The brain's privilege does not imply immune isolation, but rather, a unique mode of brain–immune communication.

Both adaptive and innate immune support are needed for brain maintenance and repair.

Neurodegenerative diseases have an essential peripheral component, which is often manifested by immune dysfunction.

While not a primary cause, the immune dysfunction develops at an early stage in neurodegenerative disease, presumably before symptoms appear, resulting in a vicious cycle that further escalates disease progression.

Breaking the vicious cycle by activating the systemic immune system can harness bone marrow-derived macrophages and regulatory T cells to the brain to help defeat disease.

For decades, neurodegenerative diseases were thought to be caused by the accumulation of toxic compounds, exacerbated by local inflammation, which together lead to neuronal loss and cognitive impairment . An additional factor that was long overlooked , is the role of the systemic immune system, which provides a defense mechanism against internal and external intruders in all bodily tissues. The evolving understanding of the life-long cross-talk between the CNS and the immune system led to an awareness of the function of systemic adaptive immunity in containing emerging destructive factors within the brain. . This includes harnessing of circulating myeloid cells to help the brain. However, as damage accumulates within the brain, the systemic immune system loses its protective capacity. Under such conditions, the dysregulated immune system becomes an escalating factor itself, thereby driving a vicious cycle that must be arrested.

Inflammation, Neurodegeneration, Adaptive immunity, Macrophages, Immunotherapy

Central Nervous System (CNS), Choroid Plexus (CP), Blood-brain-barrier (BBB), Blood-Cerbrospinal fluid-Barrier (B-CSF-B), Type-I Interferon (IFN-I)

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