Table 1.

In vitro, ex vivo, and in vivo models of neuroimmunological disorders.

Disease	Induction mechanism	Species/strain	Encephalitogenic agent	Pathological features	Advantages	Disadvantages/limitations
MS	Active EAE	Rodents NHP	MBP, PLP, MAG, MOG emulsified in CFA or IFA	BBB disruption, inflammatory cell infiltration, axonal damage, demyelination	Reproduces histopathological and immunological characteristics common to human MS	Generates granulomas at the inoculation site and lesions, leading to pain symptoms
	Passive EAE	Rodents	Transfer of MBP-specific CD4+ T cells	Inflammatory cell infiltration, axonal damage and demyelination	Evaluates the mechanisms controlling immune surveillance, effector phase of disease and T-cell-mediated neuroinflammation	This model is not useful for studying relapsing-remitting MS, cannot be used to show remyelination and does not allow evaluating B cell activity in the pathogenesis of the disease
NMOSD	In vitro	Astrocytes	AQP4-IgG	Inflammation, changes in astrocytic phenotype and morphology, astrocyte damage, necrosis and AQP4 internalization	Evaluates the pathogenicity of AQP4-IgG, cytotoxicity and cell death. It can also be used for screening drugs	Cannot be used to evaluate demyelination nor to study the relationship between inflammation and demyelination
	Ex vivo	Rodents Tissue	AQP4-IgG or AQP4-IgG + complement	Loss of AQP4/GFAP and myelin	This model allows evaluating demyelination, screening drugs and investigate the influence of inflammatory mediators soluble factors involved in the NMOSD	Requires the presence of human complement to be more efficient. Only the isolated antibody is not capable causing demyelinating lesions
	Passive Transfer in EAE Models	Rodents	MBP and CFA (EAE) + AQP4-IgG	Loss of immunoreactivity of AQP4 and GFAP, deposition of IgG and activated complement, granulocyte and macrophages influx, microglial activation and astrocyte injury	It is a consolidated model for the reproduction of typical NMOSD characteristics and useful for investigating mechanisms involved in the early stages of lesion formation. Also important to the study of NMOSD pathogenesis and therapeutics	In this model it is difficult to evaluated demyelination. Axonal damage is not observed, and the lesions in rodents are restricted to the cortical region, different from humans. In addition it requires a large amount of AQP4-IgG (approximately 10 mg) for a single animal injection
	Intracerebral Injection	Rodents	AQP4-IgG or AQP4-IgG + complement	Loss of AQP4, GFAP and myelin, infiltration of mononuclear and polymorphonuclear, glial cell edema, complement deposition, extensive demyelination, early axonal injury and neural cell death	These models requires small amounts of purified AQP4-IgG to be executed, thus are an excellent tool for the study of new drugs and small molecules that can inhibit AQP4-IgG binding to its target	In the mice model, it is necessary a co-administration of human complement to reproduce the disease. Repeated injections of purified AQP4-IgG into the cerebral hemisphere can alter the susceptibility of the CNS to react to additional inflammatory stimuli
	Intrathecal Injection	Rodents	AQP4-IgG	Intraspinal IgG deposition, loss of AQP4 immunoreactivity, astrogliosis, macrophages infiltration, loss of myelin and axons, and loss of GLT-1 and GLAST expression	This model caused lesions independent of complement and reproduces clinical characteristics similar to human as myelopathic signs. It can also be useful to investigate the role of glutamatergic excitotoxicity in the NMOSD	Microglial activation, inflammation, massive infiltration of inflammatory cells and deposition of activated complement components, typical characteristics of human disease are not reproduce in this model
NMDAR Encephalitis	In vitro	Neurons	GluN1-IgG	Reduction in NMDA receptor density, receptor internalization and decrease in synaptic currents	This model is useful for evaluating NMDA receptor functionality and expression, as well as for the study of new therapies	This model is not useful for morphological, cytotoxicity, viability and cell death studies, as no other changes are seen
	Passive Transfer	Rodents	GluN1-IgG or CSF of NMDARE patients	Reduction of NMDA receptor density, decrease in synaptic currents, increase in extracellular glutamate levels and in neuronal excitability	The animals present memory impairment, behavioral changes, seizures, and depression, characteristics observed in human NMDAR encephalitis	Cellular and structural changes are difficult to detect in the passive transfer model. Symptoms such as locomotors changes, signs of anxiety, aggressive behavior, spasms, or coma do not occur in this model
	Active Immunization	Rodents	GluN1 peptides or tetrameric GluN1/GluN2B assembled in liposomes	BBB disruption, inflammation and infiltration of peripheral immune cells as pan-leukocyte, activated macrophages, plasma cells, CD4+ T cells and B cells	The animals present clinical symptoms and histopathological features similar to humans. Thus, this model allows us to evaluate the course of the disease, the role of specific immune components and the potential for new therapies	Only the GluN1 peptides were not sufficient to mimic the clinic. An immune cascade is necessary for the development and detection of clinical features observed in human NMDAR encephalitis.

ADEM, acute disseminated encephalomyelitis; AQP4, aquaporin-4; AQP4-IgG, antibodies against AQP4; BBB, blood-brain barrier; CFA, complete Freund's adjuvant; CNS, central nervous system; CSF, cerebrospinal fluid; EAE, experimental autoimmune encephalomyelitis; GLAST, glutamate/aspartate transporter; GLT-1, glutamate transporter-1; GluN1, ionotropic glutamate receptor subunit NR1; GluN1-IgG, antibodies against NR1 subunit; GluN2B, ionotropic glutamate receptor subunit NR2 subtype B; GFAP, glial fibrillary acidic protein; IgG, immunoglobulin G; IFA, incomplete Freund's adjuvant; MS, multiple sclerosis; MAG, myelin-associated glycoprotein; MBP, myelin basic protein; NMOSD, neuromyelitis optica spectrum disorders; NMDA, N-methyl-D-aspartate receptor; NHP, nonhuman primate; PLP, proteolipid protein; rhMOG, recombinant antibodies against MOG; MOG, Myelin oligodendrocyte glycoprotein.