Part 1 David Kirby's Autism One Presentation: Metals, Myelin & Mitochondria Pathways to Autism?
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By David Kirby
REMARKS AND SLIDE PRESENTATION BY DAVID KIRBY
2009 Autism One Conference, Chicago
I first want to say that this conference was described by The New York Times as “an anti-vaccine conference.” And, you know, when I read that I actually laughed out loud. And I thought, “What would you even do at an anti-vaccine conference, anyway?” And I know there are some people in this audience who are anti-vaccine, and they have that right. I just don’t happen to be one of those people.
The reason I get upset at being called “anti-vaccine” is that, A), it’s untrue, and B), I do think vaccines are important. And I think we can vaccinate more safely than we do in this country. But the label is used as a weapon. It is used as a tool against people like me. And even though it’s a lie, it is so much easier to dismiss somebody if you think that they’re anti-vaccine. “He’s a kook. He’s a nut. He doesn’t know what he’s talking about.”
And now we’re into the rhetoric that has gotten so heated that people like me are called “pro-disease.” It’s like Karl Rove is writing the playbook for these people. Because it’s gotten that political, it’s gotten that nasty. So, I’m going to fight back against that label.
This is not an “anti-vaccine conference.” There’s a discussion tonight about athletics in autism, and one on relationships in autism.
And we are here to talk about a lot more than vaccines. And that’s sort of the theme of my speech, too. Because for quite a while now, I have believed there are many, many different ways to get to what we call “autism.” And I think we really need to step back from vaccines, we need to step back from Thimerosal, we need to step back from MMR and other specific vaccine components. We need to work backwards and look at the world in its entirety. We need to look at food, air, water, and medicine. And by medicine, yes, that would include vaccines.
Now, the Obama administration just announced they’re going to have a national meeting on toxins; and how toxins affect people. And that’s exactly where I think this conversation should go. I’m ready for a little middle ground. I’m really tired of the screaming back and forth, you know. We need to find out what’s making these kids sick. And I think there’s more consensus now that something in the environment or some things in the environment are contributing to that.
So let’s look at those things in a more general sense. And that’s where - I think - it gets really, really interesting, and where we may find some common ground in science - that there are things in nature that are triggers for autism. I truly believe there are things in the environment that can trigger autism that have nothing to do with vaccines.
I am just a journalist, I’m a layperson, so I view things in a slightly different way than scientists. And I have the luxury of doing that because I get to, you know, play around with theories a little bit, ask different kinds of questions and try to see connections between different things.
And when I look at the situation, I think we’ve moved way past thimerosal as the one and only cause of autism. And I’ve just picked three possible routes – Metals, Myelin & Mitochondria - that we’ll be talking about tonight. Now, you could make up a very, very long list of potential pathways to autism. But what’s so interesting about these three pathways -- and remember, this is all just theory, this is just me, kind of musing out loud -- is that they’re found in the natural environmental, or the man-made environment, and they’re also found in vaccines.
The other thing that’s interesting about these three things is they’re interactive. So you might have metals as a contributing factor to autism, but you can’t separate that entirely from the fact that metals can also destroy myelin. Metals can destroy mitochondria. They’re all interrelated. And I think that we should look at ALL metals. And I think one reason that we haven’t looked at all metals is because two of those metals happen to be aluminum and mercury, and those metals also happen to appear in childhood vaccines. If there never was mercury in vaccines, I can pretty much state that we would be much further along at this point in researching heavy metals in autism.
The same with live viruses. Measles virus can affect myelin as a matter of fact. Well, there is live measles virus in the MMR vaccine. Maybe that’s one reason why there’s been some reluctance to look more carefully into how viruses might be triggers of autism.
And the same is true of mitochondrial dysfunction and overstimulation of the immune system – all sorts of things can happen in that situation. And it does happen in nature - a lot. But talk with Jon and Teri Poling, and you’ll find out it can also happen when you give a child nine vaccines in one day.
So maybe what it might take to try to find some middle ground and move research forward is to just put - even for a day - vaccines aside. And let’s just look at metals. And let’s just look at myelin damage – what can damage myelin. And let’s look at mitochondria - and many, many other things.
But I am here to discuss these three things. And, I am not here to give you any answers. I don’t have any answers. My job is to ask the questions. I also draw no conclusions. But my message to you is this: If I were running the show, and if I were dishing out the research dollars, these are some of the areas that I would be pursuing, posthaste. And if I were a scientist, these are some of the things that I would be wanting to study with federal money, including some money coming into the NIH right now.
I know you’ve probably heard a lot of this stuff today, and in the past, but I just want to go over some of these things. Because I think the problem has been, we’ve been trying to look at Thimerosal in this country, and in the UK they’ve been looking at MMR, and trying to make it fit, trying to make every single child, every single autism case, be caused by that one thing and it’s not working, it’s not happening.
And instead of looking at the causes and trying to track them to the effects, I think we need to look at the effects and then go back and try to see what things in the environment might cause those effects -- particularly in combination with genetic predispositions.
And we’re getting this new vocabulary. I mean, none of these words I knew even a couple of years ago, and I’ve been at this for about five years now. Well, maybe I knew some of these words, but much of this terminology, in terms of autism, is fairly new. And when we look at the kids who actually got sick, when we look at the molecular level, the cellular level, when we look in the clinics, we notice a lot of symptoms that a lot of these children suffer from.
And the immune system is often the first thing that we notice. Now, it’s important to note that not all kids have immune problems. And not all kids have gut problems. Not all kids have central nervous system problems. So it seems like they’ve gone through different pathways to get to this general constellation of symptoms that we call “autism.” And we often see immune activation, and sometimes we see simultaneously immune suppression, and sometimes autoimmunity, going on at the same time.
You’ve heard an awful lot about oxidative stress, and we’re now learning ways that these things are all interrelated with each other, as well: Neuro-inflammation; rapid brain growth; activation of certain brain cells that causes swelling of the brain that we see in autism.
Then there’s glutathione – Dr. Haley spoke about it quite a bit - I think glutathione is going to turn out to be one of the most important things in the 21st century that we have in terms of detoxification, and living in our increasingly polluted environment. We as humans are going to have to adapt, but we can’t do it on our own, and we need some help. And I honestly believe that glutathione is a powerful detoxifier. And we know that children with autism have very low levels of glutathione - which then would lead to certain things, including mitochondrial damage, heavy metal accumulation, neuro-inflammation, oxidative stress, etcetera.
Metal metabolism disorder is the inability to excrete metals to which we are exposed. Most people have enough glutathione and other sulfur-based proteins that allow us to excrete our heavy metals through feces, urine, hair and sweat. But if you don’t have the ability to bind those metals, you won’t excrete them and they will accumulate in your body and in your organs.
There is research into glial cells, microglial cells. In the work of Thomas Burbacher we’ll see a very important role that metals might play in this whole picture of the brain.
We also see cytokine imbalances in people with autism, and we know that can be caused through heavy metal exposures, etcetera.
We’ll talk quickly about the methionine cycle, the destruction of that cycle can then interrupt a process called methylation.
Methylation is absolutely essential for production of myelin and production of glutathione. So if you have a methylation problem, you will probably be producing less glutathione. If you have less glutathione, you are most surely at risk for heavy metal accumulation, oxidative stress, etc.
Demyelination is when your myelin is weakened. Mylein is the fatty acid substance that coats the brain and the nerve connections in our body.
Vitamin D deficiency - and this is fairly new, that is, from my point of view, so I can’t speak to it too much - but I believe that vitamin D is a very important factor in producing glutathione in the liver. And I do know there’s a lot of problems with vitamin D deficiency today. And when I was looking into the situation with the Somalis in Minnesota, and the Somali ethnicity, they tend to have a genetic predisposition toward vitamin D deficiency. And a lot of the Somali women, when they moved to Minnesota, they had severe morning sickness while pregnant, which is a sign of severe vitamin D deficiency. And of course, if you move from an equatorial country with lots of sunshine, to Minnesota, in the far north where three, four, five months of the year you’re barely getting any sunlight at all, your vitamin D deficiency is going to be even more acute.
Then finally, there’s calcium – calcium channeling. Again, all of a sudden I was trying to keep up, you know, in the last couple days before I came here. But there’s a brand new study out that implicated a calcium-related genetic mutation that is more common in boys, and they think there’s some connection now between that and autism. Well, calcium channeling is very, very important for the function of nerve cells and brain cells. And guess what interferes with calcium channeling? Heavy metals - as just one example.
So, I’m just going to talk about those three tonight and we’ll how they interact – Metals, Myelin, Mitochondria.
When we talk about metals, we have to look at them all. As you probably know, there are two different kinds of mercury. There’s inorganic mercury which comes out of coal-fired power plants. It is not quite as destructive, as they say, as organic mercury, which is found in fish in the form of methylmercury, and it’s found in vaccines in the form of ethylmercury, which is manufactured.
I mentioned aluminum. It is used in vaccines as an adjuvant to increase, to boost the immune response to the vaccine. Aluminum in and of itself is neurotoxic. Aluminum is very damaging to mitochondria. And aluminum is synergistic with mercury. So if you have aluminum in your vaccine and even a trace amount of mercury, even if it’s just half a microgram, and if it’s mixed with aluminum, the toxic effect of that is going to be much greater. And we have seen more vaccines come online with aluminum in them, and we’ve also seen some vaccines actually increase the amount of aluminum that they have in them.
Arsenic – and my new book is on factory farming, industrial animal production. And just today I’ve been writing up a big section on chickens. And I was researching arsenic. They feed arsenic to chickens, I don’t know if you know that. It makes them grow faster. It also give their skin a nice pigmentation. Well, the government says that they test the chicken, that there’s no arsenic in chicken. That’s simply not true. And the federal limit for arsenic is 10 parts per billion. And I just saw a chart today – and some chicken has up to 40 parts per billion. So there is a lot of arsenic in our food, and it’s just something to think about. Again – food, air, water, medicine. We’re exposed to heavy metals in a large number of ways.
Antimony is a flame retardant that we’re finding in American women’s breast milk. Lead, tin, and cadmium, for some reason – I’ve seen a lot of chelation charts of kids with autism and for some reason they seem to be very elevated in cadmium. And more often times they’re elevated in arsenic as well.
Now, people keep saying there’s never been any evidence to support a link between thimerosal or mercury and autism. This was a preliminary study done by the CDC. And what they did was, they took the kids and they split them in half. Kids who got 25 micrograms or more by 1 month of age, and kids who got less than that by 1 month of age. And they found out that the kids in the higher exposure group were 7.6 times more likely to have autism, and much more likely to have ADD, ADHD, tics, etc.
