I would like to speak with some of the people who posted in this thread. I am looking at toddlers who developed autism right after being given all three “stages” of vaccines at once because they were behind the usual vaccine “schedule”.

Does anyone know of any studies that more directly speak to this situation?

Please contact me at chris@chriscrew.com

The intrauterine responses are due to maternal immune system stimulation, not due to immune system stimulation of the fetus. The fetus remains isolated from the maternal immune system by the placenta.

PD is incorrect in stating that there has been no analysis of what happens when the immune system is stimulated earlier and earlier. These effects have been studied. The effects of vaccines are small compared to the normal exposure to bacteria, molds and viruses that starts even before birth, as the fetus passed through the birth canal and all number of vaginal flora are ground into its skin. If the infant didn’t mount an immune system response to those bacteria, it would be dead in a few days.

It seems likely that there are many different mechanisms by which this can be happening from case to case; and indeed, it is probable there are many contributory factors in any individual child. Detangling the mess is a daunting task; assuming we even want to start looking.

We do have some evidence, however, that early life insults, even transient ones, are capable of causing changes that last into adulthood and include physiological characteristics of autism, such as chronically activated microglia as found by the 2005 Vargas paper.

For example, the same group, in 2007 published, “Neuroinflammation and behavioral abnormalities after neonatal terbutaline treatment in rats: implications for autism.” Using an agent that has been found to increase rates of autism in twins, an animal model was used and they discovered that administration of terbutaline during very specific postnatal timeframes was sufficient to cause the same physiological changes (i.e., activated microglia), as well as ‘behavioral abnormalities’, in so much as you can tell if a rat has autism. But the key was, if you gave the rats the agent postnatal day 2 – 5, you observed changes. If you gave the agent on postnatal day 11 – 14, you didn’t observe any changes. In this case, the poison was not in the dose.

Startlingly, we have similar evidence of long term, synaptic change by invocation of an immune response, but again, only if it happens during critical windows of development. Here is a neat study: Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

Here is a snipet from the discussion section, with my emphasis:

The most exciting finding of the present study is that a mild inflammatory response evoked by LPS during a critical period of development causes a long-lasting increase in hippocampal excitability in vitro, and enhanced seizure susceptibility to the convulsants LI-PILO, KA, and PTZ in vivo. The latter effect was observed over a range of mildly inflammatory doses of LPS and was only evident if administered during the second postnatal week (P7 and P14), and not before (P1) or after (P20) this time. Importantly, inactivation of the proinflammatory cytokine TNF with an intracerebroventricular TNF antibody blocked the long-term changes to seizure susceptibility induced by LPS, whereas intracerebroventricular administration of rrTNF alone mimicked the effect of LPS on seizure susceptibility. These novel results indicate that a single transient inflammatory episode during development can modify the brain through a TNF-dependant mechanism, making it more susceptible to generate seizures in adulthood.

A tnf-alpha dependent mechanism by which having an immune response, a fake one, causes the animals to be more succeptible to seizures for forever. Administration of tnf-alpha antibodies prevents changes. Remember that our particular cohort of children has been found to create tnf-alpha at exaggerated rates compared to their non diagnosed peers, in response to LPS, dietary proteins, and environmental pollutants (Jyonouchi 2002, Jyonouchi 2005, Ashwood 2008). Children with autism have also been found to grow into adulthood with with epilepsy at rates between 20 – 40% and have abnormal EEGS without clinical seizures at rates approaching 60% (Chez 2007).

Winding back to neuroinflammation, we find that having early life seizures results in increased microglial activation, and unsurprizingly, increased succeptibility to seizures into adulthood. Glial activation links early-life seizures and long-term neurologic dysfunction: evidence using a small molecule inhibitor of proinflammatory cytokine upregulation. Note again, in this case, these effects could be ameliorated by inhibition of the inflammatory immune response; a regulatory mechanism we know to be highly abberant in children with autism.

It isn’t all about the early life, though. We also have evidence that peripheral inflammation can cause changes to brain chemistry consistent with higher levels of inflammation through some still poorly understood interactions between the immune system and the brain. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. Here we see that animals with induced liver inflammation showed increased levels of MCP-1 in the brain; one of the differences found in the 2005 Vargas study. And again, these changes were blocked when tnf-alpha was inhibited; something children with autism produce in spades compared to children without autism.

Theres plenty more, but this ought to get you started.

What we should be able to take from all of this is that the immune response is what is critical towards a veritable spectrum of outcomes that have been associated with autism. That doesn’t mean that vaccines cause autism; but the fact is, we just haven’t performed any analysis, at all, as to the result of invoking our immune system at earlier and earlier ages on our children. I suppose each person much use their discretion to determine if any hypothesis should be changed or not.

– pD

“Unlike autoimmune diseases such as multiple sclerosis, there is no evidence of immune activation or inflammatory lesions in the CNS of people with autism.”

