Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) thought to be initiated by myelin-specific CD4+ T cells. MS is characterized by inflammation that leads to the destruction of myelin as well as myelin-producing cells, oligodendrocytes, and axonal degeneration within the CNS. MS disease relapses are markedly reduced during pregnancy, with the greatest suppression in disease activity observed during the third trimester. A rebound in disease activity is observed following parturition, suggesting MS disease suppression is specific to the gestation period. In order to examine the mechanisms of disease suppression, we developed a model of T cell transfer using myelin oligodendrocyte glycoprotein-specific transgenic cells as the donor population. T cell encephalitogenicity was not altered during pregnancy; however, exosomes, small lipid-bound vesicles that function as facilitators of intercellular communication, were augmented in the serum of pregnant mice and have been implicated in feto-maternal tolerance. Exosomes are able to modulate the activity of cells in both the immune and central nervous systems by relaying molecular signals from their cell of origin to target cells. Therefore, we sought to elucidate the role of serum exosomes in pregnancy-associated MS suppression.
Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of MS due to the clinical, histological, and pathological similarities with the human disease. EAE disease severity is significantly reduced when pregnancy is induced during ongoing EAE. Similar to the dynamics observed in MS, following gestation, EAE disease course mirrors that of control mice. Interestingly, serum exosomes administered to mice with EAE reduced clinical severity following a single treatment. Further, exosomes were able to suppress the activation of myelin-specific T cells measured by a reduction in proliferation and interferon-gamma expression. Conversely, pregnancy- derived serum exosomes enhanced the proliferation and maturation of oligodendrocyte precursor cells (OPC) in vitro as well as the migration of OPCs to CNS lesions in vivo during EAE. Differential gel electrophoresis followed by mass spectroscopy was used to determine proteins expressed in pregnancy- versus control-derived exosomes. Proteins enriched in pregnancy exosomes were largely liver-specific and include corticosteroid binding globulin, which facilitates the local action of corticosterone, ceruloplasmin, a scavenger of oxygen-derived free radicals, and leukemia inhibitory factor receptor, which provides survival signals to oligodendrocytes.
These data suggest that serum exosomes are critical modulators of the immune and central nervous systems during pregnancy and are able to govern the suppression of EAE and MS by downregulating T cell responses and enhancing OPC function. Harnessing the mechanism by which exosomes suppress immunity, enhance the function of OPCs, and consequently suppress clinical EAE, can provide valuable insight into therapy development in MS.