And by the way, every thimerosal study that’s looked at tics has found an increased risk for tics. And we may think of tics as mild, well, tics can be really, really bad. And if you have phonic and motor tics, you have Tourette’s syndrome, and that can lead to learning disabilities that will cause problems later on in life. So to say that thimerosal “just” causes tics, I think, is an extreme understatement.
So, this went through five different generations over 4 years, and in the end the CDC came out and said “No, there is no association between Thimerosal and autism.” And they essentially just stopped looking at it. This is all described heavily in my book; you may have seen it before.
I mentioned efflux disorder earlier, and I mentioned sulfur, and I mentioned glutathione. There are a lot of children with autism who apparently have depleted levels of glutathione. Now, glutathione belongs to a class of proteins called “thiols.” And the synonym for thiol is “mercaptan,” which comes from the Latin “mercurium captans” or literally “capturing mercury.” And it would stand to reason that if you inject mercury into a kid who doesn’t have mercury capturers, he’s going to react differently to that metal than the kid who does have mercury capturers.
So this would explain a certain genetic predisposition whereby certain children suffer from a lack of glutathione, a lack of other sulfur-based proteins, and are therefore more susceptible to metal accumulation. When we look at chelating drugs such as DMPS, we see the “M” in that stands for “mercaptan.” So we want to have mercaptans in our body. By the way, glutathione is also a very powerful antioxidant. So not only does it prevent metal accumulation, it prevents oxidative stress as well.
Dr. Jill James showed that children with autism have low levels of glutathione. In fact, they have low markers for everything in what’s called the “Methionine Cycle.” She tried to get the production of glutathione back to normal. She tried to get the methionine cycle running back to normal. She first started out with folinic acid and betaine; when she added methyl B-12 to the cocktail she found she could get all of these kids’ metabolites back to normal. And there’s at least anecdotal evidence that the clinical symptoms in many of them improved. And I certainly know a lot of parents who tried methyl B-12 on their children, and report remarkable results.
And here is some of the science behind that. Methylation is the transfer of a methyl group from one molecule to another. It happens billions of times a day in our bodies, all over throughout our system. And this is the “Methionine Cycle” right here. It takes homocysteine and - right here is the act of methylation, where this methyl group is joined using things like this enzyme, methionine synthase, methyl B-12, betaine, choline – you can see it all right there.
And then it is methylated and it becomes methionine. Well, that methionine now has an extra methyl group, a donor group, that can be donated off for other purposes. So then the methionine, if you follow it down, some of these methyl groups are then donated off on this branch for the methylation of DNA and RNA, proteins, membranes, phospholipids. In other words, the production of myelin and neurotransmitters – the synapses.
So methylation is absolutely essential for gene expression, for, in fact, a lot of the functions involved with learning, memory, attention, are all down in here. This, by the way, is the mitochondrial cycle.
What Dr. Richard Deth and others have shown is that thimerosal and mercury, right here, in certain children with certain mutations in the MTHFR gene - or excuse me, at least in the test tube – certain mutations in that gene block production of methionine synthase in the presence of mercury, and therefore interrupt methylation.
Now, I didn’t take you all the way through this, but the rest of those methyl groups, they end up back as homocysteine. Half of that homocysteine is taken up again and re-methylated back to methionine. But the other half is sent down the “Transsulfuration Pathway.”
This is how the body produces thiols – sulfur-based proteins. That homocysteine turns in to cysteine, and it ends up eventually as glutathione. If you aren’t producing glutathione, you can buy a product called NAC, which stands for N-acetyl-cysteine.. Well you can see cysteine is a precursor to glutathione.
So just to go back again, let’s say you have that genetic predisposition, that mutation in your MTHFR gene, and let’s say you were exposed to Thimerosal, maybe your first day of life when you get your hepatitis B shot. And let’s say that Thimerosal blocks production of Methionine Synthase. And all of a sudden, you stop or greatly reduce methylation. You’ve then reduced the amount of methionine.
James showed that kids with autism have less methionine. They have fewer donor groups to be donated off into these functions. And they’re going to end up eventually with less glutathione, which leaves them more susceptible to oxidative stress and mitochondrial damage and heavy metal accumulation. So when that kid comes back at his two-month visit, and used to get three shots containing mercury, you can see how this cycle would perpetuate. The more mercury you got, the more vulnerable you became to mercury and to many other things.
I mentioned the immune system, and it’s interesting to note – again, as a journalist I’d say, “That’s interesting. Thimerosal can cause certain immune imbalances.”
And then, when we look at children with autism, we see that they have certain immune imbalances including, again, increased autoimmunity, cytokine activity, unusual cytokine imbalances, and a disturbance in the TH-1/TH-2 immune responses, the antibody versus the humoral response. And again, it all may add up to nothing, but if I were a scientist, I would want to look at the immune imbalances in children with autism, and then I would look at the studies of heavy metals and immune imbalances and I would try to see if there was some kind of connection there. I don’t see why it’s so crazy to raise these questions.
Dr. Thomas Burbacher at the University of Washington took methylmercury, found in fish, and ethylmercury, found in vaccines. He took infant primates; half of them got methylmercury in a feeding tube, as if they were eating fish. The other half got injected with ethylmercury, replicating the childhood schedule. Now, the conventional wisdom has always been that methylmercury stays in the bloodstream longer; and methylmercury crosses the blood-brain barrier more readily. And Burbacher showed that, yes indeed, that was true. What happened was when the press release went out, that’s all that got put into the story. So when you read the article the next day it said, “Mercury in fish is very, very bad. Mercury in vaccines is not so bad.”
But what the story left out was that what Burbacher found was, yes, more methylmercury got into the brain. But organic mercury has a natural transport mechanism to wash into the brain, and wash out of the brain. The half-life for organic mercury in the brain - whether it’s ethyl or methyl, is about 30 days. The half life for inorganic mercury is something like 20 years. So if you have inorganic mercury in your brain, that’s really bad.
And what Burbacher found was that the ethylmercury was much more unstable. And the ethylmercury that did get into the brain began to break down and convert into inorganic mercury very quickly. Once it’s inorganic, it gets stuck there. It doesn’t wash out the way the methyl did. So he actually found that the vaccine-exposed monkeys had up to 4 times more inorganic mercury deposits in their brain than the methyl-exposed monkeys. And in fact, half of the methyl-exposed monkeys had no inorganic deposits at all.
Now this is where it gets really interesting, in my opinion. Burbacher showed in a previous study that those inorganic deposits in the brain start a reaction within the brain, and an immune reaction, and they tend to get deposited in the cells called astrocytes, which you heard about earlier tonight, and microglial cells. And he found that these cells become activated. Well, that is how neuroinflammation occurs; that’s how brain swelling occurs, at least in part through activation of the glial cells. And Burbacher found that sure enough, these deposits of inorganic mercury can activate these glial cells and presumably cause neuroinflammation.
Also very interesting about this, sometimes it took up to 6 months or more after the exposure for those cells to become activated. So you can see a delayed reaction with mercury toxicity and brain damage.
Now, when we look at the autopsied brains of people with autism, we find a lot of the same mechanisms that Burbacher found in his studies on the monkeys.
At Johns Hopkins they found inflammation in these brains, and they found activation of astroglia and microglia. The inflammation was apparently associated with activation of the brain’s immune system, and compared with controls, this was an ongoing inflammation in various sections of the brain.
And at Harvard, when Dr. Martha Herbert and her team looked at the brains of autopsied patients, they found neuro-inflammation, oxidative stress, microglia damage, chronic disease. And the cause may be “chronic disease or external environment sources,” such as heavy metals. And they wrote, “oxidative stress, brain inflammation, and microgliosis has been much documented in association with heavy metal exposures.”
So you’ve just seen a possible route: A child who has depletion in glutathione; a child that’s exposed to mercury; a child who can’t methylate it and can’t excrete that mercury. It’s going to go somewhere. Some of it gets into the brain. It converts into inorganic mercury. It deposits in the microglia. It starts oxidative stress and neuro-inflammation.
Now, this is all proof of absolutely nothing. I’m drawing zero conclusions here. I’m just saying that if I were doling out the cash, I would give somebody a big, fat grant to study this. And I don’t understand why we aren’t rushing to study this. Something’s going on in these autistic brains, and it sure looks an awful lot like what’s going on in the brains of those mercury-exposed monkeys.
Continued in Part Two.
Maria and Ray;
I'm sorry to have come in a week late on this discussion, but in case it's not too late, I'd like to say that I feel you both seem to be missing a vital point. Note that VK Singh referred to antibodies to MBP as a feature of the autoimmune aspects here, in the same breath as referring to the measles virus from the MMR. That measles virus is cultured on chick embryo cells; they can be contaminated with MBP; hence the body will mount an immune reaction to the MBP along with the other ingredients of the MMR, hence an autoimmune reaction to its OWN MBP. Singh has referred to this link a couple of times in his/their studies, but no one seems to be picking up on the matter. The MBP antibodies will attack the myelin sheathing, and the measles virus in the damaged guts of the children diagnosed with ASD will have an easier 'crack' at the brain's cranial nerve systems/CNS. And when the MMR is given at the same time as other vaccines with thimerosal and/or aluminum, the heavy metals/toxins will have an easier time invading the brain.
I'm sorry I don't have links to the various Singh studies mentioned here, but you two seem to be pretty darn good at following up on that sort of thing, so - over to you.
And well done, David Kirby, for this presentation. Incidentally, he does point out how the methylation process affects the development of myelin, and that process can be interrupted by the Hg in thimerosal...
Posted by: Stan | June 09, 2009 at 05:54 PM
and I hope you want to discuss /exchange opinions about the topic with me
.It is not my intention to enlight you about these topics- topics I read a lot to learn about, trying to discuss them with people prone to do it- but to present you why I do think the way I do.
For example, these are clues
J Neurosci Methods. 2005 Sep 30;147(2):114-25.
The experimental toxicology of metallic mercury on the murine peripheral motor system: a novel method of assessing axon calibre spectra using the phrenic nerve.Stankovic RK, Shingde M, Cullen KM.
Department of Pathology, Level 5, Blackburn Building D06, University of Sydney, Sydney, NSW 2006, Australia.
The toxicology of metallic mercury on motor neurons and their processes requires further work to resolve controversial implications in the aetiology of human motor neuron disease (MND). The assessment of experimental neurotoxicity in the peripheral motor system is, however, technically problematic and difficult to interpret. The mean number of axons in a nerve can vary considerably due to a high degree of biological variation. Atrophy of large axons can appear as loss when, in fact, their numbers appear in smaller diameter axonal categories. We addressed these quantitative problems using the murine phrenic nerve (MPN), a mono-fascicular, predominantly motor nerve as a model system. One micrometer transverse sections of gluteraldehyde/osmium tetroxide fixed MPNs were stained for myelin using a silver technique. Axon areas were measured from digital images of the nerve in cross-section (ImagePro Plus software) and transformed to circular diameter equivalents, then displayed as frequency distributions. We found a high biological variation in the mean axon number between paired nerves within experimental groups. Therefore, axon diameter data within individuals group was pooled. Theoretical simulation of axonal degeneration, atrophy and hypertrophy of larger myelinated axons (also affected in MND) were modelled by manipulating the original data set. With this model, by comparing normal distributions, it is possible to distinguish axonal atrophy, degenerative loss, and hypertrophy as distinct pathological processes in the large calibre axon subgroup that are selectively vulnerable to metallic toxins such as mercury.
