MRI and Autism
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HLA-DR4: A Potential Genetic Marker for Risk of Vaccine-njury

SMARTVAX_LOGOv1
By Scott Laster

SmartVax encourages the pursuit of novel new hypotheses that could help explain the mechanisms of vaccine-injury.  One such hypothesis is that HLA-DR4 might be a potential genetic marker for adverse-event risk in response to vaccination.

Knowledge of the human immune system has increased dramatically over the past decades with a greater understanding of the complex nature of the regulation of the immune response emerging year-by-year.  Only within the last 25 years have we learned of the different immune responses generated by Helper Th1 and Th2 cells and their different roles in attacking different types of pathogens.  Th17 cells (and their role in autoimmune disease) were not mentioned in the scientific literature until just a mere five years ago in 2006 and have yet to be fully understood.  Another area of growing research is the study of HLA subtypes and their potential as genetic markers for a variety of autoimmune diseases.  HLA stands for Human Leukocyte Antigen system and is the Major Histocompatibility Complex (MHC) in humans.  The HLA genes encode cell-surface antigen presenting proteins and can be divided into several classes.  Class I molecules present proteins from inside the cells potentially including viral proteins, whereas Class II molecules present proteins from outside the cell to T-lymphocytes ultimately resulting in an antibody response if not suppressed by suppressor T-cells.  

Increasingly, autoimmune diseases have been recognized as having a genetic basis mediated by HLA subtypes.  Certain HLA genes create a genetic disposition towards development of autoimmune disease, typically requiring some environmental trigger to evolve into a full-blown disease state.  For instance, celiac disease has been strongly associated with HLA-DQ2, while Type I diabetes, rheumatoid arthritis, and  multiple sclerosis have been associated with HLA-DR4, among many examples.  Likewise, numerous published studies have demonstrated an association between HLA-DR4 and autism (1,2,3).  Given the genetic transmission of HLA subtypes one would expect to find a relationship between parental autoimmune disease and autism.  Recent studies have shown that this indeed the case.  A recent article appearing in Pediatrics showed associations regarding a family history of infantile autism and a maternal history of rheumatoid arthritis (4). Further examples are highlighted in the article New Clues to who is Susceptible to Autism via Vaccine Injury, which suggests that children with a family history of thyroid disease or rheumatoid arthritis have a 1 in 7 and 1 in 8 chance of developing autism (5).  

To many these results would come as no surprise.  Some would go so far as to classify autism as an autoimmune disease itself.  Even if one doesn’t go that far, it is difficult to ignore the abnormalities of the immune system observed in children with autism.  Auto-antibodies against myelin basic protein have been found in children with autism, potentially resulting in brain damage and inflammation responsible for autistic symptoms (6).  Another study found that 96% of children with autism who had anti-HSV antibodies also had anti-encephalon antibodies which were “directly related to the severity of autism"(7).  Additionally, children with autism have been reported to have numerous immune system difficulties such as chronic GI inflammation and increased allergies.  Further evidence of the link between autoimmune disease and autism is summarized in a smartvax.com article, Could Autism be an Autoimmune Disease?.

Could it be possible that the regression into autism reported by countless parents may be the result of an autoimmune process triggered by vaccination?  Evidence suggests that the use of aluminum hydroxide adjuvants or thimerosal may provide two mechanisms for autoimmune disease (potentially including autism) triggered by vaccination.  One study has shown that the vaccine for lyme disease is capable of triggering arthritis in genetically susceptible hamsters and that, when aluminum hydroxide was added to the vaccine, 100% of the hamsters developed arthritis (8).  Other studies have shown that the development of inflammatory joint disease and rheumatoid arthritis in adults in response to the HepA and HepB vaccines respectively were correlated to the HLA subtype of the individuals (9,10).  Given that aluminum works as an adjuvant by increasing expression of MHC (11), it perhaps should not be surprising that individuals susceptible to autoimmune disease on the basis of the MHC HLA subtype might be adversely affected by the use of aluminum hydroxide in vaccines.  In addition to aluminum, thimerosal has also been demonstrated to induce a systematic autoimmune syndrome in transgenic HLA-DR4 mice (12), and the mice with a genetic susceptibility for autoimmune disease showed profound behavioral and neuropathological disturbances.  These results were not observed in strains of mice without autoimmune susceptibility.  Likewise, the increasing rates of autism have been mirrored by similar increases in other autoimmune diseases such as juvenile rheumatoid arthritis and juvenile type I diabetes.  These diseases are also impacted by the HLA subtype of the individual, specifically by HLA-DR4.  A further outline for the case between autoimmune disease and vaccination is discussed in the smartvax.com article, Autoimmune Diseases: Vaccine as a Possible Trigger.

