The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases

Abstract

For decades, it has been widely believed that the blood–brain barrier (BBB) provides an immune privileged environment in the central nervous system (CNS) by blocking peripheral immune cells and humoral immune factors. This view has been revised in recent years, with increasing evidence revealing that the peripheral immune system plays a critical role in regulating CNS homeostasis and disease. Neurodegenerative diseases are characterized by progressive dysfunction and the loss of neurons in the CNS. An increasing number of studies have focused on the role of the connection between the peripheral immune system and the CNS in neurodegenerative diseases. On the one hand, peripherally released cytokines can cross the BBB, cause direct neurotoxicity and contribute to the activation of microglia and astrocytes. On the other hand, peripheral immune cells can also infiltrate the brain and participate in the progression of neuroinflammatory and neurodegenerative diseases. Neurodegenerative diseases have a high morbidity and disability rate, yet there are no effective therapies to stop or reverse their progression. In recent years, neuroinflammation has received much attention as a therapeutic target for many neurodegenerative diseases. In this review, we highlight the emerging role of the peripheral and central immune systems in neurodegenerative diseases, as well as their interactions. A better understanding of the emerging role of the immune systems may improve therapeutic strategies for neurodegenerative diseases.

COVID-19 and risk of neurodegenerative disorders: A Mendelian randomization study

“…Previous study has shown that SARS-CoV-2 could infect neural tissues and cause significant neuronal death based on experimental evidence in human brain organoids, mice with over-expressing ACE2, and autopsies from patients who died of COVID-19 [ 10 ]. Meanwhile, the innate immune responses and cytokine storm triggered by COVID-19 might also promote the development or progression of neurodegeneration [ 11 ]. Peripherally released cytokines could cross the blood-brain barrier, thus causing direct neurotoxicity and contributing to the activation of microglia and astrocytes [ 12 ].…”

Terminally differentiated cytotoxic CD4+ T cells were clonally expanded in the brain lesion of radiation‐induced brain injury

“…In healthy CNS, the CD4 + T cells, although at a low number, are crucial for the maturity and function of microglia, affecting memory, behavior, and other functions of the brain 40 . Under pathological conditions, peripheral CD4 + T cells can be recruited by activated glia cells, infiltrated inflammation cells, injured neurons, or endothelial cells and produce cytokines to mediate CNS inflammation after re‐activation by MHCII + antigen‐presenting cells (APCs) 41 . Since irradiation promotes the release of autoantigens or new antigens, it is rational that brain irradiation induces unknown antigens that can be recognized by APCs, which further triggers the neuroimmunology processes as previously mentioned 32 .…”

Single-cell RNA sequencing of CSF reveals neuroprotective RAC1+ NK cells in Parkinson’s disease

“…Increasing evidence suggests that the peripheral immune system plays an essential role in the regulation of CNS homeostasis and diseases ( 20 ). Brain infiltration of the NK cells has been widely observed in neurodegenerative disorders, including AD and PD, and may play diverse roles under different conditions ( 14 , 17 ).…”