Environ Health Perspect. 1999 Oct;107 Suppl 5:767-75.
Neuroimmunotoxicology: humoral assessment of neurotoxicity and autoimmune mechanisms.El-Fawal HA, Waterman SJ, De Feo A, Shamy MY.
Pharmacology and Toxicology Laboratory, Mercy College, Dobbs Ferry, NY 10522, USA.
The interactions between the nervous and immune systems have been recognized in the development of neurodegenerative disease. This can be exploited through detection of the immune response to autoantigens in assessing the neurotoxicity of environmental chemicals. To test this hypothesis, the following questions were addressed. a) Are autoantibodies to nervous system (NS) antigens detected in populations exposed to environmental or occupational chemicals? In sera of male workers exposed to lead or mercury, autoantibodies, primarily IgG, to neuronal cytoskeletal proteins, neurofilaments (NFs), and myelin basic protein (MBP) were prevalent. These findings were confirmed in mice and rats exposed to either metal. b) Do autoantibodies to NS antigens relate to indices of exposure? In humans exposed to either metal, and similarly in exposed rats, titers of IgG against NFs and MBP significantly correlated with blood lead or urinary mercury, the typical indices of exposure. c) Do autoantibodies correlate with sensorimotor deficits? In workers exposed to lead or mercury, a significant correlation was observed between IgG titers and subclinical deficits. Doses of metals used in rat exposures were subclinical, suggesting that autoantibodies may be predictive of neurotoxicity. d) Is the detection indicative of nervous system pathology? In rats exposed to metals, histopathology indicated central nervous system (CNS) and peripheral nervous system (PNS) damage. In addition there was evidence of astrogliosis, which is indicative of neuronal damage in the CNS, and the presence of IgG concentrated along the blood-brain barrier, as indicated by immunostaining for antibodies. e) Are immune responses to NS antigens pathogenic? Immunoglobulin fractions from rat and human sera interfered with neuromuscular function. These studies suggest that the detection of autoantibodies to NS-specific antigens may be used to monitor the development of neurotoxicity to environmental chemicals and that immune mechanisms may be involved in the progression of neurodegeneration.
J Neuropathol Exp Neurol. 1998 Apr;57(4):360-6.Links
Shrinkage of motor axons following systemic exposure to inorganic mercury.Pamphlett R, Png FY.
Department of Pathology, The University of Sydney, New South Wales, Australia.
Systemically-administered inorganic mercury localizes to motor neurons, but it is not known if mercury injures these neurons. We therefore looked for signs of damage to the motor and sensory neurons of mice that had been exposed to inorganic mercury. Young adult mice were injected intraperitoneally with either 1 or 2 microg/g of mercuric chloride and perfused 1 or 30 weeks later. The cellular distribution of mercury in the spinal cord was examined with silver nitrate autometallography. The numbers and sizes of myelinated axons in the L5 anterior and posterior roots were quantitated using an image analysis program. Mercury was found throughout the cytoplasm of motor neuron cell bodies after 1 week and in paranuclear aggregations after 30 weeks. Thirty weeks after exposure to either 1 or 2 microg/g of mercury, fewer large myelinated axons were seen in mercury-injected groups than in controls, though total numbers of myelinated axons did not differ between groups. A slight increase in numbers of small axons was seen in the posterior roots of mice exposed to 1 microg/g of mercury. In conclusion, inorganic mercury remains within mouse neurons for prolonged periods and causes a reduction in the size of myelinated axons in the anterior root and to a lesser extent the posterior spinal root. Inorganic mercury within motor neurons therefore appears to behave as a slowly-acting neurotoxin that shrinks motor axons.
Posted by: María Luján | June 02, 2009 at 11:18 PM
Dear Mr Gallup
My point is that there are many aspects to be considered when toxic elements impact in human beings is studied. Between them the species of the heavy metal- that is in what chemical form is - structure, reactivity, etc, the kind of exposure- because injection, ingestion, inhalation are all different- and the topic of how there are new views about the (very) low doses exposures- with clear problems with the old" the dose makes the poison".
Now, what I tried to present you is recent research abstracts that give clues about how there are a lot about mercury in particular but toxic elements in general that points to specific kinds of damage depending on developmental vulnerability, organ of action and other aspects that need to be considered. AND in this context how xenobiotics may interact complicates things further.
Neurotoxicology. 2009 May;30(3):331-7. Epub 2009 Mar 21.
Ockham's Razor and autism: the case for developmental neurotoxins contributing to a disease of neurodevelopment.DeSoto MC.
Department of Psychology, University of Northern Iowa, Baker Hall, Cedar Falls, IA 50614-0505, United States.
Much professional awareness regarding environmental triggers for ASD has been narrowly focused on a single possible exposure pathway (vaccines). Meanwhile, empirical support for environmental toxins as a broad class has been quietly accumulating. Recent research has shown that persons with ASD have comparatively higher levels of various toxins and are more likely to have reduced detoxifying ability, and, that rates of ASD may be higher in areas with greater pollution. This report documents that within the state with the highest rate of ASD, the rate is higher for schools near EPA Superfund sites, t (332)=3.84, p=.0001. The reasons for the rise in diagnoses likely involve genetically predisposed individuals being exposed to various environmental triggers at higher rates than in past generations.
By no way I am considering thimerosal one only cause, such as viral exposures I don´t consider uniques causes. I do think that the topic of autoimmunity and connections to infections - from parasites to fungus to bacteria/ viruses- is being under full research too. Too much to research, too little really is known or has been done. There has been published reserach on coinfections in some ASD subgroups - but too much little in number and too much focused in only a few.
Now, when the recent research on autoimmunity in general is analyzed- Dr Shoenfeld, von Harrath in diabetes for example- there are several aspects that are emerging that have not been researched in ASD, that are difficult to research in ASD and in other medical conditions and whose high quality evidence is very difficult to find- due to the complexity of the
Autoimmunity seems to have many triggers and many manifestations.
My son had an adverse reaction to the MMr- he was IgA severely defficient at that time- and I do think that this was a contributor for many of his Concomitant medical problems to his diagnosis- beetween them also a completely altered answer to herpes infections (EBV, HSV-1 and CMV). This personal situation is shared with you therefore I can explain better my thinking.
For example, there is the topic of the "fertile field". I am extremely interested on research from many field related to ASD- but not in a "vertical " form- such as if the medical situations are unique only to ASD, but trying to consider an horizontal view- what is similar and what is different in CMPs in Autism from other medical conditions, what is shared in clinical aspects and what is different- in presentation, outcome or biomarkers.
Now, the subtle balance between tolerance and autoimmunity is being more and more discussed:
Nat Rev Microbiol. 2003 Nov;1(2):151-7.
Microorganisms and autoimmunity: making the barren field fertile?von Herrath MG, Fujinami RS, Whitton JL.
Division of Developmental Immunology, Immune Regulation Laboratory, La Jolla Institute for Allergy and Immunology, 10355 Science Centre Drive, San Diego, California 92121, USA.
Microorganisms induce strong immune responses, most of which are specific for their encoded antigens. However, microbial infections can also trigger responses against self antigens (autoimmunity), and it has been proposed that this phenomenon could underlie several chronic human diseases, such as type 1 diabetes and multiple sclerosis. Nevertheless, despite intensive efforts, it has proven difficult to identify any single microorganism as the cause of a human autoimmune disease, indicating that the 'one organism-one disease' paradigm that is central to Koch's postulates might not invariably apply to microbially induced autoimmune disease. Here, we review the mechanisms by which microorganisms might induce autoimmunity, and we outline a hypothesis that we call the fertile-field hypothesis to explain how a single autoimmune disease could be induced and exacerbated by many different microbial infections.
How some viral infections may be protective whereas other may be dangerous
Clin Microbiol Rev. 2006 Jan;19(1):80-94. Links
Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease.Fujinami RS, von Herrath MG, Christen U, Whitton JL.
Department of Neurology, University of Utah School of Medicine, 30 N 1900 E, 3R330 SOM, Salt Lake City, UT 84132-2305, USA.
Virus infections and autoimmune disease have long been linked. These infections often precede the occurrence of inflammation in the target organ. Several mechanisms often used to explain the association of autoimmunity and virus infection are molecular mimicry, bystander activation (with or without epitope spreading), and viral persistence. These mechanisms have been used separately or in various combinations to account for the immunopathology observed at the site of infection and/or sites of autoimmune disease, such as the brain, heart, and pancreas. These mechanisms are discussed in the context of multiple sclerosis, myocarditis, and diabetes, three immune-medicated diseases often linked with virus infections.
Now, there is a recent manuscript on the topic
Curr Opin Investig Drugs. 2009 May;10(5):463-73.Links
Autoimmunity in autism.Enstrom AM, Van de Water JA, Ashwood P.
University of California at Davis, Department of Medical Microbiology and Immunology/UC Davis MIND Institute, 2805 50th Street, Sacramento, CA 95817, USA.
Autism spectrum disorders is a heterogenous group of neurodevelopmental disorders, the etiology or etiologies of which remain unknown. Increasing evidence of autoimmune phenomena in individuals with autism could represent the presence of altered or inappropriate immune responses in this disorder, and this immune system dysfunction may represent novel targets for treatment. Furthermore, in recent studies, antibodies directed against the fetal brain have been detected in some mothers of children with autism; these antibodies have the ability to alter behavioral outcomes in the offspring of animal models. A better understanding of the involvement of the immune response in early brain development, with respect to autism, may have important therapeutic implications.
J Toxicol Environ Health B Crit Rev. 2008 Oct;11(8):660-80. Links
Potential for early-life immune insult including developmental immunotoxicity in autism and autism spectrum disorders: focus on critical windows of immune vulnerability.Dietert RR, Dietert JM.
Department of Microbiology and Immunology, Cornell University, Ithaca, NY14852, USA.
