Yes, I took bee venom injections on a monthly basis for about 15 years with about half those being post-dx.

I find that I very nearly hijacked this thread and apologize. I am going to leave my text here for continuity but also paste it to a new thread and allow the community to rule.

But lets not limit ourselves too quickly. If we are experiencing the effects of our own immune reaction to something in our environment, and I believe that we are, then a lot of things fall into place very quickly.

But "allergie" shots is too limited. And, if we can free up our thinking a moment we can glimpse a much greater view. What if we realize that with just one of two required "starters" available that there is nothing?

But I digress. Yes, even I.
The immune system works by spotting an intruder, taking his picture, going back to headquarters, showing the picture around and checking reords, telling everyone what a bad dude he be, and telling everyone to go into "attack mode" and execute operation "Communicate" to let the rest of us to know if he ever is seen again.

Now I admit that that is a little bit simplified. And that there is a little bit of "dopabrain" gumming up this keyboard at present. But it is true. A human being is not a frozen water droplet sitting on the deep space window sill of life. (Dopabrain warning! Seek shelter immediately!) We are actually more a walking, talking, sack of boiling chicken soup and nothing that we do is simple.

A quote from that Great American Tina Turner just before she crushed Ike like a little black beetle using only one thigh: "We don't do NOTHING easy."

I am going to try to wind this up and copy it to start another thread and not hijack this one. I have been getting stoned as s**t about this same time of day for several weeks now and I am beginning to wonder why, but now, back to our story...

The point that I am trying to make is that limiting our suspects in the emergence of PD is a major mistake because it is physically impossible for the "perps" to less than a certain number. "There had to be at least two, Sarge, to have one driving the getaway car."

We get to a solution way quicker when we stop looking at "micro-causes" (e.g. paraquat) and shift to "macro-causes" (e.g. neuroinflammation resulting from paraquat exposure). This brings us to the crux of the matter. Neuroinflammtion is observed in PD and it comes from literally dozens of origins. Anything that contributes to neuroinflammation is a "cause" and that includes dozens of factors.

Anything that triggers the primitive, innate immune system to react in a defensive manner is a "cause". (Actually, "trigger" is a much better term in this case.) And if you take a list of all the factors that have been proposed over the years as causes, you will find almost without exception that they are also on a new list of things which "trigger" the PD.

Vaccines? Of course! That one is self-evident.
But how about stress? Anxiety? That fight with the "Old Lady" last night when you slipped and called her the "Old Lady"?
Pesticide? Yep. Corn syrup? Manganese? H. pylori? A bad tooth? A UTI?

The list goes on and on. I have yet to find one single item that has showed promise as a cause that does not promote inflamation.

And, to make it interesting, the opposite holds just as firmly. All the things that make a plausible case to be a treatment for PD show themselves to be anti-inflammatory. It is plain that the link is there een if it is a bit dark to make out detail.

So, there it is. The cause. The trigger. The cure?

I don't doubt that this is true but what about the other 99% who don't get PD? Are they not exposed to triggers, too? What is different about us?

Senior Onset is typically the result of the normal aging of the immune system and is of little interest to me. Young Onset, however, is another matter. It begins with fetal exposure to the waste products of maternal bacterial infection (the toxin lipopolysaccharide or LPS in particular). While the fetal defenses are normally up to their task, there are occasional breeches. If these happen to occur at times of critical development the result can be a fetal immune system that is hypervigilant and which poses a danger to itself.

This is a lot to swallow at one sitting, but it is true. And it is all drawn from the work of "real" scientists and their peer reviewed work. I am going to quote liberally from that work and try to fill in the messy parts afterward.
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A Matter of Balance
Thus, exposure to the bacteriotoxin, lipopolysaccharide (LPS) during a critical developmental window in rats, leads to the birth of animals with fewer than normal dopamine (DA) neurons. This DA neuron loss is apparently permanent as it is still present in 16 months old animals (the longest period studied to date). Moreover, the loss of DA neurons seen in these animals increases with age thereby mimicking the progressive pattern of cell loss seen in human PD. (Carvey 2003)


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One is a reduced density of dopaminergic neurons in the substantia nigra and another is hypersensitivity to further exposure – the system is “primed”. Future exposure to LPS, particularly after the changes of puberty, will trigger a greater reaction whose magnitude will vary with individual sensitivity.

