21 Century Acquired Endocannabinoid Immune Dysfunction: Targeting Crosstalk of ECS, Purinergic Signaling, Myeloid Stem Cells

21st Century
Acquired Endocannabinoid Immune Dysfunction:

Targeting crosstalk of ECS, Purinergic Signaling, Myeloid Stem Cells
Klinghardt Academy
Judy A. Mikovits, PhD

May 3, 2019
www.plaguethebook.com
[email protected]
[email protected]
805-797-6967
21st Century Acquired Endocannabinoid Immune Dysfunction:
Associated with Retroviruses & Vaccines
Diabetes
Cardiovascular Disease*
Neuroendocrine tumors*
Psychosis
“One of the most widely distributed biological products that frequently involved mice or mouse tissue, at least up to recent years,
are vaccines, especially vaccines against viruses . . .
It is possible that XMRV particles were present in virus stocks cultured in mice or mouse cells for vaccine production,
and that the virus was transferred to the human population by vaccination
Frontiers in Microbiology published January 2011
The Human Endocannabinoid System (eCS)
Key Regulator of stem cell development & Immune Homeostasis
A signaling system that helps to
modulate all other physiological,
behavioral, and energetic
processes in the body.
• neuroprotection & plasticity

• immunity & inflammation
• apoptosis &carcinogenesis
• pain and emotional memory
• Supports detoxification:
• repairs Fibrosis
•fatty Liver disease
Anxiety
Depression
Sleep Disorders
Pain
Itch
Wound healing
TGF Beta: a Master Regulator of the Hematopoietic Stem Cell
Induction of CB2 on Lymphocytes is THC dependent
Endocannabinoid system (eCS) critical for Stem Cell Development
Endocannabinoids: Modulators of Innate Immunity via Hematopoietic Stem Cell
CB2 Regulates the Generation of Immune Cell Lineages
CB2 Is associated with Chronic inflammation of the nervous system
Cardiovascular system and Bone Disorders
• Nitrogenous bases of DNA
• Deoxyadenosine
• Deoxyguanine
Purinergic Signaling in the immune system
Structure is as important as Function
But does Structure Dictate Function?
Hierarchical organization of Hematopoietic stem cells (HSCs) & Endothelial Progenitor Cells (EPCs)
Endocannabinoid and Macrophage dysregulation in
Cardiovascular Disease?
Lymphatics and Glymphatics: Highways and Dishwashers of the Brain
Model of molecular mechanism of immune-mediated resolution of Mental Stress
Brain Homeostasis Maintained by Danger Signals
INTESTINE : THE FIRST BRAIN
a Complex Ecosystem harboring Dense and Diverse
Microbial Community key to Maintaining Health
Intestinal Microbiota: Important Player:

• Metabolic and Nutritional
Homeostasis
• Immune system maturation
• Brain activity
• Dysbiosis =Loss of Balance=Disease

• Perturbation Host cell Microbiota Cross
talk
• Initiating or reinforcing
Neuroinflammation
Most Studied Categories of Metabolites;
1. Short Chained Fatty acids bacterial
fermentation of fibers
2. Bile acids in liver transformed by microbiota
3. Tryptophan (Trp) metabolism
4. Endocannabinoids (Phytocannabinoids)
Stress induced Brain-Immune Activation leads to enhanced Myelopoiesis & Monocyte Trafficking
Molecular & Cellular Mechanisms of Myelopoiesis in Homeostasis & Infection
Cellular & Molecular Mechanisms of Myelopoiesis In Acute Inflammation & Trained immunity
Tissue Macrophages Self Renew & Perform Unique Homeostatic Functions
Role of ECS in retrovirus pathogenesis:
Dysregulation of EndoCannabinoid Purinergic Signalling and Myelopoeisis?
Brain Development and Microglial Homeostasis
Cascade of events in Microglial & Monocyte/Macrophage Homeostatic Function in the CNS
Putative Model for the Induction of Neurodegeneration
by PVC-211 muLV
BLOOD BCEC BRAIN

Microglia
Leaky
Vessels
Activated
Microglia
VEGF
i Superoxide
MIP-1α PVC-211 MIP-1α
Myeloperoxidase
MuLV iNOS other
factors
N
NO Neuron
monocytes
NO
Damage of
Neuron
Proteoglycans
Virus receptor
5 Genyous Confidential
042113
Microglia Activation in Neurodegeneration
Stimuli
Loss of cell:cell communication,
matrix breakdown, infections,
vascular damage,
others
HAPPY
ANGRY
others
Fetler, L and S Amigorena,
Homeostasis
Science 2005, 309:392
Phagocytosis of debris,
neurotrophins Damage
Neurotoxins, phagocytosis of
normal neurons, apoptosis
- Parkinson’s disease
Neurodegenerative - Alzheimer’s disease
disorders
- Multiple sclerosis
- Autism
- ME/CFS
Purinergic Signaling plays a critical Role In Chemotaxis of Multiple Cell Types
Purinergic Signaling
In Neural and Mesenchymal Stem cell maintenance and Differentiation
Working Model of Microglia Polarization
Activated Microglia exist in a Continuum between Two Functional Sates of Polarization
Activation of (Endo)cannabinoid receptor CB2 drives microglia to M2 (pro-resolution) state,
Decreasing the production of pro-inflammatory mediators and protecting neurons from damage
Emergency (Demand) Adapted Myelopoiesis and the Expansion of the MDSC Population
C U E N CA E T A L . | M O L M E D 1 7 ( 3 - 4 ) 2 8 1 - 2 9 2 , M A R C H - A P R I L 2 0 1 1
Cannabinoid Receptor Activation of Macrophages
Driver of Development of Myelosuppressive (MDSC)/and Tumor associated Macrophages (TAM)

Neuroprotection by Endocannabinoid Modulation in
Neurodegenerative/Neuroinflammatory Disease
Endocannabinoids Dampen Tissue Injury to Prevent Progression of
Neurodegenerative Disease and Cancer
Cannabinoids are Anti-Viral and Reduce Inflammation
Summary /Conclusion
The diversity and plasticity of macrophages lead to the identification of functional
polarization states (classically activated M1 type and alternatively activated M2
type) are dependent on environmental signals
The endocannabinoid system is involved in immunoregulation and

neuroprotection.
Lipid mediators of the Endocannabinoid System and their receptors exert

pleiotropic and complex immunoregulatory effects at the level of the stem cells.
CB2 modulation play a major role in the functional polarization of microglia in the
CNS
Endocannabinoids are master regulators of the innate adaptive-immune axis.
The effect of endocannabinoids on the orchestrators of the immune response, the

monocyte/ macrophage, is a key therapeutic target to modulate inflammation and
protect tissues from damage from excessive inflammatory mediators.
Phytocannabinoids can Enhance Vaccine Efficacy and Reduce Neuroinflammation

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How does the endocannabinoid system regulate stem cell development and immunity?

What role does purinergic signaling play in the immune system and stem cell maintenance?

21st Century

Acquired Endocannabinoid Immune Dysfunction:

Judy A. Mikovits, PhD

• neuroprotection & plasticity

But does Structure Dictate Function?

Intestinal Microbiota: Important Player:

• Dysbiosis =Loss of Balance=Disease

BLOOD BCEC BRAIN

Driver of Development of Myelosuppressive (MDSC)/and Tumor associated Macrophages (TAM)

The endocannabinoid system is involved in immunoregulation and

Lipid mediators of the Endocannabinoid System and their receptors exert

Endocannabinoids are master regulators of the innate adaptive-immune axis.

The effect of endocannabinoids on the orchestrators of the immune response, the

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