A neuropathological analysis of experimental autoimmune encephalomyelitis with predominant brain stem and cerebellar involvement and differences between active and passive induction

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune demyelinating disease that can be induced in a variety of animal species and which is commonly used as an animal model of multiple sclerosis. In rodent EAE models, the clinical disease is typified by ascending paralysis; however, other clinical patterns can also be observed by inducing disease with particular peptides of myelin proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein. Here we describe EAE induced in C3H/HeJ mice by inoculation with residues 190-209 of PLP. This form of EAE is manifested clinically by a movement disorder, with axial rotation of the head and trunk. Histologically, this form of EAE is characterized by predominant cerebellar or brain stem involvement, depending on whether EAE is induced by active immunization with the PLP peptide, or by passive transfer of T cells specific for the peptide. The inflammatory cell infiltrate is composed of polymorphonuclear cells and mononuclear cells. This rotatory form of EAE may be a useful model for studying the neuropathological characteristics of multiple sclerosis affecting the brain stem and cerebellum.

T-Cell Properties Determine Disease Site, Clinical Presentation, and Cellular Pathology of Experimental Autoimmune Encephalomyelitis

“…Studies presented here are in agreement with the correlation between histological profile and clinical presentation reported in detail by Muller and colleagues, 24 and Sobel 25 in that mice with conventional ascending paralysis tend to have more numerous and severe lesions in spinal cord, whereas mice with axial-rotatory EAE have significant lesions in the brainstem and/or cerebellar regions, and limited spinal cord disease. The consistent transfer of particular disease phenotypes with defined T-cell lines described in this report supports the notion of a given T-cell clone having distinct preference for a particular region or regions of the CNS.…”

“…24,25,35,36 Here we demonstrate two distinct EAE phenotypes induced in a single mouse strain and begin to investigate the cellular basis for its heterogeneous manifestations. Unlike EAE-resistant wild-type BALB/c mice, BALB-GKO mice are reported to present with the conventional clinical signs of EAE when immunized with native MBP.…”

“…24 -27,37,38 Greer and colleagues, 38 Muller and colleagues, 24 26 describe an atypical or nonclassical clinical presentation of EAE induced in recipients of T H 2 cells producing high levels of IL-5, derived from B10.PL mice transgenically expressing a TCR for MBP Ac1-11; the description of spinning and rolling is very similar to axial-rotatory EAE described by Greer and colleagues, 38 Muller and colleagues, 24 and Sobel, 25 and observed here. Finally, Huseby and colleagues 27 describe a similar clinical presentation of EAE induced in C3H recipients of class I-restricted MBP 79-87-recognizing CD8 ϩ T cells from C3H/HeJ mice.…”

IFN-γ Determines Distinct Clinical Outcomes in Autoimmune Encephalomyelitis

“…Clinically, the spontaneous disease appears to be similar to the disease reported by Greer et al (8,9) in PLP 190 -209 -immunized C3H mice (8, 9) and mice adoptively transferred mice with PLP 190 -209 -specific cells (9). Systematic occurrence of a form of nonclassical EAE has also been reported in mice transferred with MBP 79 -87 -specific CD8 ϩ T cells (10) and upon reinduction of recovered Lewis rats with MBP and adjuvant (7).…”

“…The clinical signs of classical EAE correlate strongly with inflammation in the CNS, with a strong spinal cord involvement and limited brainstem and cerebellum inflammation. Interestingly, there have been reports of a nonclassical form of EAE with axial rotatory movement or front leg without hind leg involvement (5)(6)(7)(8)(9)(10). Nonclassical EAE has been shown to primarily involve the brain, cerebellum, and/or brainstem, a feature also observed in MS (11).…”