Immune Thymic Profile of the MOG-Induced Experimental Autoimmune Encephalomyelitis Mouse Model

Abstract

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease that affects the neurons of the central nervous system. Activated T cells, specific for myelin epitopes, cross the brain barriers, and react against the myelin sheath, leading to demyelination. Since T cells are generated within the thymus, here we explored, in mice, the alterations occurring in this organ throughout the different phases of the disease. We induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 females and sacrifice them at the onset (day 16) and chronic phases of disease (day 23), along with non-induced controls. We observed thymic atrophy in EAE mice at the onset that remained until the chronic phase of disease. This atrophy was associated with a preferential loss of the CD4+CD8+ double positive thymocytes, an intermediate population between the more immature CD4−CD8− double negative and the most mature single positive thymocytes. This was accompanied by an increase in the thymic medullary/cortical ratio and by an altered expression levels of genes important for T cell survival. During the chronic phase, the thymi remained atrophic, but reacquired the normal proportion of the main four thymocyte populations and the normal medullary/cortical ratio. Importantly, at the onset phase, and accompanying these thymic alterations, EAE animals presented an increased percentage of demyelinating lesion area in the cerebellum, and an increased expression of interferon gamma (Ifng), interleukin (Il) 12a, and Il17a. This study suggests dynamic thymic alterations occurring in response to EAE, from the induction to the chronic phase, that might help to elucidate the MS pathophysiology.

Thymic Innervation Impairment in Experimental Autoimmune Encephalomyelitis

“…It has been previously reported that during EAE peak and chronic stages, there is a thymic atrophy with lymphocyte loss and increase in the percentage of natural regulatory T cells [22,27,28]. We showed that the thymic disturbance starts together with the first clinical symptoms of EAE and that thymocyte loss positively correlates with the increase of EAE clinical signs, e.g., disease score.…”

“…Based on the disturbance in the thymic innervation of MOG peak thymus and in the recently reported thymic atrophy during the EAE model [22], we hypothesized that these changes would also be compromising the thymic microenvironmental compartment, eliciting a dysfunctional T-cell development along with the clinical evolution of EAE. 1) and in the peak (14 d.a.i +/− 1) of the disease.…”

Liver X receptor beta deficiency attenuates autoimmune-associated neuroinflammation in a T cell-dependent manner

“…It also remains unclear why homeostatic changes in peripheral immune composition in Lxrβ − /− mice are nullified after EAE induction. Of interest, thymic involution and loss of cellularity are not only apparent in Lxrβ − /− mice but also after EAE immunization [18,34]. Moreover, Lxrαβ-deficient mice show spontaneous breakdown in self-tolerance and develop age-dependent systemic autoimmune disease [35].…”

Systemic immune derangements are shared across various CNS pathologies and reflect novel mechanisms of immune privilege

“…Specifically, thymic and splenic involution was reported transiently in EAE, acutely post-intracranial TMEV infection, and during cuprizone-induced demyelination. 5 , 71–74 While one paper reported reduced B and T-cell counts in the spleen within 6 days post EAE induction, 75 another study reported that spleen involution in the EAE model is heterogenous and dependent on mouse strain, pathology, and time points measured. 76 …”