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 neuroendocrine and neurogenic pathways that modulate cytokine production and reduction (“downregulation”). This complex neurological control mechanism is the ultimate regulatory hierarchy for chronic inflammation (CI). Nonneural macrophages can infiltrate the CNS and maintain a separate identity from the brain’s glial cells that function as CNS macrophages. This infiltration of nonneural macrophages suppresses the glial neural functions (impulse transmission) as invading macrophages replace the neural (glial) cells. This opens up the possibility for neural-mediated inflammatory reactions. Age-related or genetic, central nervous system (CNS) diseases 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 impact 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 from 1999 to 2018 during development, disease, and immunosenescence. A better understanding of this bidirectional neuroimmune crosstalk will be 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 homeostasis and so too is 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 molecular and chemical actions and reactions to downregulate the immune system. The sympathetic nervous system amplifies immune cell activity and makes bidirectional systemic immune responses possible, while the parasympathetic nervous system (PNS) and the hypothalamic-pituitary-adrenal (HPA) axis generally inhibit CI. Negative feedback on glucocorticoid receptors in the hippocampus can cause cortisol to stop the further release of ACTH which can modulate the HPA-axis and nuclear factor-kappa B (NF-kB) which increases proinflammatory mediators. It has been known for decades that dysregulation of the HPA-axis CI 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 of greater NF-kB (Nuclear Factor kB, a protein transcription factor) activity due to reduced cortisol sensitivity. Cytokines 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.
Finally, all of these inflammatory (acute and chronic) disturbances in the immune system cause dysregulation in homeostasis “or stress” in the system. This physiological stress can be considered an autoantigen that began with an antigenic reaction and eventually generated a cycle of autoantigenicity (from homeostatic imbalance inciting neurogenic and neuroendocrine reactions) collectively referred to as a “clinical autoimmune cycle” (my idiom, see Blog #9, Figure 5.1)
Discussion Questions:
Neuroendocrine and neurogenic pathways that modulate “downregulation” of the immune system. What immune cell infiltrates the CNS, what does it do, and what can it produce?
The sympathetic nervous system amplifies immune cell activity while the parasympathetic nervous system (PNS) and the hypothalamic-pituitary-adrenal (HPA) axis generally inhibit CI. Can you describe the role of the hippocampus in modulating the HPA-axis to increase proinflammatory mediators and produce what clinical neuropsychiatric result?
I have Relapsing Polychondritis. It's a rare disease that causes systemic inflammation. The main hallmarks, are damage of our bodies cartilage, tendons, ligaments, airways, heart, eyes, bronchial tubes, trachea, well you get the picture... However, our CNS involvement is VERY poorly studied or documented. I am on 3 Bio meds, DMARDS , and Prendisone. When I have bad flares fluid builds up at the base of my neck/brainstem, I get fluid under my scalp and all up around my ears. I get extremely confused, I have blurry vision and MAJOR migraines. This article/blog is the first real dive deep into Autoimmune and CNS involvement. Thank you so much!