(Selected Tables and Figures referenced, but not present in this blog
can be found in their corresponding Science Version blogs)
Buckle up folks. This next blog is a “brain teaser” (pun intended).
Contrary to previous beliefs, the brain is not an “immune-privileged” organ. The nervous system and the immune system share an intimate relationship wherein they modulate each other through sophisticated “bidirectional crosstalk” and very complex neuroendocrine and neurogenic pathways. These neural connections control much of the immunochemical production and reduction (“downregulation”) in the immune responses. This neurological control mechanism is the ultimate regulatory ordering for chronic inflammation (CI). Certain white blood cells (WBCs, specifically macrophages) not associated with the nervous system can infiltrate the central nervous system (CNS or the brain and spinal cord) and maintain a separate identity from the brain’s glial cells that normally function as CNS macrophages. This infiltration of non-CNS macrophages suppresses the glial neural functions (impulse transmission) as the invading macrophages replace the neural (glial) cells. This opens up the possibility for neural-mediated inflammatory reactions. Age-related or genetic CNS diseases that produce this glial macrophage replacement (with non-CNS macrophages) share common hallmarks including cognitive impairment, loss of brain volume, and the possible cause of the “brain fog” associated with the COVID-19 long hauler’s syndrome following acute and CI.
Innate and adaptive immune cells operating in an inflamed CNS produce neurodegeneration. Genome-wide association studies (GWAs, an approach used in genetics research to associate specific genetic variations with particular diseases) can help to identify gene variants that increase the risk of developing neurodegenerative inflammatory diseases. Despite a number of different causes (viral infections, stroke, neoplastic disorders, genetic mutations, trauma, and epigenetics [chemicals affecting genes]), neuronal damage is most frequently associated with chronic activation of an innate immune response in the CNS.
It is well established that the immune system is inextricably involved in shaping the brain during development as well as mediating damage during aging. Research is being conducted on these neuroimmune interactions during development, disease, and with aging. A better understanding of this bidirectional neuroimmune crosstalk will be the key to manipulating these responses and developing effective immunotherapies to reduce the impact of neurodegenerative diseases. Some of these diseases include Alzheimer’s, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, spinocerebellar ataxia, brain trauma, epilepsy, multiple sclerosis, and senile dementia.
As described in previous blog discussions, the body is constantly striving to maintain or reestablish a physiological balance called homeostasis and so too is it in the case with CI. In such cases, the neurological system becomes the main player in a highly complex (you didn’t expect anything less now, did you?) set of cellular and chemical actions and reactions in an effort to downregulate the immune system during CI. The sympathetic nervous system (system that increases heart rate, blood pressure, breathing rate) increases immune cell activity and makes bidirectional systemic immune responses possible, while the parasympathetic nervous system (PNS that slows the heart rate, dilates blood vessels) and the hypothalamic-pituitary-adrenal (HPA) axis generally reduces CI. Negative feedback on certain receptors (glucocorticoids) in the hippocampus can cause cortisol to stop the release of ACTH which can modulate the HPA-axis and increase brain protein (nuclear factor-kappa B or NF-kB, a protein transcription factor) which increases proinflammatory mediators. It has been known for decades that dysregulation of the HPA-axis is associated with depression.
Major depressive disorder and depressive symptoms are associated with CI. Uncontrolled or dysregulated immune cells, due to prolonged and exaggerated stress activation, may be a factor in the greater production of NF-kB activity due to reduced cortisol sensitivity. Certain immune chemical mediators also influence the production and metabolism of neurotransmitters such as serotonin and dopamine that play critical roles in mood. These effects can be mitigated with antidepressant serotonin inhibitors combined with nonsteroidal anti-inflammatories. These paragraph really highlights the complexity of the immune-neural relationships. It also highlights the level of confusion the relationship can produce!
Finally, all of these inflammatory (acute and chronic) disturbances in the immune system cause dysregulation (loss of homeostasis) “or stress” in the system. This physiological stress can be considered an autoantigen that began with an antigenic reaction (self versus non-self) and eventually generated a cycle of autoantigenicity (from dysregulation inciting neurogenic and neuroendocrine reactions) collectively referred to as a “clinical autoimmune cycle” or the “danger hypothesis.”
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