Time-of-Day Influence on Central Nervous System Autoimmunity.

Circadian rhythms are a characteristic of most living organisms and describe biological processes experiencing an oscillation of about 24h. These rhythms regulate multiple physiological systems, including innate and adaptive immune responses. Circadian disruption is an important risk factor in neuroinflammation such as multiple sclerosis (MS), a T-cell mediated autoimmune disease affecting around 2.8 million people worldwide. In the central nervous system (CNS), autoimmune T cells attack oligodendrocytes leading to progressive demyelination and neurological impairment. Studies performed by our lab demonstrate that the circadian clock plays an important role in the severity of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. However, the mechanisms responsible for this time-of-day difference are unknown. We investigated time-of-day differences in adhesion molecule expression and immune cell infiltration to the CNS that could explain differences in disease phenotype. Our results indicate a time-of-day-dependent infiltration of cells into spinal cords during EAE development that correlates with expression of the adhesion molecules VCAM-1 and ICAM-1 in the CNS vasculature. Targeting leukocyte-endothelial cell interactions in a time-of-day dependent manner with an anti-VLA4 antibody that blocks VLA-4/VCAM-1 engagement reduces leukocyte infiltration and disease severity. This study shows the importance of circadian oscillations in adhesion molecule expression and cell infiltration in the CNS, and identifies an axis to target for chronotherapy purposes in MS patients.