Early-life immune insults (ELII) including xenobiotic-induced developmental immunotoxicity (DIT) are important factors in childhood and adult chronic diseases. However, prenatal and perinatal environmentally induced immune alterations have yet to be considered in depth in the context of autism and autism spectrum disorders (ASDs). Numerous factors produce early-life-induced immune dysfunction in offspring, including exposure to xenobiotics, maternal infections, and other prenatal-neonatal stressors. Early life sensitivity to ELII, including DIT, results from the heightened vulnerability of the developing immune system to disruption and the serious nature of the adverse outcomes arising after disruption of one-time immune maturational events. The resulting health risks extend beyond infectious diseases, cancer, allergy, and autoimmunity to include pathologies of the neurological, reproductive, and endocrine systems. Because these changes may include misregulation of resident inflammatory myelomonocytic cells in tissues such as the brain, they are a potential concern in cases of prenatal-neonatal brain pathologies and neurobehavioral deficits. Autism and ASDs are chronic developmental neurobehavioral disorders that are on the rise in the United States with prenatal and perinatal environmental factors suspected as contributors to this increase. Evidence for an association between environmentally associated childhood immune dysfunction and ASDs suggests that ELII and DIT may contribute to these conditions. However, it is not known if this linkage is directly associated with the brain pathologies or represents a separate (or secondary) outcome. This review considers the known features of ELII and DIT and how they may provide important clues to prenatal brain inflammation and the risk of autism and ASDs.
Now, in this context, xenobiotics ( including toxic elements and medications) and infections/vaccines are part of the picture-such as individual biochemical/metabolic situation at the time of the exposure but it is different for each individual. Reading the research on autoimmunity the frustation of the researchers in terms of how difficult is to approach to a multifactorial (causation) medical condition of individual presentation- linked to genetic susceptibilities is very clear- and I feel the same frustation around the CMPs in ASD about how much is needed to do- and well- to get some useful answers.
Posted by: María Luján | June 02, 2009 at 10:54 PM
I don't see any scientific research showing that mercury/thimerosal cause any autoimmunity and myelin dysfunction in children with autism including the article you posted.
I'm not aware of any metal that does the damage to the myelin of kids with autism.....only what I have seen regarding the measles virus/MMR vaccine.
Please enlighten me with the research that mentions this....that says that mercury causes autoimmunity and myelin dysfunction.
Posted by: Raymond Gallup | June 02, 2009 at 06:55 PM
There are recent published studies on the activation of metallothioneins in cerebellum and cerebrum by injected thimerosal
Toxicology. 2009 Apr 19.
Expression of metallothionein mRNAs on mouse cerebellum microglia cells by thimerosal and its metabolites.Minami T, Miyata E, Sakamoto Y, Kohama A, Yamazaki H, Ichida S.
Department of Life Sciences, School of Science & Engineering, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
Effects of thimerosal and its metabolites, ethyl mercury and thiosalicylate, on the expression of metallothionein (MT) mRNAs in mouse cerebellum microglia cell line, C8-B4 cells, were studied. The level of MT-1 mRNA significantly decreased at early hours and recovered time-dependently 24h after thimerosal was added to the C8-B4 cells. However, MT-2 and MT-3 mRNA expressions did not change from the control group. In contrast, the expression of MT-1 mRNA increased in a mouse neuroblastoma cell line 6h after incubation with thimerosal. In addition, the level of MT-1 mRNA decreased in C8-B4 cells 6h after the addition of thiosalicylate, but ethyl mercury induced MT-1 mRNA expression. When cell viability was compared with thimerosal, thiosalicylate, and ethyl mercury, the viability of C8-B4 cells decreased dose-dependently 24h after either thimerosal or ethyl mercury was added; however, the viability increased dose-dependently until 15muM thiosalicylate was added. From the present results, it is concluded that the expression of MT-1 mRNA may be mediated by different factors than the expression of MT-2 mRNA in C8-B4 cells. The reduction of MT-1 mRNA level by thiosalicylate may affect the proliferation of C8-B4 cells.
Cell Biol Toxicol. 2009 Apr 9. [
Induction of metallothionein in mouse cerebellum and cerebrum with low-dose thimerosal injection.Minami T, Miyata E, Sakamoto Y, Yamazaki H, Ichida S.
Department of Life Sciences, School of Science & Engineering, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan, Thimerosal, an ethyl mercury compound, is used worldwide as a vaccine preservative. We previously observed that the mercury concentration in mouse brains did not increase with the clinical dose of thimerosal injection, but the concentration increased in the brain after the injection of thimerosal with lipopolysaccharide, even if a low dose of thimerosal was administered. Thimerosal may penetrate the brain, but is undetectable when a clinical dose of thimerosal is injected; therefore, the induction of metallothionein (MT) messenger RNA (mRNA) and protein was observed in the cerebellum and cerebrum of mice after thimerosal injection, as MT is an inducible protein. MT-1 mRNA was expressed at 6 and 9 h in both the cerebrum and cerebellum, but MT-1 mRNA expression in the cerebellum was three times higher than that in the cerebrum after the injection of 12 microg/kg thimerosal. MT-2 mRNA was not expressed until 24 h in both organs. MT-3 mRNA was expressed in the cerebellum from 6 to 15 h after the injection, but not in the cerebrum until 24 h. MT-1 and MT-3 mRNAs were expressed in the cerebellum in a dose-dependent manner. Furthermore, MT-1 protein was detected from 6 to 72 h in the cerebellum after 12 microg/kg of thimerosal was injected and peaked at 10 h. MT-2 was detected in the cerebellum only at 10 h. In the cerebrum, little MT-1 protein was detected at 10 and 24 h, and there were no peaks of MT-2 protein in the cerebrum. In conclusion, MT-1 and MT-3 mRNAs but not MT-2 mRNA are easily expressed in the cerebellum rather than in the cerebrum by the injection of low-dose thimerosal. It is thought that the cerebellum is a sensitive organ against thimerosal. As a result of the present findings, in combination with the brain pathology observed in patients diagnosed with autism, the present study helps to support the possible biological plausibility for how low-dose exposure to mercury from thimerosal-containing vaccines may be associated with autism
Now, the Singh manuscript measured in serum metallothioneins and anti-metallothioneins but they did not discuss the possibility that the reaction to thimerosal in certain individuals and under certain metabolic or biochemical circunstances may be focused in brain mainly. The comments are related to other ways of exposures-speciation and so on.
Pediatr Allergy Immunol. 2006 Jun;17(4):291-6. Links
ssessment of metallothionein and antibodies to metallothionein in normal and autistic children having exposure to vaccine-derived thimerosal.
Singh VK, Hanson J.
Department of Biology, Utah State University, Logan, UT 84322, USA.
Allergic autoimmune reaction after exposure to heavy metals such as mercury may play a causal role in autism, a developmental disorder of the central nervous system. As metallothionein (MT) is the primary metal-detoxifying protein in the body, we conducted a study of the MT protein and antibodies to metallothionein (anti-MT) in normal and autistic children whose exposure to mercury was only from thimerosal-containing vaccines. Laboratory analysis by immunoassays revealed that the serum level of MT did not significantly differ between normal and autistic children. Furthermore, autistic children harboured normal levels of anti-MT, including antibodies to isoform MT-I (anti-MT-I) and MT-II (anti-MT-II), without any significant difference between normal and autistic children. Our findings indicate that because autistic children have a normal profile of MT and anti-MT, the mercury-induced autoimmunity to MT may not be implicated in the pathogenesis of autism.
Now, the main point to address is how thimerosal induced MT mRNAs in cerebrum/cerebellum and if this kind of situation is correlated to a (mis) location of Hg - from thimerosal- in cerebrum/cerebellum (and how /why/where) when thimerosal is injected ( through transporters, molecular mimicry, What concomitant medical problems (s) are predisposing to this) and if the situation may be present in certain susceptible individuals.
Clin Exp Immunol. 2009 Jan;155(1):117-124
Mercury and silver induce B cell activation and anti-nucleolar autoantibody production in outbred mouse stocks: are environmental factors more important than the susceptibility genes in connection with autoimmunity?
Department of Biochemistry and Biophysics, Arrhenius Laboratories for the Natural Sciences, Stockholm University, Stockholm, Sweden.
Environmental and predisposing genetic factors are known to play a crucial role in the development of systemic autoimmune diseases. With respect to the role of environmental factors, it is not known how and to what extent they contribute to the initiation and exacerbation of systemic autoimmunity. In the present study, I considered this issue and asked if environmental factors can induce autoimmunity in the absence of specific susceptible genes. The development of genetically controlled mercury- and silver-induced B cell activation and anti-nucleolar autoantibodies (ANolA) production in genetically heterozygous outbred Institute of Cancer Research (ICR), Naval Medical Research Institute (NMRI) and Black Swiss mouse stocks were analysed. Four weeks of treatment with both mercury and silver induced a strong B cell activation characterized by increased numbers of splenic antibody-secreting cells of at least one or more immunoglobulin (Ig) isotype(s) in all treated stocks. The three stocks also exhibited a marked increase in the serum IgE levels in response to mercury, but not silver. More importantly, in response to mercury a large numbers of ICR (88%), NMRI (96%) and Black Swiss (100%) mice produced different levels of IgG1 and IgG2a ANolA (a characteristic which is linked strictly to the H-2 genes). Similarly, but at lower magnitudes, treatment with silver also induced the production of IgG1 and IgG2a ANolA in 60% of ICR, 75% of NMRI and 100% of Black Swiss mice. Thus, the findings of this study suggest that long-term exposure to certain environmental factors can activate the immune system to produce autoimmunity per se, without requiring specific susceptible genes.
Ann N Y Acad Sci. 2008 Nov;1143:240-67.
Immunology of mercury.Vas J, Monestier M.
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
The heavy metal mercury is ubiquitously distributed in the environment resulting in permanent low-level exposure in human populations. Mercury can be encountered in three main chemical forms (elemental, inorganic, and organic) which can affect the immune system in different ways. In this review, we describe the effects of these various forms of mercury exposure on immune cells in humans and animals. In genetically susceptible mice or rats, subtoxic doses of mercury induce the production of highly specific autoantibodies as well as a generalized activation of the immune system. We review studies performed in this model and discuss their implications for the role of environmental chemicals in human autoimmunity.
Posted by: María Luján | June 02, 2009 at 05:52 PM
The VK Singh and Jeff Hanson article is
Pediatric Allergy and Immunology
Volume 17 Issue 4, Pages 291 - 296
Published Online: 8 Dec 2005
© 2009 John Wiley & Sons A/S
Assessment of metallothionein and antibodies to metallothionein in normal and autistic children having exposure to vaccine-derived thimerosal
Posted by: Ray Gallup | June 02, 2009 at 03:21 PM
"So you might have metals as a contributing factor to autism, but you can’t separate that entirely from the fact that metals can also destroy myelin."
David Kirby is wrong about mercury and myelin (and mercury is not involved with autoimmunity either).
Measles virus/MMR vaccine IS involved with myelin problems and autoimmunity regarding children with autism.