Sensitivity to LPS is genetically determined, varying considerably among different species. The sensitivity of normal animals (mice) to endotoxin may be enhanced considerably under different experimental conditions that include treatment with live (infection) or killed Gram-negative and -positive bacteria. (Fruedenberg 1993)

We conclude that prenatal exposure to LPS produces a long-lived THir cell loss that is accompanied by an inflammatory state that leads to further DA neuron loss following subsequent neurotoxin exposure. The results suggest that individuals exposed to LPS prenatally, as might occur had their mother had bacterial vaginosis, would be at increased risk for Parkinson’s disease. (Carvey 2004)

Thus, this disrupted immune system can lead to chronic inflammation and microglial activation with elevated levels of cytokines and related pro-inflammatory chemicals leading to “cell death.

The twin roots (immune and endocrine) of Parkinson’s Disease reaching back to the earliest moments of existence represent the extreme of a spectrum of causal scenarios and produce the earliest onset of symptoms. The two arise together and interact to produce the disorder by means of a self-perpetuating immune-endocrine reaction.

Rick,

Thanks for starting a debate on this topic: you can't get anything more important for us than the aetiology of PD.

Where I agree with your theory:

I can buy into the importance of neuroinflammation.

I think you're right to say that anti-inflammatories are inversely associated with PD, and inflammatories are positively associated with PD.

I think that your no one cause theory of PD is correct. This leads to a scoring system, a bit of this plus a bit of that, which builds up to something that leads to real damage.

But, all of that is insufficient to show direct causality.

GerryW's question is a good one: many people have exceptionally stressful lives, flu, h.pylori etc., but don't get PD; many people with PD haven't had noticeably stressful lives.

Where I disagree with your theory:

I think what's missing is the role of genetics and the role of alpha-synuclein.

I believe that the true significance of inflammation is that it increases the chance of misfolding, aggregation and clumping of alpha-synuclein. This leads to the death of neurones and the collection of symptoms that we see in PwP.

(I've written this post without references, but references to most of the post's assertations can be found by searching for the string johnt:alpha-synuclein .)

John

John-
First, let me make it clear that this portion of the hypothesis is not "mine" other than in the sense that I champion it because I find it to be the best out there. The part that I posted should be credited to Carvey at Rush and Bin Liu and others at NIH. Later parts of the hypothesis are the work of myself in collaboration with Anne Frobert, MD of Lyon, France and a still later part is indeed my work. It is quite involved but thus far holds water. I will dust it off and start posting it for comment. So much work has gone into it (three years with Dr. Frobert for example) that I need to get it out while I still can.

Briefly-
It is known that a fetus can be programmed by a number of chance events including exposure to LPS and a similar exposure to maternal stress hormones. Both of these can have a dramatic effect on the immune and endocrine systems if they occur at critical times of development. These effects may not manifest until the chemical changes of puberty.

In the case of the immune system the observed changes include the decreased neuronal density noted above but also a overly vigorous response by the primitive innate part of the system called the microglia. In short, the microglia fail to respond to shut down instructions as they should. As a result it has been observed that a response that should have been over within a few hours was still going strong ten *months* later. While the microglia do not seem to attack the nervous system directly, there is collateral damage and waste of resources.

Most importantly, at least to me, is the role of the immune system's communication chemicals, the cytokines. Like their corresponding "cousins" in the CNS (the neurotransmitters) and in the endocrine system (the hormones), the cytokines are neuroactive and impact our behavior on various levels. It is here, BTW, that I enter new territory so your thoughts would be of considerable interest. And I have barely started on the endocrine system....

There is a lot more than dopamine at work, as we have long known. But I think that once we know just how far reaching it is that we will be suprised. -Rick

Things tend to pop up that fit neatly `(more or less) into the framework of the hypothesis and a good example showed up in this morning's email at www.sciencedaily.com.

New Culprit That May Make Aging Brains Susceptible to Neurodegenerative Diseases Identified

Aug. 13, 2013 — The steady accumulation of a protein in healthy, aging brains may explain seniors' vulnerability to neurodegenerative disorders, a new study by researchers at the Stanford University School of Medicine reports.


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The study's unexpected findings could fundamentally change the way scientists think about neurodegenerative disease.

The pharmaceutical industry has spent billions of dollars on futile clinical trials directed at treating Alzheimer's disease by ridding brains of a substance called amyloid plaque. But the new findings have identified another mechanism, involving an entirely different substance, that may lie at the root not only of Alzheimer's but of many other neurodegenerative disorders -- and, perhaps, even the more subtle decline that accompanies normal aging.

The study, published Aug. 14 in the Journal of Neuroscience, reveals that with advancing age, a protein called C1q, well-known as a key initiator of immune response, increasingly lodges at contact points connecting nerve cells in the brain to one another. Elevated C1q concentrations at these contact points, or synapses, may render them prone to catastrophic destruction by brain-dwelling immune cells, triggered when a catalytic event such as brain injury, systemic infection or a series of small strokes unleashes a second set of substances on the synapses.

