The first description of Parkinson's disease (PD) was made in 1817 by James Parkinson. In his first description, Parkinson postulated the involvement of the immune system in PD pathology (Parkinson, 2002, Parkinson, 1817). How did we get so far off-course?
Dogma #1 - PD is not just an age related movement disorder. Young onset is becoming more common.
Dogma #2 - Alpha-synuclein aggregation as a cause of dementia was shown to be false - fraudulent research conducted at the University of Minnesota turned the theory of a-synuclein aggregation on its head.
This particular paper was published prior to the revelation of research fraud, which sent us on a 20 year turd hunt. It has value in discussing how innate and adaptive immunity plays a role in neurodegenerative diseases.
This paper is out of France (abstract only). doi.org/10.1016/j.autrev.20...
PARKINSON'S DISEASE IS AN AUTOIMMUNE DISEASE
"The disease results from an interplay of genetic and environmental factors, including pharmacological molecules, which destroy dopaminergic neurons. Recently, several notable data have highlighted various immune alterations underlying that PD is associated to autoimmune features and could be considered as an autoimmune disease.
Autoimmune diseases (AID) are defined as ailments in which an immune response occurs in the host body against autologous [self] tissues and provokes a pathological state of the host tissue due to damages. Patients affected with AIDs have autoantibodies or autoreactive antigen-specific T cells driving the disease process.
There is a growing body of evidence suggesting that PD could be considered as an autoimmune disease. In addition to T cell responses, an abundant literature has been documented on the B cells producing autoantibodies against SNCA antigen, neo-antigens, GM1-gangliosides, catecholamine-based melanins, and others."
NEUROINFLAMMATION PLAYS A KEY ROLE IN PARKINSON'S DISEASE
The role of T- cells in the pathogenesis of Parkinson's disease (abstract only). doi.org/10.1016/j.pneurobio...
"Recent evidence has shown that neuroinflammation plays a key role in the pathogenesis of Parkinson’s disease (PD). However, different components of the brain’s immune system may exert diverse effects on neuroinflammatory events in PD. The adaptive immune response, especially the T cell response, can trigger type 1 pro-inflammatory activities and suppress type 2 anti-inflammatory activities, eventually resulting in deregulated neuroinflammation and subsequent dopaminergic neurodegeneration. Additionally, studies have increasingly shown that therapies targeting T cells can alleviate neurodegeneration and motor behavior impairment in animal models of PD. Therefore, we conclude that abnormal T cell-mediated immunity is a fundamental pathological process that may be a promising translational therapeutic target for Parkinson’s disease."
INVOLVEMENT OF THE IMMUNE SYSTEM IN PARKINSON'S DISEASE
Immune - related biomarkers for Parkinson's disease (open access). doi.org/10.1016/j.nbd.2022....
"The immune system is a highly regulated system that helps protect the host from pathogenic stimuli and tissue injury. The brain was once thought to be an immune-privileged tissue due to the separation of the central nervous system (CNS/brain) from the peripheral immune system (PIS/body) by the blood-brain-barrier (BBB) as well as its maintenance of an immunosuppressant microenvironment under physiological conditions.
Studies have since proven that the CNS is capable of eliciting its own immune response when insulted with pathogenic stimuli (Louveau et al., 2015) with accumulating evidence of the involvement of both innate and adaptive immune responses in PD, which has been extensively reviewed (Harms et al., 2021; Kannarkat et al., 2013).
Parkinson's disease is the second most common neurodegenerative disorder in the world, yet no established diagnostic markers [DAT Scans do NOT diagnose PD it is still a clinical diagnosis] or disease modifying therapies are available [Levodopa modifies the symptoms of PD, it does not treat PD or cure it].
Understanding the mechanisms involved in its pathogenesis and identifying markers capable of diagnosing or tracking progression of PD is greatly needed. Among the several factors identified to be involved in Parkinson's disease, the immune system has had increasingly growing evidence that presents a fresh avenue to investigate the pathology of the disease.
The involvement of the immune system in the pathology of Parkinson's disease has been linked to an interaction between the peripheral and central nervous system immune response. Whether this involvement is due to an immune response being a cause or consequence of Parkinson's disease pathology is still a matter of debate.
The strongest of the evidence derive from three observations: the first being systemic post-mortem analysis of brains from PD patients which has revealed increased number of reactive microglial cells which were associated with death of dopaminergic neurons (McGeer et al., 1988). The second observation resulted from an altered immune system in animal models for PD which consequently altered the incidence and severity of the disease (Cebrián et al., 2015). The third observation is key genetic associations which were identified to be linked to an increased risk of developing PD such as major histocompatibility complex genes (HLA-DR) which are expressed on antigen-presenting cells (Hamza et al., 2010; McGeer et al., 1988; Saiki et al., 2010).
Recent work to understand the association between the immune system and PD provides an opportunity to investigate potential immune-related biomarkers for PD as studies have postulated neuroinflammation to occur at the earlier stages of the disease before death of neurons (Emmer et al., 2011; Su et al., 2008; Theodore et al., 2008; Watson et al., 2012).
POTENTIAL IMMUNE-RELATED BIOMARKERS
Evidence of alterations in immune-related marker levels between PD cases and controls (See Table 1.)
- CNS markers of microglia activation with increased level in regions with damaged neurons.