5. Mercury and autism: Mercury is not related to autoimmunity.
Because both autism and mercury exposure involve autoimmunity, mercury has
recently been proposed as an environmental risk factor in autism. However, the laboratory
analysis showed that the blood levels of mercury do not rise above safe levels in infants and
children receiving thimerosal-containing vaccines . We hypothesized that if autism
involved a connection between mercury exposure and autoimmunity then autistic children
should harbor elevated levels of mercury-induced autoimmune markers, namely the
antinucleolar antibodies and antilaminin antibodies. So, we recently conducted a pilot study
of these two autoimmune markers in autistic children and normal children. The results of our
experimental study, for the first time, showed that the distribution of these two markers did
not change in autistic children. Quite plainly, mercury is not a risk factor for autoimmunity in
autism [Our research in progress].
Vijendra K. Singh and Jeff Hanson
Autism is a biological disorder that impairs the functioning of the brain in children, affecting their ability for social interaction, language, imagination, communication and cognition. The aetiology and pathogenesis of the disorder are not well known but the immune factors such as autoimmunity to brain might play a pathogenetic role in autism (1–4). Although the trigger agent for autoimmunity is not well known, there is serological evidence for a virus infection (5–7). Heavy metals like mercury are also capable of eliciting autoimmune reaction but a recent study of autoimmune markers in autism did not support this possibility (8). In the body, the biological response to heavy metals is exerted by metallothionein (MT), which is a cysteine (Cys)-rich protein that chiefly transports heavy metals for detoxification purposes. The MTs are a family of proteins that are inducible by a variety of environmental factors and stress conditions (9–13). The mammalian MT is characterized by a molecular weight of 6–7 kD, containing 60–68 amino acid residues, among them 20 Cys, and binding a total of seven equivalents of bivalent metal ions. Because of diverse biochemical properties of MT proteins, we hypothesized that if the children with autism have heavy metal or mercury toxicity then they might also have up-regulation of MT and anti-MT as a sign of metal-induced autoimmune process. Therefore, we conducted present study to assess the status of MT and anti-MT as biomarkers of detoxification response to vaccine-derived mercury in children with autism. MT is known to exist in four isoforms, the ubiquitous MT-I and MT-II, the brain specific MT-III, and the squamous epithelium specific MT-IV (9, 14, 15), but in the present study we screened antibodies against MT, MT-I and MT-II proteins only because of their availability from commercial sources.
The serum profiles of MT protein and anti-MT are shown in Figs. 1–3. Firstly, the experimental data for MT in sera of normal and autistic children are depicted in Fig. 1. Although the MT protein was found in both populations of children, its concentration in the serum did not differ significantly (p = 0.792) between the normal and autistic children. Secondly, the determination of antibodies to MT was carried out first to study the effect of serum dilution (Fig. 2). Using MT as the screening antigen, we found the presence of anti-MT in both normal
and autistic children. At four serum dilutions (1:50, 1:100, 1:200 and 1:400 dilutions), autistic children harboured about the same level of anti-MT as the normal children did (Fig. 2) and the difference between these two groups did not attain statistical significance (p-values being ?0.385 at all four dilutions). Not included here but the effect of serum dilution was about the same when MT-I and MT-II were used as the screening antigens. Because a serum dilution of 1:50 showed the highest level of antibody, it was subsequently used to screen all other sera of subjects in the study. The outcome of this screen is shown in Fig. 3, which contains quantitative levels of anti-MT, -MT-I and -MT-II. The serum level of anti-MT proteins in autistic children did not change significantly (p-values being ?0.1) when compared with their levels in normal children (Fig. 3). Thus, there was no significant difference in the distribution of antibodies to MT proteins in normal and autistic children.
Metallothioneins are ubiquitous low molecular weight proteins. Owing to their extremely high metal and sulphur content, they are thought to play a multitude of biological roles, including the neutralization of heavy metal toxicity and protection from stress conditions (9–15). Although the mercury is widespread in the environment, humans are exposed to mercury mainly through the consumption of contaminated fish and medicinal products such as vaccines, dental amalgams and skin ointments. As the childhood vaccines contain mercury derivative thimerosal as a preservative, they represent the primary source of mercury exposure to children. Mercury is a well-known environmental agent with toxic effects on just about all biosystems, including the nervous system and the immune system (16–21).
Mercury from thimerosal-containing vaccines has recently been suspected as a risk factor for neurodevelopmental disorders, including autism. Anecdotally, the mercury poisoning was speculated to resemble autistic disorder, implying that the neurological manifestations of autism originate from the exposure to thimerosal-derived mercury (22). However, a careful literature review by neurologists showed that the neurological manifestations of autism did not resemble the clinical signs of mercury poisoning, thus precluding an aetiological link between thimerosal and autism (23). Moreover, there is very little, if any, laboratory-based experimental research on this topic. Because mercury is well known to influence immune system, people generally tend to think that mercury is always immunotoxic. This could be misleading because mercury also exerts positive effects such as lymphoproliferation (24). Fundamentally, there is very little research on mercury-induced immune regulation and autoimmunity but this topic needs to be investigated with scientific rigour. As mercury can induce autoimmunity (19–21), we explored the possibility that mercury could trigger autoimmunity in autism also. However, this may not be the case because of the novel findings as discussed below.
Investigations of faulty immune regulation in autism and mercury-induced immune abnormalities have revealed some important differences between these two conditions. The mercury-induced autoimmunity is generally typified by the presence of circulating autoantibodies, in particular the anti-nuclear (anti-nucleolar) antibodies and anti-laminin antibodies (20, 21). This autoimmune reaction is rare in man but when it occurs it causes nephrotic syndrome (21). As far as we know, children with autism do not have nephrotic syndrome and they do not harbour abnormal titres of anti-nuclear (anti-nucleolar) antibodies and/or anti-laminin antibodies (8). Moreover, the people with mercury-induced autoimmunity have auto-antibodies to the low-molecular weight (68 kD) neurofilament protein (19) whereas the antibodies to this antigen are virtually absent in autistic children (2). In contrast, however, the children with autism harbour autoantibodies predominantly to brain myelin basic protein (MBP) (1, 2), which are rarely detected in individuals exposed to mercury (19). Furthermore, autism involves a Th1 immune response (3) whereas the mercury exposure induces a Th2 response (25). Immunologically, therefore, the two conditions demonstrate some important differences, which could imply that mercury is not likely the environmental agent for setting up the autoimmune reaction in autism.
Until recently, antibodies to MT were not known to exist in man. Jin et al. (26) recently showed the occurrence of these antibodies in the human population. They studied anti-MT in sera of 39-year-old Japanese population comprised of about twice the number of females than males. They found the presence of anti-MT in approximately 4% of healthy adults, 6% of adult patients with atopic dermatitis, and 51% of adult patients with atopic dermatitis after metal allergy that was experimentally induced against predominantly nickel and to a much lesser degree mercury also. These researchers concluded that the exposure to metals induces the synthesis of antibodies to MT in adult patients suffering from atopic dermatitis. However, the pathological significance of these antibodies remains unclear at the present time.
As described here, we conducted the first ever study of serum profiles of MT protein and anti-MT in autistic children who might show up-regulation of these biomarkers if the exposure to mercury was related to autoimmunity in autism. The outcome of this study clearly showed that there was no significant difference in autistic and normal children as far as the MT and anti-MT serum profiles are concerned. Both populations had almost the same profile for these two biomarkers, a result that might be expected because both normal and autistic children have had their immunizations in compliance with the US government policy. Now, there are at least two different lines of studies (present study and Ref. 8) that did not render support for a mercury and autoimmunity connection in autism. But, these negative findings alone are probably not sufficient to rule out such a relationship completely. While more experimental research is necessary on this topic, we conclude that the chance of setting up an autoimmune response from exposure to small amounts of vaccine-derived mercury is rather rare, unless of course some other factors concurrently contribute and increase the susceptibility to mercury-induced autoimmunity. The other factors might include bacterial toxins, toxic chemicals or dietary peptides, which by binding to lymphocyte receptors and tissue enzymes could potentially be relevant to autism (27). But because of the lack of disease-specific correlations, the significance of these factors remains to be established.
Conceptually, autism is generally considered to be a multi-factorial disorder. To this end, it is instructive to explore and pay attention to other causative mechanisms for autism. One such mechanism could be the virus-induced autoimmune pathogenesis (1–4) that was demonstrated by a specific serological association between brain MBP and measles virus but not between other brain proteins and other viruses in autism (2, 4–7). The MBP antibody and the measles virus antibody were the only two parameters that showed a positive correlation in >90% of the autistic children (5, 6), but none of the other autoimmune parameters investigated so far has shown any correlation that might be of pathological relevance to autism. This observation might be an important clue to identifying viral aetiology of this brain disorder. Accordingly, a novel protocol has recently been developed for testing virus serology and brain-specific autoimmunity in autistic patients, who might also draw benefits of the immune modulation therapy (4). Based on the negative findings of the present study and that of our previous study (8), we conclude that the vaccine-derived thimerosal is probably not a contributing factor for autoimmunity in autism. While one such factor might be a virus (4–6), we think that more laboratory-based research is needed to identify the agent for setting off the autoimmune process in autism.
This work was supported by charitable contributions from the Autism Research Institute, BHARE Foundation and Dudley T. Dougherty Foundation. The authors did not have any conflict of interest in this regard. Jeff Hanson was a pre-med student.
From the following by VK Singh
Posted by: Ray Gallup | June 02, 2009 at 02:46 PM
This is a tremendous amount of work ... There is a great supplement called MaxGXL that increases natural glutathione at the Mitochondrial level in all your cells by providing your body with the precursors L Glutatmine, N-Acetyl Cysteine, and Alpha Lipoic Acid.
This products works!!!
Posted by: Jeff White | June 01, 2009 at 02:10 PM
This is about CFS and mitochondria, but may be of interest here too
Posted by: Beta | June 01, 2009 at 10:53 AM
Thank you!! It's so hard living with Autism but reading this brings not only hope but a realisation that we are not alone in our struggles. God bless you.
Posted by: Kacey | June 01, 2009 at 12:34 AM
I personally think that the main aspect to consider is the combination of exposure in time- that is how antibiotics, wild infections, gastrointestinal problems- and gut microbiota- and dietary aspects, immune immaturities and genetic susceptibilities with vaccines- being some of them more stress- generating than others- should be more carefully researched and analyzed. The lack of an integrative view has been tragic and how the oversimplification has hindered true progress is very concerning, IMHO.
In that sense, toxic elements are part of the picture- at least for my son- and not only from vaccines, from diet- Aluminium, water- Arsenic may be high in certain geographic zones- and exposure from air pollution- and particulates in urban areas (for example). And the toxic elements imbalances have been hand in hand with disturbance of metabolism -absorption and management- that produced loss/imbalances of essential elements for my son, therefore how essential elements metabolism is disturbed is very important to analyze also.