"No other protein has ever been shown to increase nearly so profoundly with normal brain aging," said Ben Barres, MD, PhD, professor and chair of neurobiology and senior author of the study. Examinations of mouse and human brain tissue showed as much as a 300-fold age-related buildup of C1q.

<snip>

these C1q deposits weren't randomly distributed along nerve cells but, rather, were heavily concentrated at synapses. Analyses of brain slices from mice across a range of ages showed that as the animals age, the deposits spread throughout the brain.

"The first regions of the brain to show a dramatic increase in C1q are places like the hippocampus and substantia nigra, the precise brain regions most vulnerable to neurodegenerative diseases like Alzheimer's and Parkinson's disease, respectively," said Barres. Another region affected early on, the piriform cortex, is associated with the sense of smell, whose loss often heralds the onset of neurodegenerative disease.

<snip>

ut in this study, Barres and his colleagues used biochemical measures of the protein itself. "The 300-fold rise in C1q levels we saw in 2-year-old mice -- equivalent to 70- or 80-year-old humans -- knocked my socks off," Barres said. "I was not expecting that at all."

C1q is the first batter on a 20-member team of immune-response-triggering proteins, collectively called the complement system. C1q is capable of clinging to the surface of foreign bodies such as bacteria or to bits of our own dead or dying cells. This initiates a molecular chain reaction known as the complement cascade. One by one, the system's other proteins glom on, coating the offending cell or piece of debris. This in turn draws the attention of omnivorous immune cells that gobble up the target.

The brain has its own set of immune cells, called microglia, which can secrete C1q. Still other brain cells, called astrocytes, secrete all of C1q's complement-system "teammates." The two cell types work analogously to the two tubes of an Epoxy kit, in which one tube contains the resin, the other a catalyst.

<snip>

In a 2007 paper in Cell, Barres' group reported that the complement system is essential to synaptic pruning in normal, developing brains. Then in 2012, in Neuron, in a collaboration with the lab of Harvard neuroscientist Beth Stevens, PhD, they showed that it is specifically microglia -- the brain's in-house immune cells -- that attack and ingest complement-coated synapses.

Barres now believes something similar is happening in the normal, aging brain. C1q, but not the other protein components of the complement system, gradually becomes highly prevalent at synapses. By itself, this C1q buildup doesn't trigger wholesale synapse loss, the researchers found -- although it does seem to impair their performance. Old mice whose capacity to produce C1q had been eliminated performed subtly better on memory and learning tests than normal older mice did.

Still, this leaves the aging brain's synapses precariously perched on the brink of catastrophe. A subsequent event such as brain trauma, a bad case of pneumonia or perhaps a series of tiny strokes that some older people experience could incite astrocytes -- the second tube in the Epoxy kit -- to start secreting the other complement-system proteins required for synapse destruction.

Most cells in the body have their own complement-inhibiting agents. This prevents the wholesale loss of healthy tissue during an immune attack on invading pathogens or debris from dead tissue during wound healing. But nerve cells lack their own supply of complement inhibitors. So, when astrocytes get activated, their ensuing release of C1q's teammates may set off a synapse-destroying rampage that spreads "like a fire burning through the brain," Barres said.

"Our findings may well explain the long-mysterious vulnerability specifically of the aging brain to neurodegenerative disease," he said. "Kids don't get Alzheimer's or Parkinson's. Profound activation of the complement cascade, associated with massive synapse loss, is the cardinal feature of Alzheimer's disease and many other neurodegenerative disorders. People have thought this was because synapse loss triggers inflammation. But our findings here suggest that activation of the complement cascade is driving synapse loss, not the other way around."

n 2011, Barres co-founded a company, Annexon, to develop drugs that inhibit the complement cascade to treat Alzheimer's, glaucoma, Parkinson's, stroke, multiple sclerosis and several other neurodegenerative diseases characterized by massive synapse loss. Annexon has licensed multiple associated patent applications from Stanford, which filed them.

Other Stanford co-authors of the study were Daniel Madison, PhD, associate professor of molecular and cellular physiology; Mehrdad Shamloo, PhD, associate professor of comparative medicine; postdoctoral scholar Laurence Coutellier, PhD; research associate Emilie Lovelett; and graduate student Dominic Berns.

The study was funded by the Ellison Medical Foundation and the National Institute of Drug Addiction (grant DA15403).

<end quote>

Comment- So we all have a part of our immune system called the complement. It is the most primitive part of that system and mounts a basic (non-antibody) defense by way of the microglia and astroglia. In more peaceful times it is a "gardner" and "trash collecter" as it prunes and disposes of excess synaptic tissue. But even in normal times this balance is on a hair trigger that increases with age. And what should we expect to happen if we are born with a hypersensitive version of all this???

These guys are worth keeping an eye on...