The Extracellular Domain of Myelin Oligodendrocyte Glycoprotein Elicits Atypical Experimental Autoimmune Encephalomyelitis in Rat and Macaque Species

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.

Myelin‐specific T cells in animals with Japanese macaque encephalomyelitis

“…As an NHP model for immune‐mediated CNS disease, atypical EAE does have advantages, as disease can be induced, is self‐limiting, stable, and does not progress to humane endpoints like JME. However, there are distinct differences, specifically atypical EAE is associated with robust IgG response to conformational MOG epitopes, whereas JME exhibits positive CSF finding that have not yet been further evaluated for myelin specificity 3,12 . Interestingly, although we isolated and detected JMRV in JME lesions, we have not detected anti‐JMRV antibodies in the CSF, implying that CSF IgG targets other antigens.…”

“…And second, EAE is studied primarily in inbred mouse strains and this is in large contrast to MS, which occurs in a heterogeneous population with highly variable genetic diversity. More recently, however, others have shown that induction of EAE with recombinant myelin oligodendrocyte glycoprotein (MOG) encoding the extracellular domain (aa 1‐170) or MOG encephalitic peptide (aa 34‐56) emulsified in incomplete Freund’s adjuvant in cynomolgus macaques ( Macaca fascicularis ) can lead to atypical EAE disease that displays heterogeneity in clinical course, including less progressive disease accompanied with periods of remission 3 . Additionally, atypical EAE disease in macaques includes comparable MRI results, demyelination, and MOG‐specific T‐cell proliferation resulting in Th1 and Th17 responses 4 .…”

Demyelination Lesions Do Not Correlate with Clinical Manifestations by Bordetella pertussis Toxin Concentrations

“…In this study, the results obtained from the induction of the Lewis rats model follow those in the literature. Histopathological aspects such as leukocyte infiltration, microglia activation, and the presence of demyelinated plaques are classic demonstrations of induction [ 23 , 24 ]. Thus, the indirectly proportional relationship between clinical score increases, as well as the reduction in the weight of induced animals [ 24 , 25 ].…”

Lewis Rat Model of Experimental Autoimmune Encephalomyelitis

“…Further immunization protocols include immunization with the rat immunoglobulin variable (IgV)–related extracellular domain of myelin oligodendrocyte glycoprotein (IgV‐MOG) in CFA followed by one or more injections of rat IgV‐MOG in incomplete Freund's adjuvant (IFA). The resulting atypical disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti‐ MOG antibody against conformational epitopes of MOG (Curtis et al., ).…”

“…CFA + PT Antigen-specific T cells plus demyelinating anti-MOG Ab cause severe active disease Adelmann et al, 1995;Kojima et al, 1994;Linington et al, 1993 High-dosage PLP (1000 μg/rat) d CFA Monophasic active EAE Chalk et al, 1994 IgV-MOG e CFA + IgV-MOG injections + IFA Atypical EAE Curtis et al, 2014 Guinea pig MBP in Gimap5 mutant Lewis rats CFA T cell-mediated EAE despite lymphopenia Fischer et al, 2016 a The MBP-induced, Lewis rat model of EAE is commonly used as a model for an acute demyelinating attack in MS or acute disseminated encephalomyelitis. A central combined with a peripheral demyelination in the ventral and dorsal nerve roots has been reported (Pender, 1987;Pender, Tabi, Nguyen, & McCombe, 1995).…”