Posted by: María Luján | May 31, 2009 at 02:11 PM
Thank you David are NOT big enough words for you sticking by this cause. Thanks David. I know this is a hard road to continue to walk down but we are grateful you are here.
Posted by: lisa@TACA | May 31, 2009 at 10:40 AM
Maria: Very impressive material! I have read it three times - and I re-read David Kirby's article agian too. Pink disease and kawaskis - maybe? I will keep an open mind that heavy metals may be the culprit, but I still am not sure.
Posted by: Benedetta Stilwell | May 31, 2009 at 06:14 AM
Wow, very impressive! You did a great job. I feel the picture is incomplete, but explained much better than the average doctor could, sadly. When I think about it all, it seems like the real cause of autism is just plain poor medical care. These kids have too many pathogens and toxins and doctors who won't look for it. If the doctors would start treating everyone that comes to them, rather than picking and choosing who can be helped and who they don't feel like helping, then maybe we might start reversing this very serious epidemic. Sadly, it's not just autism, but many other diseases are not being treated as well. All this non-treatment has led to an increase in diseases in general We have got to redo the whole medical system because it's not working.
Posted by: Heidi N | May 30, 2009 at 10:39 PM
Kim - it is painful to go through old photos. I did it recently for my son's kindergarten graduation (they're doing a photo montage for all of the kids). Even more painful, was the realization that for about a year, we simply didn't take any photos. We lived close to a cement plant in Eastern Oregon at the time (hello, mercury anyone?) and now that I know what I know, I can see a lot of those facial features that my son developed in the kids that still live in the area (dark circles, puffy faces, drooping mouth, glassy/spaced out eyes). Good news however, things are looking up and my son is engaging, laughing and shedding the poison mask that he's been behind for years. Thanks David for all of your work, your persistence, your tenacity and your dedication to our kids. We are eternally grateful.
Posted by: Amy in Idaho | May 30, 2009 at 10:27 PM
Yes Yes Yes!! Thank you David!! You just put our biomed kids "in a nut shell". How freakin' long has it taken...but you all have DONE IT!!
Seriously, our kids are not "autistic" - they are SICK!!
BTW - I went to my first DAN conf. in Boston in 2005 and you were the very first speaker. I have never looked back....and now my kid is off the ASD spectrum....or rather...he is getting healthier. He is still doing biomed therapies since I believe he is "medically fragile". (ie: if he goes off his supps and therapies, he regresses.)
What are you going to name this new disease/disorder??
"POor Sick Kids whO No One Listened tO For Years."
....Except for people like you who kept this movement moving forward.
Posted by: Jacey | May 30, 2009 at 10:26 PM
A recent manuscript on Kawasaki disease
Curr Med Chem. 2008;15(28):3000-10.
Kawasaki's disease, acrodynia, and mercury.Mutter J, Yeter D.
Department of Environmental and Complementary Medicine, Salusmed Medical Center, Wieslistrasse 34, CH - 8267 Berlingen, Switzerland.
A superantigen or autoimmunity has been hypothesized to be the main cause of the Kawasaki's Disease but the etiology is unknown. Medical literature, epidemiological findings, and some case reports have suggested that mercury may play a pathogenic role. Several patients with Kawasaki's Disease have presented with elevated urine mercury levels compared to matched controls. Most symptoms and diagnostic criteria which are seen in children with acrodynia, known to be caused by mercury, are similar to those seen in Kawasaki's Disease. Genetic depletion of glutathione S-transferase , a susceptibility marker for Kawasaki's Disease, is known to be also a risk factor for acrodynia and may also increase susceptibility to mercury . Coinciding with the largest increase (1985-1990) of thimerosal (49.6% ethyl mercury) in vaccines, routinely given to infants in the U.S. by 6 months of age (from 75microg to 187.5microg), the rates of Kawasaki's Disease increased ten times, and, later (1985-1997), by 20 times. Since 1990 88 cases of patients developing Kawasaki's Disease some days after vaccination have been reported to the Centers of Disease Control (CDC) including 19% manifesting symptoms the same day. The presented pathogenetic model may lead to new preventive- and therapeutic strategies for Kawasaki's disease.
Med Lav. 2002 May-Jun;93(3):139-47.
Mercury exposure and early effects: an overview.Kazantzis G.
Environmental Geochemistry Research Group, Department of Environmental Science and Technology, Imperial College of Science, Technology & Medicine, Prince Consort Road, London SW7 2BP, UK.
OBJECTIVES: This paper was given as a keynote address at the conference on The Assessment of the Effects Due to Low Doses of Inorganic Mercury following Environmental and Occupational Exposures: Human and in vitro Studies on the Specific Mechanisms of Toxicity in Gargnano, Italy, in September 2001. METHODS: The most relevant literature over the past 40 years has been reviewed, and in particular, the proceedings of the World Health Organisation conferences on the health effects of inorganic and organic mercury exposure have been considered. RESULTS: In an uncontaminated environment the general population is exposed to mercury vapour from the atmosphere and from dental amalgam, while the diet, mainly from fish, is the principal source for methyl mercury absorption. Mercury vapour release from amalgam fillings increases with chewing, with absorption and uptake by the brain and kidneys. Infants exposed to phenyl mercury from treated diapers and young children ingesting mercurous chloride in teething powders have developed acrodynia (pink disease), and Kawasaki disease and the use of mercurial skin lightening creams has been followed by the development of the nephrotic syndrome. Both mercury compounds and mercury vapour have given rise to contact dermatitis in the general population. Epidemics of mercury poisoning have followed release of mercury into the environment from industrial activity, with uptake of methyl mercury from fish eating in Minamata Bay and uptake of both inorganic and methyl mercury following release of mercury vapour and deposition into waterways from gold recovery procedures in the Amazon basin. The ingestion of wheat and barley seed treated with an alkyl mercury fungicide for sowing, by a largely illiterate population in Iraq, led to a major outbreak of poisoning with a high fatality rate. Following exposure to mercury vapour, the earliest clinically observed adverse effects at urine mercury levels of the order of 30-100 mg/g creatinine, are objectively detectable tremor, psychological disorder and impaired nerve conduction velocity in sensitive subjects, with subjective symptoms of irritability, fatigue and anorexia. At these and at lower levels, proteinuria has also been observed. Both glomerular and tubular damage may occur at exposure levels lower than those giving rise to central nervous system effects. An immunological effect has also been observed in studies on clinically asymptomatic workers with low level exposure. CONCLUSIONS: As mercury can give rise to allergic and immunotoxic reactions which may be genetically regulated, in the absence of adequate dose-response studies for immunologically sensitive individuals, it has not been possible to set a level for mercury in blood or urine below which mercury related symptoms will not occur.
Pediatrics. 1980 Oct;66(4):633-6.Links
Urine mercury levels in Kawasaki disease.Orlowski JP, Mercer RD.
Six patients with diagnostic criteria for Kawasaki disease had abnormally high urinary excretions of mercury. They were compared by age, sex, and geographic location with matched controls. Improvement of one patient was temporally related to chelation of mercury with penicillamine. There are numerous clinical similarities between acrodynia and Kawasaki disease and the appearance of the mucocutaneous lymph node syndrome (Kawasaki disease) has been related temporally and geographically to environmental pollution with mercury. The mucocutaneous lymph node syndrome (Kawasaki disease) may represent a disease caused by environmental pollution with mercury, or clinical symptoms compatible with Kawasaki disease may indicate environmental exposure to mercury.
Clin Rheumatol. 2003 Dec;22(6):461-3. Epub 2003 Oct 7.
Kawasaki disease in an infant following immunisation with hepatitis B vaccine.Miron D, Fink D, Hashkes PJ.
HaEmek Medical Center, Afula, Technion Medical School, Haifa, Israel.
The known association between hepatitis B and vasculitis has been reported in rare cases in adults after hepatitis B vaccination. We here describe a 35-day-old infant who developed Kawasaki disease 1 day after receiving his second dose of hepatitis B vaccine. Although extremely rare, this possible side effect should be noted and further investigated.
J Infect Dis. 1999 Dec;180(6):1869-77. Links
Kawasaki disease: a maturational defect in immune responsiveness.Kuijpers TW, Wiegman A, van Lier RA, Roos MT, Wertheim-van Dillen PM, Pinedo S, Ottenkamp J.
Emma Children's Hospital, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands. T.W.Kuijpers@amc.uva.nl
Kawasaki disease (KD), an acute febrile disease in children of unknown etiology, is characterized by a vasculitis that may result in coronary artery aneurysms (CAAs). In new patients with KD, a selective and prolonged T cell unresponsiveness to activation via the T cell antigen receptor CD3 was observed, whereas proliferation to other stimuli was intact. This "split T cell anergy" delineated KD from other pediatric infections and autoimmune diseases and correlated with CAA formation (P<.001). A transient immune dysfunction was also suggested by an incomplete responsiveness to measles-mumps-rubella (MMR) vaccination in patients with KD versus controls (P<.0001; odds ratio, 15.6; 95% confidence interval, 4.8-51.1), which was overcome by revaccination(s). The reduced responsiveness to MMR in patients with KD suggests a subtle and predetermining immune dysfunction. An inherent immaturity to clear certain antigens may be an important cause that precipitates KD and the immune dysregulation during acute disease.
Posted by: María Luján | May 30, 2009 at 08:39 PM
Just read it and happy to see the new material and extreme clarifications added since last year's DK presentation. David Kirby has such a talent for collating all this material and making it comprehensible to us non-science majors. I can tell it's not a false understanding because of how I'm then more easily able to grasp further developments in the science. In other words, what David serves up doesn't lead to a dead end or a disconnect later-- the gift that keeps on giving.
I think the Dartmouth study on arsenic's deadly facilitation of swine flu that Kent Heckenlively posted is an excellent complement to the information here as well. Slowly but surely, the picture is coming together.
As far as mito-toxic household products and pregnant moms being at risk while doing housework, I just found out that an ingredient in Palmolive dish soap, for instance, breaks down into formaldehyde. If it's true of this commercial product, it's surely true of others. Add chlorine-based Soft Scrub and you get World War I era chlorine gas as a bonus. Don't soak your hands in it.
Posted by: Gatogorra | May 30, 2009 at 07:47 PM
Maybe it is Glial cells and mercury ---OR it could be just part of a natural build up of the immune system -well a natural over- reaction of the immune system; causing a inflamation of the blood vessels. After all they are injecting these antigens right into the body - blood vessels.
My daughter came down with Kawaskis 6 weeks after her fourth DPT shot. The day she received it her leg swelled very large and it was very painful. I would never have put 2 and 2 together if years later after my son's immediate reaction to a vaccine the peditrician slyly asked me what I thought brought on my daughter's Kawaskis.(The peditrician - sly, deceitful, lying) - oh well that is another matter. I had no idea why she came down with Kawasaki,except I knew it was not cleaning carpets (foolish notion).
