PAMPS and DAMPS
PAMPS (Pathogen-associated molecular patterns) "are molecules associated with groups of pathogens, that are recognized by cells of the innate immune system. These molecules can be referred to as small molecular motifs conserved within a class of microbes. They are recognized by Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals.”
(
http://en.wikipedia.org/wiki/Pathogen-a ... ar_pattern)
“They activate innate immune responses, protecting the host from infection, by identifying some conserved non-self molecules. Bacterial lipopolysaccharide (LPS), an endotoxin found on the bacterial cell membrane of a bacterium, is considered to be the prototypical PAMP. LPS is specifically recognised by TLR 4, a recognition receptor of the innate immune system. Other PAMPs include bacterial flagellin (recognized by TLR 5), lipoteichoic acid from Gram positive bacteria, peptidoglycan, and nucleic acid variants normally associated with viruses, such as double-stranded RNA (dsRNA), recognized by TLR 3 or unmethylated CpG motifs, recognized by TLR 9.”
“DAMPS (Damage-associated molecular pattern molecules or danger-associated molecular pattern molecules ) are molecules that can initiate and perpetuate immune response in the noninfectious inflammatory response.”
(
http://en.wikipedia.org/wiki/DAMPs)
This distinction is important as immune responses are clearly not always dependent on an infection.
“DAMPs vary greatly depending on the type of cell (epithelial or mesenchymal) and injured tissue. Protein DAMPs include intracellular proteins, such as heat-shock proteins or HMGB1(high-mobility group box 1), and proteins derived from the extracellular matrix that are generated following tissue injury, such as hyaluronan fragments.[9] Examples of non-protein DAMPs include ATP, uric acid, heparin sulfate and DNA.”
So things that can arise from fighting infection successfully can create their own problems.
Let us look at ATP
Normally, we think of ATP as being intracellular, What happens if it arises in abundance outside the cell?
I quote now from -
Adenosine 5′-triphosphate and adenosine as endogenous signalling molecules in immunity and inflammation by M.J.L. Bours a,⁎, E.L.R. Swennen a,b, F. Di Virgilio c, B.N. Cronstein d, P.C. Dagnelie (you will have to buy it from science Direct
www.sciencedirect.com for around USD$35 There are many cross references so I urge you to support the scientists and buy a copy)
“The naturally occurring nucleotide adenosine 5’-triphosphate (ATP) and its metabolite adenosine (Ado) probably constitute an intrinsic part of this extensive immunological network through purinergic signaling by their cognate receptors, which are widely expressed throughout the body.”
“The overwhelming evidence indicates that ATP and Ado (Adenosine) are important endogenous signalling molecules in immunity and inflammation.”
“ATP in the extracellular compartment is thought to contribute to the regulation of a variety of other biological processes, including cardiac function, neurotransmission, muscle contraction, vasodilatation, bone metabolism, liver glycogen metabolism and inflammation”
“Whereas intracellular concentrations of ATP are very high, its extracellular concentrations are considerably lower. Physiological ATP concentrations in plasma are normally submicromolar”
“Compared to ATP, plasma concentrations of Ado are usually about 10-fold lower”
“Concentrations of ATP and Ado in the extracellular compartment are controlled by enzymes catalyzing their conversion.”
“These so-called ecto-enzymes are located on cell surfaces or may be found in soluble form in the interstitial medium or in body fluids.”
A review of this work shows the large family of membrane-bound receptors which mediate cell
signaling by ATP and Ado. receptors cover just about everything we look at in immune cell distribution: Neutrophils, monocytes, macrophages; dendritic cells, T lymphocytes and B lymphocytes.
Inflammation can cause ATP to be released outside the cell-
“Neutrophils are the body's first line of defence against pathogens and are critical effectors in both innate and humoral immunity.” “neutrophils are capable of releasing both ATP and Ado following inflammatory activation.”
Stephen Harrod Buhner makes the following observation in his book “Healing Lyme disease coinfections”;
“Extreme ATP signalling is severely deleterious to the oliogodendrocyctes that form the myelin sheaths for axons in the brain and spinal cord…ATP also impairs white-matter function in the brain. ATP functions as an excitatory neurotransmitter in the brain, spinal cord, and peripheral nerve terminals; it’s a potent transmitter of astrocytic calcium signalling, as a mediator of axo-oligodendroglial communication and is a potent immunomodulator affecting microglia recruitment and activation. ATP signalling is a major factor in neuroinflammation. Excess ATP release results in neurodegeneration- in severe cases even to the destruction of the spinal cord.”
Buhner makes the point that ATP stimulates P2X7 receptors which leads to oligodendrocyte death, myelin damage and axon dysfunction. There are an abundance of these receptors in oligodendrocytes and myelin.
As Buhner says” Preventing P2X7 activation has been shown to reduce or even eliminate this”
Wikipedia (
http://en.wikipedia.org/wiki/P2RX7) says “The P2X7 receptor current can be blocked by zinc, calcium, magnesium, and copper “
Perhaps this is the basis for these supplements being useful. Buhner points the finger at mycoplasmas as the root cause so the effectiveness of these treatments would be prophylactic not curative as the infection itself would be unharmed .
What does all this tell us ?
When ATP is extracellular it can mediate cell signalling. It can be neurotoxic when the P2X7 receptor is activated. This activation can be modulated by Zinc, Calcium, Magnesium and Copper. Those minerals may be uninvolved in the liberation of extracellular ATP which, as Buhner and the other paper both argue is likely to be triggered by bacteria.
Nonetheless, suppressing P2X7 is very important. More importantly, dealing with infection becomes paramount. None of this invalidates the EBV/iNOS/Peroxynitrite argument at all. It tends to support it as we are weakened by that earlier mechanism before this mechanism takes hold.
Better go get some minerals.
Regards
