Neuroimmunological characterization of a mouse model of primary progressive experimental autoimmune encephalomyelitis and effects of immunosuppressive or neuroprotective strategies on disease evolution

Activation of innate immunity within demyelinated regions during cuprizone treatment lasts about 1 month, which is shorter than the 2-4 months necessary for progression onset in NOD animals.

“It is worth noting, indeed, that activation of innate immunity within demyelinated regions during cuprizone treatment (Fig. 2 and (Skripuletz et al. 2013)) lasts for an extent of time of about 1 month that is shorter than that of 2–4 months necessary for progression onset in NOD animals (Buonvicino et al. 2019).”

Progression of EAE in NOD mice is insensitive to immune suppression.

“whereas progression of EAE in NOD mice is insensitive to immune suppression (Buonvicino et al. 2019)”

Reduction of cytotoxic CD8+ lymphocytes by dexamethasone does not provide protection from disease progression in EAE NOD mice.

“reduction of this neuroimmune response by dexamethasone does not provide protection from disease progression (Buonvicino et al. 2019).”

B cells and MOG-specific autoantibodies are increased in the NOD-EAE model.

“Furthermore, B cells and MOG-specific autoantibodies are increased in the NOD-EAE model potentially making this model useful for mimicking and studying the role of mature plasma cells, which are found in the CNS of PMS patients.”

The NOD-EAE model captures key features of PMS, including a disease course progressing from relapsing-remitting to progressive, earlier onset in older mice, and progressive accumulation of neurological deficits.

“The NOD-EAE model captures several key features of PMS, including a disease course progressing from relapsing–remitting to progressive, earlier onset in older mice, and progressive accumulation of neurological deficits [95, 168, 169].”

In 288 NOD mice immunized by Buonvicino et al., EAE had a primary progressive disease course; only 5.6% had a partial remission phase and none had an early remission phase.

“However, Buonvicino et al. (2019) immunized a total of 288 NOD mice and found a primary progressive disease course. Only 5.6% of mice had a partial remission phase, and none had an early remission phase.”

NOD mice represent a unique strain that recapitulates some aspects of progressive MS when subjected to EAE.

“NOD mice represent a unique strain that recapitulates some aspects of progressive MS when subjected to experimental autoimmune encephalomyelitis (EAE).”

The neuropathological correlate of EAE NOD progression consists in widespread spinal cord demyelination invariably accompanied by axonal loss heralded by impairment of mitochondrial structure and function.

“the neuropathological correlate consists in widespread spinal cord demyelination that is invariably accompanied by axonal loss heralded by impairment of mitochondrial structure and function.”

Histological sections were analyzed by a blinded operator.

“sections were analyzed by a blinded operator by using ImageJ software (Buonvicino et al. 2019).”

In NOD-EAE, there is a 13-fold increase in CD8+ T cells and a 20-fold increase in CD4+ T cells in the spinal cord compared to control mice.

“In this model a 13-fold increase in CD8 + T cells and a 20-fold increase in CD4 + T cells in the spinal cord was reported when comparing the percentage of infiltrates to control mice [169].”

In that NOD mouse study, all animals eventually reached a severe disease score, but the rate of progression varied from 12 to 122 days.

“They observed that while all animals eventually reached a severe disease score, the rate of progression varied dramatically, with some mice reaching this endpoint within 12 days and others taking up to 122 days.”

TFH cells are increased in the spinal cord of NOD-EAE, and ELFs form in the spinal cord, identified as clustering of B cells, CD4+ T cells, and CD35+ FDCs in the chronic stage.

“Additionally, TFH cells have been found to be increased in the spinal cord and immunohistochemical analyses have shown formation of ELFs in the spinal cord, identified as clustering of B cells, CD4 + T cells, and CD35 + FDCs in the chronic stage of disease [165, 169].”