It made me think though about after my son's immediate stroke to his shot-because 6 weeks later (notice the time) he woke up with a strange fever and had his first grand mal seizure. Then another 6 weeks went by and another strange fever and another grand mal seizure.
In the old vaccine tables for vaccine compensation back in 1986 - evidence of injury was the infant having two grand mal seizures within a year. Of course they slyly put in the exact temperature of- I forgot 102, and it had to be documented. Anything higher than 102 the vaccine claims court claimed was just a febrile seizure.
Growing up- my son continued to get these strange fevers, had to be put in a dark room, his illness would last about two weeks. These illness were similar and he usually had two if not three episodes a year. I am pretty sure we would be millionaires if I still had the money- from the times I took my son to the peditricians and they said virus - go on home and he will get better in a day.
It HAS to be some type of vasculitis! There are many, many kinds of vasculitis depending on the place in the body it affects. Kawaski disease is vasculitis which affects the mucus membranes, lymph nodes, walls of the blood vessels in the coranary arteries. There is a Central nervous system vasculitis that causes confusion, headache, personality changes, seizures,muscle weakness. There is wegener's granulomatosis that affects the upper respiratory tract nose, sinuses, throat, lungs, kidneys. There is hypersensitivity vasculitis that they say is related to drug reactions, skin disorders, red spots, and if the skin spots are biopsyed it reveals inflammation of the small blood vessels. Where this mitochondrial stuff comes into play- I just cannot figure that out, but that is what my husband has - Emory Clinic says it is not inherited by environmental induced. He came down with severe muscle pain three weeks after he received a tetanus shot when he was 34 years old. (Before this at age 28 he had passed out with a tetanus shot- some people or just tooo hard headed) I could be wrong but I don't think it is mercury or aluminium. Can some of you tell me how or who or what tests indicated heavy metals?
Posted by: Benedetta Stilwell | May 30, 2009 at 07:19 PM
You can look at photos of my Mia and watch the lights going out in her eyes over time. It's startling. She was a vibrant toddler with bright eyes and a killer smile. By 6 she looked like a refugee child. I have a photo of her two months before her massive seizure disorder started - it was Christmas 2000. She looks deathly ill. And yet at the time, I just didn't know. Bella was a newborn, I was up to my eyeballs with Mia and Gianna and just trying to keep my head above water. Dan Olmsted was at my house today for lunch - (I know, aren't I lucky!) he was at a class reunion at Yale - Mark showed him photos of the girls. It hurts to look back, doesn't it, knowing what we now know.
Posted by: Stagmom | May 30, 2009 at 05:21 PM
Someone recently asked why other parents she met did not recall vaccine reactions in their kids with autism. This quote is interesting in relation to that question:
"And Burbacher found that sure enough, these deposits of inorganic mercury can activate these glial cells and presumably cause neuroinflammation.
"Also very interesting about this, sometimes it took up to 6 months or more after the exposure for those cells to become activated. So you can see a delayed reaction with mercury toxicity and brain damage."
Posted by: Twyla | May 30, 2009 at 05:11 PM
Trends Immunol. 2006 Jan;27(1):1-4. Epub 2005 Nov 23. Links
CARD games between virus and host get a new player.Johnson CL, Gale M Jr.
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
A growing family of cellular proteins encoding the caspase activation and recruitment domain (CARD) has a crucial role in immunity by sensing virus infection and signaling antiviral immune defenses. Four independent studies have identified a novel CARD-containing protein, variously called IPS-1, MAVS, VISA and Cardif, which is an essential signaling adaptor of the host defense mediating CARD-CARD interactions with retinoic acid inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDAS), sensors of virus infection.
Disruption of this novel signaling pathway by hepatitis C virus (HCV) might provide a foundation for viral persistence.
Now, why NOBODY is interested to know how antibiotics use and vaccines may produce a mitochondrial dysfunction that -upon further exposures that requires a strong innate immune activation-is further imbalanced by vaccines/other infections. The mechanisms seems related to these CARD or the mitochondrial protein MAVS-VISA and IPS-1 , the NLRX1 and the RIG-like helicase (RLH) family of intracellular receptors-that detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS (also known as Cardif, VISA and IPS-1) during a viral infection.
MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons.
Now Caspase recruitment domains, or CARD domains, are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARD domains are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors
Posted by: María Luján | May 30, 2009 at 12:47 PM
Trends Mol Med. 2006 Feb;12(2):53-6. Epub 2006 Jan 6. Links
MasterCARD: a priceless link to innate immunity.Hiscott J, Lin R, Nakhaei P, Paz S.
Lady Davis Institute for Medical Research--Jewish General Hospital, Department of Microbiology & Immunology, McGill University, Montreal, QC, H3T 1E2, Canada.
Intracellular viral infection is detected by the cytoplasmic RNA helicase RIG-I, which has an essential role in initiating the host antiviral response. The adaptor molecule that connects RIG-I sensing of incoming viral RNA to downstream signaling and gene activation has recently been elucidated by four independent research groups, and has been ascribed four different names: MAVS, IPS-1, VISA and Cardif.
The fact that MAVS/IPS-1/VISA/Cardif localizes to the mitochondrial membrane suggests a link between viral infection, mitochondrial function and development of innate immunity. Furthermore, the hepatitis C virus NS3/4A protease specifically cleaves MAVS/IPS-1/VISA/Cardif as part of its immune-evasion strategy. These studies highlight a novel role for the mitochondria and for caspase activation and recruitment domain (CARD)-containing proteins in coordinating immune and apoptotic responses.
Posted by: María Luján | May 30, 2009 at 12:35 PM
Cell Res. 2006 Feb;16(2):141-7.
Antiviral innate immunity pathways.Seth RB, Sun L, Chen ZJ.
Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Recent studies have uncovered two signaling pathways that activate the host innate immunity against viral infection. One of the pathways utilizes members of the Toll-like receptor (TLR) family to detect viruses that enter the endosome through endocytosis. The TLR pathway induces interferon production through several signaling proteins that ultimately lead to the activation of the transcription factors NF-kappaB, IRF3 and IRF7. The other antiviral pathway uses the RNA helicase RIG-I as the receptor for intracellular viral double-stranded RNA. RIG-I activates NF-kappaB and IRFs through the recently identified adaptor protein MAVS, a CARD domain containing protein that resides in the mitochondrial membrane.
Please look at this
MAVS is essential for antiviral innate immunity, but it also serves as a target of Hepatitis C virus (HCV), which employs a viral protease to cleave MAVS off the mitochondria, thereby allowing HCV to escape the host immune system.
Posted by: María Luján | May 30, 2009 at 12:34 PM
My printer broke last week, but with this I'll have to buy another. This is a MUST print and i can understand it too. Thanks soooo much David.
Posted by: Maurine Meleck | May 30, 2009 at 12:33 PM
Hi Thank you for posting
Recent on Al and mito
J Neurosci Res. 2009 May 1;87(6):1474-83. Links
Aluminum-induced defective mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells.Lemire J, Mailloux R, Puiseux-Dao S, Appanna VD.
Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada.
Although aluminum (Al), a known environmental toxin, has been implicated in a variety of neurological disorders, the molecular mechanism responsible for these conditions is not fully understood. In this report, we demonstrate the ability of Al to trigger mitochondrial dysfunction and ineffective adenosine triphosphate (ATP) production. This situation severely affected cytoskeletal dynamics. Whereas the control cells had well-defined structures, the Al-exposed astrocytoma cells appeared as globular structures. Creatine kinase (CK) and profilin-2, two critical modulators of cellular morphology, were markedly diminished in the astrocytoma cells treated with Al. Antioxidants such as alpha-ketoglutarate and N-acetylcysteine mitigated the occurrence of the globular-shaped cells promoted by Al toxicity. Taken together, these data reveal an intricate link between ATP metabolism and astrocytic dysfunction and provide molecular insights into the pathogenesis of Al-induced neurological diseases.
Cell Physiol Biochem. 2007;20(5):627-38. Links
Aluminum-induced mitochondrial dysfunction leads to lipid accumulation in human hepatocytes: a link to obesity.Mailloux R, Lemire J, Appanna V.
Department of Chemistry and Biochemistry, Laurentian University, Ontario, Canada.
Mitochondrial dysfunction is the cause of a variety of pathologies associated with high energy-requiring tissues like the brain and muscles. Here we show that aluminum (Al) perturbs oxidative-ATP production in human hepatocytes (HepG2 cells). This Al-induced mitochondrial dysfunction promotes enhanced lipogenesis and the accumulation of the very low density lipoprotein (VLDL). Al-stressed HepG2 cells secreted more cholesterol, lipids and proteins than control cells. The level of apolipoprotein B-100 (ApoB-100) was markedly increased in the culture medium of the cells exposed to Al. (13)C-NMR and HPLC studies revealed a metabolic profile favouring lipid production and lowered ATP synthesis in Al-treated cells. Electrophoretic and immunoblot analyses pointed to increased activities and expression of lipogenic enzymes such as glycerol 3-phosphate dehydrogenase (G3PDH), acetyl CoA carboxylase (ACC) and ATP-citrate lyase (CL) in the hepatocytes exposed to Al, and a sharp diminution of enzymes mediating oxidative phosphorylation. D-Fructose elicited the maximal secretion of VLDL in the Al-challenged cells. These results suggest that the Al-evoked metabolic shift favours the accumulation of lipids at the expense of oxidative energy production in hepatocytes.
Toxicology. 2009 Jan 31;255(3):117-23. Epub 2008 Nov 1. Links
Susceptibility of mitochondrial superoxide dismutase to aluminium induced oxidative damage.Kumar V, Bal A, Gill KD.
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
Aluminium has been implicated in various neurodegenerative diseases but exact mechanism of action is still not known. Mitochondria being a major site of reactive oxygen species production are considered to be target of oxidative stress and it seems that the oxidative damage to mitochondrial proteins may underlie the pathogenesis of aluminium induced neurodegeneration. Thus, the present study was undertaken to reveal the effects of chronic aluminium exposure (10mg/kg b.wt, intragastrically for 12 weeks) on the oxidative damage to mitochondrial proteins in male albino Wistar rats. Chronic aluminium exposure resulted in decrease in the activity of mitochondrial superoxide dismutase (MnSOD) and aconitase in different regions of rat brain suggesting increased oxidative stress. This decrease in MnSOD activity in turn might be responsible for the increased protein oxidation as observed in our study. All these processes taken together may cause increased oxidative damage to mitochondrial proteins in general. By taking the advantage of recent immunochemical probe for oxidatively modified proteins, we identified MnSOD to be susceptible to oxidative damage in aluminium treated animals. The quantitative RT-PCR analysis for Lon protease, a protease involved in the removal of oxidatively modified proteins from mitochondria, showed decreased mRNA expression suggesting increased oxidative damage and decreased removal of mitochondrial proteins. The identification of specific proteins as targets of oxidative damage may provide new therapeutic measures to reverse the effects of aluminium induced neurodegeneration.
