TABLE 2.

“Inside-out” and “Outside-in” disease model systems highlighted in this review.

	“Inside-Out” models			“Outside-In” models
	Epsilon Toxin Model	Diphtheria Toxin A (DTA) Model	Cuprizone autoimmune encephalitis (CAE) Model	Chronic Experimental Autoimmune Encephalomyelitis (C-EAE) Model	Relapsing Remitting Experimental Autoimmune Encephalomyelitis (R-EAE) Model	Theiler’s Virus-Induced Demyelinating Disease	Japanese Macaque Encephalomyelitis (JME) Model
Model species	Mouse	Mouse	Mouse	Mouse	Mouse	Mouse	Macaque
Induction of disease model (in Adults)	Epsilon toxin, produced by type B and D strains of Clostridium perfringens, a spore-forming gram-positive bacterium	Timed genetic expression of diphtheria toxin (tamoxifen induced PLPCreERT for targeting OL)	Cuprizone diet for 2 weeks, then inject CFA (SubQ) and Pertussis Toxin (IP)	MOG35–55 + CFA (SubQ) and Pertussis Toxin (IP)	PLP139–151 + CFA (SubQ)	Theiler’s Murine Encephalomyelitis Virus (TMEV) intracerebral infection	Japanese Macaque Rhadinovirus (JMRV), spontaneous or injected
Disease model trigger	Epsilon Toxin induced cytotoxicity (OL)	DTA induced cell death (OL), secondary MOG peptide immune response	Cuprizone destabilizes myelin, Citrullinated MBP drives immune response	MOG35–55 peptide immune response	PLP139–151 peptide immune response	Response to TMEV and subsequent spreading to PLP and MBP epitopes	JMRV infection, MBP peptide immune response
Disease model pathogenesis	OL cytotoxicity, triggers demyelination	OL ablation, triggers demyelination/remyelination, secondary immune response (respond to MOG peptide)	Myelin breakdown, secondary immune response (respond to MBP epitope)	Immune infiltration (respond to MOG peptide), secondary CNS degeneration	Immune infiltration (initially respond to PLP peptide, later to MBP), secondary CNS degeneration	Immune response to virus, release of myelin epitopes inducing autoimmune pathology, secondary CNS degeneration	Immune response to virus and infiltration (respond to MBP peptide), secondary CNS degeneration