Harmful and Beneficial Roles for the Adaptive Immune System in Neurodegenerative Conditions

To a first approximation, cells of the adaptive immune system are barred from the brain by the blood-brain barrier. This is only a first approximation, however, and more careful research has shown that a small number of adaptive immune cells do in fact enter the brain. This appears to be the case throughout life, a part of the normal interaction between immune system and central nervous system. The presence of adaptive immune cells in the brain in later life is also thought to be pathological, however, the result of age-related dysfunction of the blood-brain barrier, allowing unwanted cells into the brain to cause harm.

Neurodegenerative disease defines conditions in which there is progressive neuronal loss in the central nervous system (CNS), leading to either physical disability, cognitive deficits or both. Classical neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Aging is a major risk factor for neurodegenerative disease, and with a growing elderly population, its prevalence is continuously increasing. Beyond being a risk factor, aging also increases the severity of disease and results in an impaired recovery following insult. Although these diseases have different pathogenetic mechanisms such as protein aggregation, demyelination, ischaemia, or direct trauma, they all share a hallmark of neuroinflammation.

The immune system plays a key role in CNS homeostasis and disease. The innate immune system is the first line of defense against pathogens and central nervous system (CNS)-resident macrophages, microglia, are of vital importance as early respondents to CNS alterations such as damage or infection but also in development and homeostasis. Microglia activation is also an important component of neuroinflammation, aging, and different neurodegenerative diseases either directly via phagocytosis and cytokine production, as shown by the identification of disease-specific microglia, or indirectly in response to cues from the adaptive immune system.

The adaptive immune system is an important component of the host defense against pathogens, through the recognition of non-self antigens. This defensive mechanism is mediated by B lymphocytes and T lymphocytes which display a diverse range of specific antigen receptors during humoral and cellular-mediated immunity. Although the CNS was once considered an 'immune-privileged' site, recent studies have indicated the presence and importance of the adaptive immune system in the CNS for immune-surveillance and defense against neurotropic viruses. Studies have also highlighted the role of adaptive immunity in maintaining CNS homeostasis and integrity, promoting neurogenesis and improving cognitive function.

In healthy individuals, this immune-CNS interaction is highly regulated to maintain the beneficial relationship. However, during both aging and neurodegenerative disease, the blood-brain barrier (BBB) is disrupted, leading to an increased infiltration of peripheral immune cells into the CNS, where they can potentiate further neurodegeneration or facilitate tissue regeneration. In both neurodegenerative disease and the normal aging process, there is a common theme of immune dysregulation and abnormal immune responses.

Link: https://doi.org/10.3389/fnagi.2020.572090

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