J Neuroimmune Pharmacol. 2008 Dec;3(4):286-95. Epub 2008 Oct 1. Links
Manufactured aluminum oxide nanoparticles decrease expression of tight junction proteins in brain vasculature.Chen L, Yokel RA, Hennig B, Toborek M.
Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky Medical Center, 593 Wethington Bldg., 900 S Limestone, Lexington, KY 40536, USA.
Manufactured nanoparticles of aluminum oxide (nano-alumina) have been widely used in the environment; however, their potential toxicity provides a growing concern for human health. The present study focuses on the hypothesis that nano-alumina can affect the blood-brain barrier and induce endothelial toxicity. In the first series of experiments, human brain microvascular endothelial cells (HBMEC) were exposed to alumina and control nanoparticles in dose- and time-responsive manners. Treatment with nano-alumina markedly reduced HBMEC viability, altered mitochondrial potential, increased cellular oxidation, and decreased tight junction protein expression as compared to control nanoparticles. Alterations of tight junction protein levels were prevented by cellular enrichment with glutathione. In the second series of experiments, rats were infused with nano-alumina at the dose of 29 mg/kg and the brains were stained for expression of tight junction proteins. Treatment with nano-alumina resulted in a marked fragmentation and disruption of integrity of claudin-5 and occludin. These results indicate that cerebral vasculature can be affected by nano-alumina. In addition, our data indicate that alterations of mitochondrial functions may be the underlying mechanism of nano-alumina toxicity.
Brain Res. 2008 Sep 26;1232:94-103. Epub 2008 Jul 16. Links
Impairment of mitochondrial energy metabolism in different regions of rat brain following chronic exposure to aluminium.Kumar V, Bal A, Gill KD.
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India.
The present study was designed with an aim to evaluate the effects of chronic aluminium exposure (10 mg/kg b.wt, intragastrically for 12 weeks) on mitochondrial energy metabolism in different regions of rat brain in vivo. Mitochondrial preparations from aluminium treated rats revealed significant decrease in the activity of various electron transport complexes viz. cytochrome oxidase, NADH cytochrome c reductase and succinic dehydrogenase as well, in the hippocampus region. The decrease in the activity of these respiratory complexes was also seen in the other two regions viz. corpus striatum and cerebral cortex, but to a lesser extent. This decrease in the activities of electron transport complexes in turn affected the ATP synthesis and ATP levels adversely in the mitochondria isolated from aluminium treated rat brain regions. We also studied the spectral properties of the mitochondrial cytochromes viz. cyt a, cyt b, cyt c1, and cyt c in both control and treated rat brains. The various cytochrome levels were found to be decreased following 12 weeks of aluminium exposure. Further, these impairments in mitochondrial functions may also be responsible for the production of reactive oxygen species and impaired antioxidant defense system as observed in our study. The electron micrographs of neuronal cells depicted morphological changes in mitochondria as well as nucleus only from hippocampus and corpus striatum regions following 12 weeks exposure to aluminium. The present study thus highlights the significance of altered mitochondrial energy metabolism and increased ROS production as a result of chronic aluminium exposure in different regions of the rat brain.
Microbes Infect. 2009 May 7. Mitochondrial factors in the regulation of innate immunity.Scott I.
Molecular Biology Section, Translational Medicine Branch, National Heart Lung and Blood Institute, Building 10-CRC, Room 5-3216, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Viral infection stimulates multiple signalling pathways in the innate immune system, leading to type 1 interferon production.
Recent research has identified the mitochondrial protein MAVS as a key component of one intracellular pathway, definitively linking mitochondria to the mammalian antiviral defence system for the first time.
For the first time.....
J Immunol. 2009 May 1;182(9):5682-92. Links
Actin and RIG-I/MAVS signaling components translocate to mitochondria upon influenza A virus infection of human primary macrophages.Ohman T, Rintahaka J, Kalkkinen N, Matikainen S, Nyman TA.
Protein Chemistry Research Group, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Influenza A virus is one of the most important causes of respiratory infection. During viral infection, multiple cell signaling cascades are activated, resulting in the production of antiviral cytokines and initiation of programmed cell death of virus-infected cells. In the present study, we have used subcellular proteomics to reveal the host response to influenza A infection at the protein level in human macrophages. Macrophages were infected with influenza A virus, after which the cytosolic and mitochondrial cell fractions were prepared and analyzed by using two-dimensional electrophoresis for protein separation and mass spectrometry for protein identification. In cytosolic proteomes, the level of several heat shock proteins and fragments of cytoskeletal proteins was clearly up-regulated during influenza A virus infection. In mitochondrial proteomes, simultaneously with the expression of viral proteins, the level of intact actin and tubulin was highly up-regulated. This was followed by translocation of the components of antiviral RNA recognition machinery, including RIG-I (retinoic acid-inducible protein I), TRADD (TNFR1-associated death domain protein), TRIM25 (tripartite motif protein 25), and IKKepsilon (inducible IkappaB kinase), onto the mitochondria. Cytochalasin D, a potent inhibitor of actin polymerization, clearly inhibited influenza A virus-induced expression of IFN-beta, IL-29, and TNF-alpha, suggesting that intact actin cytoskeleton structure is crucial for proper activation of antiviral response. At late phases of infection mitochondrial fragmentation of actin was seen, indicating that actin fragments, fractins, are involved in disruption of mitochondrial membranes during apoptosis of virus-infected cells. In conclusion, our results suggest that actin network interacts with mitochondria to regulate both antiviral and cell death signals during influenza A virus infection.
Mol Cell Biol. 2009 Jun;29(12):3401-12. Epub 2009 Apr 20. Links
Ubiquitin-regulated recruitment of IkappaB kinase epsilon to the MAVS interferon signaling adapter.Paz S, Vilasco M, Arguello M, Sun Q, Lacoste J, Nguyen TL, Zhao T, Shestakova EA, Zaari S, Bibeau-Poirier A, Servant MJ, Lin R, Meurs EF, Hiscott J.
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Ste. Catherine, Montreal, Quebec, Canada H3T 1E2.
Induction of the antiviral interferon response is initiated upon recognition of viral RNA structures by the RIG-I or Mda-5 DEX(D/H) helicases. A complex signaling cascade then converges at the mitochondrial adapter MAVS, culminating in the activation of the IRF and NF-kappaB transcription factors and the induction of interferon gene expression. We have previously shown that MAVS recruits IkappaB kinase epsilon (IKKepsilon) but not TBK-1 to the mitochondria following viral infection. Here we map the interaction of MAVS and IKKepsilon to the C-terminal region of MAVS and demonstrate that this interaction is ubiquitin dependent. MAVS is ubiquitinated following Sendai virus infection, and K63-linked ubiquitination of lysine 500 (K500) of MAVS mediates recruitment of IKKepsilon to the mitochondria. Real-time PCR analysis reveals that a K500R mutant of MAVS increases the mRNA level of several interferon-stimulated genes and correlates with increased NF-kappaB activation. Thus, recruitment of IKKepsilon to the mitochondria upon MAVS K500 ubiquitination plays a modulatory role in the cascade leading to NF-kappaB activation and expression of inflammatory and antiviral genes. These results provide further support for the differential role of IKKepsilon and TBK-1 in the RIG-I/Mda5 pathway.
Biochem Biophys Res Commun. 2008 Oct 10;375(1):101-6. Epub 2008 Aug 8. Links
The mitochondrial antiviral signaling protein, MAVS, is cleaved during apoptosis.Scott I, Norris KL.
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 2C-1014, Building 35, 9000 Rockville Pike, Bethesda, MD 20892, USA. firstname.lastname@example.org
Apoptosis of virus-infected cells is one important host strategy used to limit viral infection. Recently a member of the innate immune signaling pathway, MAVS, was localized to mitochondria, an organelle important for apoptosis regulation. Here we investigate what role MAVS may play in apoptosis. Induction of cell death led to the rapid cleavage of MAVS, resulting in its release from the outer mitochondrial membrane. This cleavage is blocked in cells incubated with proteasome or caspase inhibitors. Transfection of synthetic viral dsRNA and dsDNA also led to cleavage of MAVS, indicating that this process may be important during infection. Preventing apoptosis by over-expression of anti-apoptotic Bcl-xL blocks MAVS cleavage, placing this process downstream of caspase activation in the apoptotic program.
and on nature
Nature. 2008 Jan 31;451(7178):573-7. Epub 2008 Jan 16. Links
NLRX1 is a regulator of mitochondrial antiviral immunity.Moore CB, Bergstralh DT, Duncan JA, Lei Y, Morrison TE, Zimmermann AG, Accavitti-Loper MA, Madden VJ, Sun L, Ye Z, Lich JD, Heise MT, Chen Z, Ting JP.
Department of Microbiology-Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
The RIG-like helicase (RLH) family of intracellular receptors detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS (also known as Cardif, VISA and IPS-1) during a viral infection. MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons. Although MAVS is vital to antiviral immunity, its regulation from within the mitochondria remains unknown. Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promotes virus-induced type I interferon production and decreases viral replication. This work identifies NLRX1 as a check against mitochondrial antiviral responses and represents an intersection of three ancient cellular processes: NLR signalling, intracellular virus detection and the use of mitochondria as a platform for anti-pathogen signalling. This represents a conceptual advance, in that NLRX1 is a modulator of pathogen-associated molecular pattern receptors rather than a receptor, and identifies a key therapeutic target for enhancing antiviral responses.
Posted by: María Luján | May 30, 2009 at 12:33 PM
Thank you so much, David Kirby, for doing this research, sticking with this cause, making this presentation, and having such a wonderful ability to summarize and explain science. Thank you so much AoA for posting this!!
Posted by: Twyla | May 30, 2009 at 12:21 PM
This is great research. Thank you David Kirby for doing all this. I do hope the Medical establishment will at least listen and start doing the research themselves.
Posted by: Jacky | May 30, 2009 at 06:12 AM
Thumbs up! I'm tired now, but I'm keeping this one up so I can read in the morning with a fresh mind.
Posted by: Deb in IL | May 29, 2009 at 10:31 PM
Cathy, go to bed! LOL! Have a good weekend. So happy to get to meet you last week!
Posted by: Stagmom | May 29, 2009 at 10:06 PM
Oh, THANK YOU for posting these. I was rereading my notes from the A1 conference the other night and didn't write enough from David's presentation. This is great! I'm going to share this link with my family too.
Posted by: Cathy Jameson | May 29, 2009 at 10:01 PM