Objective:

To test how astrocytic immune cell receptors, junctional adhesion molecule-A (JAM-A) and major histocompatibility complex-I (MHC-I), control the pattern of experimental autoimmune encephalomyelitis (EAE), an animal model of CNS autoimmune disease. 

Background:

Multiple sclerosis (MS) is characterized by two clinical stages: 1) relapsing remitting (RR) MS, in which recurrent relapse with remission is driven by immune cell infiltration and fulminant neuroinflammatory activity and 2) progressive (P) MS, in which smoldering glial cell and resident immune cell activation drives neurodegeneration. Mechanisms mediating the transition from RR to PMS are not well-understood. Animal models are lacking as EAE consists of a single relapse-remission followed by a chronic stable stage. Inflamed astrocytes upregulate the immune cell receptors, JAM-A and MHC-I, in vitro and in EAE, and astrocyte-immune cell contacts persist histopathologically within the perivascular spaces of both acute and chronic MS lesions.

Design/Methods:

To study how astrocytic JAM-A and MHC-I affect the pattern of EAE, we created astrocyte-specific conditional JAM-A and MHC-I knock-out (CKO) mice by crossing an astrocyte-specific promoter (mGFAP-Cre) line with floxed JAM-A and MHC-I lines. CKOs and littermate wild-type controls (WTs) were subjected to EAE at 10-12 weeks of age and then rated blind to genotype for 35 days from disease onset. Flow cytometry and immunohistochemistry were performed at critical EAE timepoints. 

Results:

JAM-A and MHC-I CKOs converted EAE from a single relapse-remission, chronic stable pattern into a multiple relapsing-remitting, chronic progressive disease. This novel phenotype was most pronounced in males. In JAM-A CKOs, a higher proportion of CD122⁺ CD8⁺ T cells was found in the CNS at peak disease. 

Conclusions: