Autoantibody-boosted T-cell reactivation in the target organ triggers manifestation of autoimmune CNS disease

Significance Although T cells are the main players in autoimmune CNS inflammation, the role of B cells is being increasingly appreciated. We here investigated possible scenarios of how B cells could participate in the initiation of autoimmune CNS disease. We show that myelin-reactive autoantibodies accumulate in CNS-resident phagocytes, thereby concentrating myelin antigens in these cells and increasing the cells’ capacity to present the autoantigen to invading myelin-reactive T cells. Consequently, these T cells are stimulated and more easily reach the threshold for clinically relevant reactivation within the CNS tissue. This previously unidentified mechanism is of potential clinical relevance because it provides a scientific explanation for immune processes leading to disease initiation and induction of relapses in multiple sclerosis and other autoimmune CNS disorders. Multiple sclerosis (MS) is caused by T cells that are reactive for brain antigens. In experimental autoimmune encephalomyelitis, the animal model for MS, myelin-reactive T cells initiate the autoimmune process when entering the nervous tissue and become reactivated upon local encounter of their cognate CNS antigen. Thereby, the strength of the T-cellular reactivation process within the CNS tissue is crucial for the manifestation and the severity of the clinical disease. Recently, B cells were found to participate in the pathogenesis of CNS autoimmunity, with several diverse underlying mechanisms being under discussion. We here report that B cells play an important role in promoting the initiation process of CNS autoimmunity. Myelin-specific antibodies produced by autoreactive B cells after activation in the periphery diffused into the CNS together with the first invading pathogenic T cells. The antibodies accumulated in resident antigen-presenting phagocytes and significantly enhanced the activation of the incoming effector T cells. The ensuing strong blood–brain barrier disruption and immune cell recruitment resulted in rapid manifestation of clinical disease. Therefore, myelin oligodendrocyte glycoprotein (MOG)-specific autoantibodies can initiate disease bouts by cooperating with the autoreactive T cells in helping them to recognize their autoantigen and become efficiently reactivated within the immune-deprived nervous tissue.