stained with 4% paraphenylenediamine to visualize myelin. (B) Extensive demyelination evident in the spinal cord of an SJL/J mouse infected for 180 days with Theiler's virus. (C) Higher magnification of white matter from a normal, uninfected mouse. Note the thick myelin sheaths. (D) Higher magnification view of a demyelinated lesion in (B). Note the almost complete loss of myelinated profiles, the thinness of the myelin sheaths that are present, and the presence of a large number of dark debris inclusions. (E) Immunostaining for the neurofilament heavy chain in an area of normal white matter in an unin-fected mouse. Note the intensely stained axon profiles seen in cross-section. (F) A comparable region in a mouse chronically infected with Theiler's virus. This demyelinated region shows substantial loss of neurofilament staining.

(Continues)

Figure 7 Evidence of demyelination and axon loss in the Theiler's virus model of MS. (A) Appearance of normal white matter in an uninfected SJL/J mouse. Ultrathin sections of araldite-embedded spinal cord were stained with 4% paraphenylenediamine to visualize myelin. (B) Extensive demyelination evident in the spinal cord of an SJL/J mouse infected for 180 days with Theiler's virus. (C) Higher magnification of white matter from a normal, uninfected mouse. Note the thick myelin sheaths. (D) Higher magnification view of a demyelinated lesion in (B). Note the almost complete loss of myelinated profiles, the thinness of the myelin sheaths that are present, and the presence of a large number of dark debris inclusions. (E) Immunostaining for the neurofilament heavy chain in an area of normal white matter in an unin-fected mouse. Note the intensely stained axon profiles seen in cross-section. (F) A comparable region in a mouse chronically infected with Theiler's virus. This demyelinated region shows substantial loss of neurofilament staining.

(Continues)

Figure 7—cont'd (G) Another example of neurofilament staining in a normally myelinated area of the spinal cord of an uninfected mouse. (H) The same location as in (G) within the demyelinated lesion of a chronically infected mouse. (F) and (G) suggest that severe axon loss is associated with demyelination in the Theiler's virus model of MS.

Figure 7—cont'd (G) Another example of neurofilament staining in a normally myelinated area of the spinal cord of an uninfected mouse. (H) The same location as in (G) within the demyelinated lesion of a chronically infected mouse. (F) and (G) suggest that severe axon loss is associated with demyelination in the Theiler's virus model of MS.

Axon damage is also associated with EAE (Ahmed et al., 2002; Bjartmar and Trapp, 2003; Bjartmar et al., 2003; Kornek et al., 2000, 2001; Linker et al., 2002; Madrid and

Figure 8 An example of demyelination in the spinal cord associated with EAE. Note the focal nature of the lesion, surrounded by relatively normal appearing white matter.

Wisniewski, 1977; Mancardi et al., 2001; Mead et al., 2002; Penkowa et al., 2003; Penkowa and Hidalgo, 2003; Petzold et al., 2003; Pluchino et al., 2003; Raine and Cross, 1989; Raine et al., 1984; Storch et al., 2002). Both acute axonal damage within actively demyelinating lesions, and chronic axonal injury within inactive lesions and normal-appearing white matter are observed in EAE (Kornek et al., 2000). However, the mechanisms responsible for this axon damage are unclear, and, in contrast to the Theiler's virus model of MS, no study to date has identified a specific effector cell or process that is indispensable for axon injury but dispensable for demyelination.

0 0

Post a comment