-Activation of the Complement System (C3 and C4, C7 and C9 in late stage)
-Immune cell elevation (T-helper, T-cytotoxic, B cell, NK cells)
-Cytokine elevation (TNF-a, IFN-y, IL-2, IL-4, IL-6, IL-1B)
-Chemokine activation (lower compared to controls)
-Inflammatory response (C-reactive protein, neuroimaging)
IMMUNE-CELLS MEDIATED INFLAMMATION
An acute insult to the CNS can trigger the activation of microglial and astrocytic cells [in the brain]. This activates the recruitment of peripheral leukocytes [from the body] to the CNS via the production and proliferation of inflammatory mediators. This stimulation of inflammation in the CNS has been coined “neuroinflammation” and has been a point of investigation in several studies to understand whether it occurs as a cause or consequence of PD or neurodegenerative disorders in general (Chen et al., 2016; DiSabato et al., 2016; Sochocka et al., 2016). [Based on my experience with pesticide poisoning, it's my opinion that an immune response to neurotoxin exposure is the cause of non-hereditary neurodegenerative disorders.]
Microglial [glial] cells function as the primary immune cells of the CNS [brain and spinal cord], they are different from bone-marrow-derived hematopoietic [blood] cells and constitute up to 12% of CNS cell population (Hickman et al., 2018). During the physiological state, the microglial cells, in a ramified morphology, surveil and maintain homeostasis of the CNS. Upon contact with stimuli that disturb brain homeostasis, microglial cells get activated into an ameboid-like morphology that occurs in two states: M1 (pro-inflammatory) or M2 (anti-inflammatory).
INFLAMMATORY RESPONSE OF THE CNS
The M1 pro-inflammatory state has been linked with exacerbated immune response, dopaminergic neuronal loss, and destruction of the blood-brain-barrier (BBB) in PD MPTP model, while the M2 anti-inflammatory state in general alleviates induced inflammation, increases neuronal viability, and limits the BBB permeability.
When M1 microglial cells are activated it stimulates the release of cytokines and chemokines that then activate the M2 response with T and B peripheral immune cells and natural killer (NK) cells, that occurs due to the disrupted BBB, which were shown to be increased in the substantia nigra of PD patients.
The second state of M2 anti-inflammatory response is further sub-categorized: the M2a state is associated with tissue repair by expressing anti-inflammatory and neurotrophic factors; the M2b state promotes the recruitment of regulatory T-cells; and the M2c state has primarily phagocytic [cleanup] functions. The effect of NK cells in the brain has been thought to be neuroprotective as it functions to internalize and clear out α-syn aggregates that are linked to PD pathology. In support of this, a study has shown that systemic depletion of NK cells in PD mouse models increase the neuropathology of PD (Earls et al., 2020).
Depending on the activation state, inflammatory/immune related mediators are released by the cells in order to restore homeostasis coupled with the release of inflammatory molecules including cytokines, and chemokines. Chronic expression of TNF-α was demonstrated to lead to dopaminergic neuronal death and motor symptoms, as well as prolonged induction of an immune response as it promotes microglial activation associated with recruitment of peripheral monocytes (De Lella Ezcurra et al., 2010). [In neurodegenerative diseases, the insult to the CNS results in a toxic neuroinflammatory cascade (falling dominos) that progresses unchecked as the cells die and spill the toxin through a process call autoinduction. Doesn't this also describe cancer metastasis?]
Analogous to microglia, astrocytes also contribute to the regulation of immune system in the brain, and undergo transformative activation in response to inflammatory stimuli. They are categorized into A1 and A2 states of activation. A1 like M1, has pro-inflammatory functions and upregulates genes the disrupt synaptic function; while A2 has a more protective function and upregulates neurotropins that promote neuronal growth and development.
Studies have shown that the complement system, a major inflammatory mechanism whose components are mainly synthesized by the liver and found in the periphery, can also be synthesized in the CNS or carried in from the periphery due to damaged BBB (Morgan et al., 1997; Morgan and Gasque, 1996; Rus et al., 2006). Activation of the complement system is known to occur via three pathways: classical, alternative, and lectin pathways. The classical pathway is triggered by the antibody-antigen complexes which activates Complement C1. The lectin and alternative pathways are triggered by mannose residues which in turn trigger mannose-binding lectin and Complement C3. Activation of the three pathways lead to the downstream production of other complement proteins which form the membrane attack complex (MAC). [Further research on Mannitol/Lectin is needed].
INFLAMMATION AND REACTIVE OXYGEN SPECIES
Evidence presented shows that chronic neuroinflammation which is hallmarked by elevated immunoreactivity and low-scale constant production of cytokines, can contribute to neuronal death in disorders such as PD.
[Reactive Oxygen Species (ROS) are chemically reactive molecules that have been implicated in the pathogenesis of neuro-degenerative diseases. They are naturally generated within the biological system as a function of the breakdown of oxygen and play a significant role in mediating cellular activities including stress response, inflammation and cell survival. Neuroinflammation and ROS are rapidly induced in the brain after acute cerebral insult. Over production of ROS and neuroinflammation have been implicated in inciting subsequent brain injury. ROS can trigger detrimental effects on cellular functions by causing damage to proteins, lipids, and nucleic acids. Neurodegenerative disorders are not diseases - they are injuries.]
CONCLUSION
There isn't a specific biomarker for Parkinson's. The identified markers of neuroinflammation and the production of reactive oxygen species occur across the spectrum of neurodegenerative disorders and all should be considered autoimmune diseases.
Peace,
SE
*I do this research for myself - I share it with you 
*My opinions are my own - you don't have to agree with me
*Don't like what I say - do your own research
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