Given the relationship between autoimmune disease, HLA subtypes, autism, and triggering of autoimmune disease via vaccination, it sounds reasonable that a genetic screening could be performed to identify children at-risk for adverse events from vaccination.  And while the CDC publicly maintains the stance that vaccines are safe for ALL children ALL the time, they appear to be quietly exploring just such a possibility.  Among the Immunization Safety Office’s (ISO) 2008 scientific agenda are included studies of HLA subtype resulting in rheumatoid arthritis following HepB vaccination and investigation of the increase adverse reaction risk due to a family history of autoimmune disease or atopic disease.  The complete draft recommendation can be found at the Immunization Safety Office Scientific Agenda. Moreover, HLA-DR4, which has been linked to rheumatoid arthritis following hepatitis B vaccination, is also associated with a low response rate to this vaccine.  This creates an inverted risk to benefit ratio for this vaccine in this subgroup.  HLA subtype has been identified a key contributor to the variability in immunization response (13). 

As research continues to expand our knowledge of the relationship between the immune system and autism and our understanding of the control of immune responses and autoimmune disease, the development of a genetic screening tool to identify individuals susceptible to vaccine injury becomes more and more plausible.  Given the rapid expansion of the routine immunization schedule and the difficulty in obtaining vaccine exemptions in many states, it is a moral imperative to do this research and identify these individuals as soon as possible. 

References:

  1. Lee LC, Zachary AA, Leffell MS, Newschaffer CJ, Matteson KJ, Tyler JD, Zimmerman AW.  HLA-DR4 in families with autism.  Pediatr Neurol. 2006 Nov;35(5):303-7.
  2. Torres AR, Maciulis A, Stubbs EG, Cutler A, Odell D.  The transmission disequilibrium test suggests that HLA-DR4 and DR13 are linked to autism spectrum disorder.  Hum Immunol. 2002 Apr;63(4):311-6.
  3. Reed P. Warren, Vijendra K. Singh, Phyllis Cole, J. Dennis Odell, Carmen B. Pingree, W. Louise Warren, Charles W. DeWitt and Maxine McCullough.  Possible association of the extended MHC haplotype B44-SC30-DR4 with autism.  Immunogenetics.  Volume 36, Number 4, 203-207. 
  4. Hjördís Ó. Atladóttir,  Marianne G. Pedersen, Cand Scientb, Poul Thorsen, Preben Bo Mortensen, Bent Deleuran, William W. Eaton, BA, Erik T. Parner.  Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders.  PEDIATRICS Vol. 124 No. 2 August 2009, pp. 687-694.
  5. Laster, S.  New Clues to Who is Susceptible to Autism Via Vaccine Injury.  Age of Autism Dec 20 2008.
  6. Singv VK, Lin SX.  Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism, J Biomed Sci, 2002 July-August; 9(4): 359-364.
  7. Mora M, Quintero L, Cardenas R, Suárez-Roca H, Zavala M, Montiel N. Invest Clin. Association between HSV-2 infection and serum anti-rat brain antibodies in patients with autism. 2009 Sep;50(3):315-26.
  8. Cindy L. Croke, Erik L. Munson, Steven D. Lovrich, John A. Christopherson, Monica C. Remington, Douglas M. England, Steven M. Callister and Ronald F. Schell.  Occurrence of Severe Destructive Lyme Arthritis in Hamsters Vaccinated with Outer Surface Protein A and Challenged with Borrelia burgdorferi .  Infection and Immunity, February 2000, p. 658-663, Vol. 68, No. 2. 
  9. Ferrazzi V, Jorgensen C, Sany.  Inflammatory joint disease after immunizations. A report of two cases.   J Rev Rhum Engl Ed. 1997 Apr;64(4):227-32.
  10. Pope J, Stevens A, Howson W, Bell D.A. The development of rheumatoid arthritis after recombinant hepatitis B vaccination.  Journal of Rheumatology, 1998, Vol. 25, No. 9, p 1687-1693.
  11. Marina Ulanova, Andrej Tarkowski, Mirjana Hahn-Zoric and Lars Å. Hanson.  The Common Vaccine Adjuvant Aluminum Hydroxide Up-Regulates Accessory Properties of Human Monocytes via an Interleukin-4-Dependent Mechanism. Infect Immun. 2001 February; 69(2): 1151–1159.
  12. Havarinasab S, Lambertsson L, Qvarnström J, Hultman P.  Dose-response study of thimerosal-induced murine systemic autoimmunity.  Toxicol Appl Pharmacol. 2004 Jan 15;194(2):169-79. 
  13. Kimman TG, Vandebriel RJ, Hoebee B. Genetic Variation in the Response to Vaccination.  Public Health Genomics, 2007, Vol. 10, No. 4.

 

Comments

nomie

If the myelin protein is attacked by the autoimmune disease, would protecting the myelin sheath help?

Benedetta

Barry:
Percentages?

I may be the only one in my family with a thyroid disease -- And if anyone is interested - I was vaccinated with a tetanus shot (probable DPT ) shot at age 21 and came down with a yeast infection. I also had another tetanus shot some time later - probably in my mid or late 30's maybe my early 40s - too much was going on at that time as we all know how it is to raise sick kids.

