Study On The Pathogenesis Of A Novel EAE Model With Demyelination In The Brain

Objective: It is reported that a new EAE model with inflammation and demyelination in the brain is induced by Putussis aminsitrated intracerebroventricularly on the day after immunization with MOG,which is different from a classical MOG-induced EAE mouse model whose inflammation and demyelination are located in the spinal cord.The pathogenesis of the MOG-induced EAE is recognized that the blood-brain barrier at the distal end of the spinal cord hinders the increase of permeability and the susceptibility of motor and sensory fibers to macrophage/microglia,which can not be applied to this new EAE mouse model.To this end,we will explore the possible pathogenesis of this new EAE model and further elaborate the main roles of PTx and macrophage/microglia in it.Method: Compared with MOG-induced EAE mice,the motor function of the new EAE mice models as observed.The proliferation ability of splenic monocytes,changes of immune cells and cytokines were measured and the pathological changes in of spinal cord including inflammatory infiltration and demyelination were observed.BBB permeability,especially changes of macrophages/microglia of brain and spinal cord at different time points were compared using immunohistochemistry and western blot.In addition,the effect of PTx on microglia migration in vitro was observed by Transwell method.Results: PTx icv at 7 days after MOG immunization could significantly alleviate themotor deficit in EAE mice,and the dose of PTx was negatively correlated with the severity of motor deficit.PTx icv at 7 days after MOG immunization did not alter the proliferation ability of T cells,the number and composition of immune cells in spleen.PTx icv at 7 days after MOG immunization could significantly reduce inflammation and demyelination of EAE spinal cord,and decrease the expression of proinflammatory factors(TGF-beta,IL-17 and IL-16)in spinal cord and the infiltration of Th17 cells,but increase the expression of proinflammatory factors(TGF-beta,IL-17 and IL-16)and the infiltration of Th17 cells in brain.In this new mouse EAE model,the brain barrier was compromised in the brain whereas spinal cord BBB integrity remained intact.PTx icv markedly activated microglia in the brain preventing their migration to the spinal cord.An in vitro transwell study demonstrated that PTx inhibited migration of microglia.Conclusion: The possible pathogenesis of this new EAE mouse model is that intracerebroventricularly administrated PTx can induce the inflammatory microenvironment in the brain,increase the permeability of blood-brain barrier in the brain and promote the entry of immune cells into the brain,thus inhibiting the migration of microglia to spinal cord and preventing the spinal cord from demyelination.This study also provides a way to further study the role and mechanism of infectious factors in autoimmune diseases,especially in central nervous system.