Unfortunately for Mr. Offit’s credibility, when you use five year old science in the area of autism, you are going to get some things wrong. His source for this particular quote is the 2004 IOM paper regarding vaccination and autism. The lack of an observations regarding immune activation in autism is referenced several times in the IOM report.

Here is something from the IOM paper on page 131:

Although a number of studies have suggested immune dysregulation in autism, there is as yet no evidence that these findings are directly related to the pathogenesis of autism. Unlike what is known about neuroimmunological disorders that affect the brain, such as multiple sclerosis and acute disseminated encephalomyelitis, there is no evidence of immune activation or an inflammatory process within the autistic brain. Neuropathological studies of autism have revealed no evidence of cerebral inflammatory lesions or microglial activation, which is a common feature in immune-mediated encephalitis (Bauman and Kemper, 1997). However, there are very few autopsy studies of brains from people with autism and this has not been fully investigated. Analysis of CSF from young children with autism, including screening for sensitive inflammatory markers such as quinolinic acid and neopterin, has also found no evidence of inflammation (Comi et al., 1999). The sample size in these studies is small, however.

http://www.nap.edu/openbook.php?isbn=030909237X&page=131

So, it would seem, in 2004 anyways, that we hadn’t really looked all for immune activation in the brains of children with autism very much. Strange that this little tidbit didn’t make it into Mr. Offit’s analysis. If I hadn’t gone out to the IOM report myself, and read parts of it, I’d never have known that such strong qualifiers were in place regarding our knowledge of immune activation in the brains of children with autism. I wonder why Mr. Offit didn’t acknowledge that our information set was incomplete, and in fact, seemed to be based on studies from 1999 or 1997? [Although, looking at some of the dates on his other references might explain that somewhat.]

But anyways, what a difference five years makes! It just so happens, anyone paying attention to the findings in autism research over the past five years will find that, in fact, we have lots of evidence that we didn’t have in 2004.

For example, in 2005, Vargas reported chronically activated microglia and immune activation in the brains of people with autism in “Neuroglial activation and neuroinflammation in the brain of patients with autism” Fancy that, evidence of exactly what the IOM defines as “a common feature in immune-mediated encephalitis ” in autism! It reported highly increased levels of pro-inflammatory cytokines like tnf-alpha, IL-6, and MCP-1; as well as chronically activated microglia.

In 2007, Chez reported highly increased levels of tnf-alpha in the CSF of children with autism, “Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children”. And so again, long after the IOM report we have evidence of immune activation in the CNS of children with autism. How strange that these studies seem to have escaped Mr. Offit’s keen eye.

In 2009, it happened again. Li reported that children with autism had a highly pro-inflammatory cytokine set in their brains when compared to normal children. “Elevated immune response in the brain of autistic patients.”

If I didn’t know any better; I’d think that either Mr. Offit either hasn’t been paying attention to autism science, or is intentionally giving us a highly selective view of our availbable information in such a way that benifits his case.

Since 2004, we also have at least three studies that directly correlate abberant circulating values of immune system modulators with autism severity. For example, you might take a look at “Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes.”, “Macrophage migration inhibitory factor and autism spectrum disorders”, and “Serum levels of P-selectin in men with high-functioning autism.”. There are many, many other studies of abberant values, but these are the ones I know of with correlations to severity.

Mr. Offit goes on to say: “In fact, current data suggest that genetic variation in neuronal circuitry that affects synaptic development might in part account for autistic behavior” In fact, he is correct. But that by no means exhonerates immune system dysfunction.

Over the past two years, several papers have come out regarding the association of a downregulated allele to the MET gene and interactions with HGF, with functions in synapse formation, immune system functioning, and gastro intestinal repair. In 2006, “Dynamic Gene and Protein Expression Patterns of the Autism-Associated Met Receptor Tyrosine Kinase in the Developing Mouse Forebrain” was published.

“Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits, with particular relevance to the social and emotional dimensions of behavior.”

The singalling factor critical towards MET interactions, HGF, is particularly interferred with by TNF-alpha (Sugano 2008). It just so happens, children with autism have been shown to create more tnf-alpha than their undiagnosed peers in response to a vareity of stimulants, including LPS, common environmental pollutants, and some boogeyman dietary proteins that some folks are keeping out of their childrens diets. (Ashwood 2008, Jyonouchi 2005, Jyonouchi 2002). So, take a set of children known to produce tnf-alpha at exaggerated rates, and induce immune responses right after birth, a time that is characterized by “extensive neurite outgrowth and synaptogenesis” by a set of operations known to be hindered by tnf-alpha. Great stuff.

The reason we shouldn’t worry about any of this? A 2004 IOM report that (when read) acknowledges a dearth of underlying evaluations, and a series of studies about thimerosal or the MMR. As scientists, I would think that when you get more information, you might consider a new hypothesis, but that would disqualify that catchy title of the ‘paper’. Tough call.

– pD