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Immune complex\u2010mediated activation of Fc receptors on infiltrating blood\u2010borne cells and tissue resident cells amplifies an inflammatory cascade with resulting damage to tissue function, ultimately leading to tissue destruction. This pathophysiology appears to explain tissue injury throughout the body, except in the central nervous system. This review addresses a paradigm we have developed for autoantibody\u2010mediated brain damage. This paradigm suggests that antibody\u2010mediated brain disease does not depend on immune complex formation but rather on antibody\u2010mediated alterations in neuronal activation and survival. Moreover, antibodies only access brain tissue when blood\u2010brain barrier integrity is impaired, leading to a lack of concurrence of brain disease and tissue injury in other organs. 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