The extracellular domain of myelin oligodendrocyte glycoprotein elicits atypical experimental autoimmune encephalomyelitis in rat and Macaque species.

Alan D Curtis,Shaun P Reece,Robert L Wardle,Matthew D Rosenbaum,Najla Taslim,Michael R Van Scott,Elena Grebenciucova,Mark D Mannie,Richard H Ray

doi:10.1371/journal.pone.0110048

Alan D Curtis, Shaun P Reece + Show 7 more

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https://doi.org/10.1371/journal.pone.0110048

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Journal: PloS one	Publication Date: Oct 10, 2014
Citations: 6	License type: CC BY 4.0

Affiliation: East Carolina University, University of Chicago

Abstract

Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund’s adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund’s adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6–7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction.

Highlights

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by focal inflammatory lesions and demyelinating plaques in periventricular and perivascular regions of the CNS [1,2,3]
Immunization of seven Lewis rats with 25 mg GP69-88 and 50 mg rat immunoglobulin variable (IgV)-myelin oligodendrocyte glycoprotein (MOG) emulsified in complete Freund’s adjuvant (CFA) caused a monophasic episode of EAE marked by an ascending flaccid paralysis followed in 3–5 days by a full and spontaneous recovery
Subsequent boosts of rat IgV-MOG in incomplete Freund’s adjuvant (IFA) on days 45 and 85 caused a second bout of chronic ‘atypical’ EAE marked by unusual clinical signs: forelimb weakness without hindlimb involvement, ataxia without flaccid paralysis of the tail, dystonia, rigid asymmetric extension of a hindlimb or forelimb, and/or vertigo/disequilibrium and torticollis

Summary

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by focal inflammatory lesions and demyelinating plaques in periventricular and perivascular regions of the CNS [1,2,3]. MS is a clinically heterogeneous disease with substantial variability in both clinical presentation and disease progression. Research in EAE has focused on ‘classical’ models in which disease progression is marked by a stereotypical ascending flaccid paralysis. Rats afflicted with classical EAE initially present with flaccid paralysis of the distal tail followed by an anterior progression over the 1–3 days culminating in a symmetric paralysis of both hindlimbs. Classical disease courses are monophasic, relapsing-remitting, or chronic-progressive depending on the rodent strain and immunizing antigen, with focal mononuclear inflammatory lesions observed in the spinal cord and brainstem. A stereotypical ascending flaccid paralysis, which is the defining clinical hallmark of classical EAE, is seldom observed in MS

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