On the other hand my husband's mother and her three sisters all had thyroid problems starting in their 30's . There were only four children in my mother-in-law's family - only four girls.

That makes it 100 percent.

Lynn Bardsley

Has anyone researched HLA-B27 ??

Scott Laster

Regarding the increased risk of autism in families with history of thyroid disorder, Jen asked "is that before or after the vaccines?"

The 2008 article (there is a link to it within this article) used results of two studies to calculate the increased risk of autism in families with a history of thyroid disorders. Rates of vaccination in families with history of thyroid disorders was not traced, so the data was unavailable in these studies to determine whether vaccination in those families is another risk factor.

Eileen Nicole Simon

Consider the possible interaction of two or more environmental insults. Vaccination of newborn infants is especially unsafe for babies who needed help to begin breathing.

Within the past 3 decades, not only was the vaccination schedule increased without evidence of safety, but also amputation of the placenta immediately at birth likewise became routine without evidence of safety. Most infants withstand vaccination without apparent harm, and most appear to suffer no harm from immediate clamping of the umbilical cord. Nevertheless neither of these procedures is natural or healthy.

Submicroscopic ischemic injury from even a brief lapse in placental to pulmonary respiration weakens the blood brain barrier. Then any foreign substance injected into the circulation is more likely to get into neurons of the brain and undermine normal cell function.

I submitted a research strategy to the IACC for investigating the effects of two or more environmental insults, and I posted it at
http://www.conradsimon.org/files/IACC4feb2009strategy.pdf

I would be interested in any comments from AOA families on this proposal. It was ignored by members of the IACC.

Barry

Jen wrote: “.. is that before or after the vaccines? My girls both have autism and neither have ever had a vaccine, not even vitamin K.

BUT, i have thyroid disease, my mom has it, my aunt has it, my gran had it, my other aunt has RA, my 3 uncles and a cousin have Crohns, two aunts have Fibromyalgia, one has epilepsy, ... the list, frighteningly, goes on and on.

Is this the missing link, i wonder?

*******************

I don't know about a missing link, but your post definitely raised some questions for me

- According to Dan Olmsted’s findings, the incidence of autism among the un-vaccinating Amish is ~ 1 in 10,000. It's also well known that autism is ~ 4 times more prevalent in boys than it is in girls. And you're saying that you have 2 girls, both completely un-vaccinated... and they both have autism?

- According to the Crohn's and Colitis Foundation of America, the North American incidence of Chrohn's disease is approx 149 in every 100,000, or about 4 in every 2685 people. And you're saying that 4 of your uncles and cousins have Crohns’s disease?

_ According to the National Fibromyalgia Association, the incidence of Fibromyalgia in North American females is around 11 in every 1000, or around 2 in every 180 females. And you're saying that 2 of your aunts have Fibromyalgia ?

- Hypothyroidism affects around 6 % of North American Women over 60, or around 3 in every 50. Hyperthyroidism in the United States is around 1 in every 1000 women, or around 3 in every 3000 women. And you’re saying that you have 3 older female relatives with thyroid disease?


Are you sure that the numbers you’ve quoted in your post are accurate?

Benedetta

It is no doubt like this article said; but I can't help remembering an article that came out in a science magazine last fall saying that even though a lot of people have thyroid problems - it is really nothing new. It is just that in the past - people "hunters" "meat eaters" got most of their thyroid through their food and really this is nothing new - has been going on since man learned to throw a rock at rabbits.

The explaination reminds me of why there are so many kids in Silicon Valley that have autism. The one were the fathers are mostly engineers, mothers are really artistic, and really smart people have kids with autism because --- well really smart people are so smart that their kid's brains just comes out rewired different.

100 percent under the right environment, makes it - genetic?

Benedetta

Jen;
I am the only one in my family with a thyroid disease. I slowly came down with it after the age of 45. I am the only one out of dozens of family members on both sides of the family that lived well into their late 90s and beyond.

I am the only one.

What did it say about 100 percent of those hampesters?

Nick

This is what I have found too. I have avoided mentioning the overlaps with Neuropsychiatric Lupus because people without in depth understanding of my wife's overall condition would have simply presumed it was just NSLE or some personality disorder. It was a different animal and I think totally unique in many ways, but with brain effects in primary ways that are the same as in most respects as immune related autism and in some ways worse. Just for a small evidence of her early disruption that reflects the early occurrence, her pupils were staying dilated when she was in her earliest years and was taken to a doctor at 5 years of age to see why, but the doctor said it was nothing and just an unimportant congenital trait. Yet, after treaing her for a a number of months her dilations returned to near normal function. The organic components I think do often overlap with SLE, yet the aspect of the process starts much earlier in autism and leaves kids with missing conceptual psychological realities instead of altered, sometimes severly, ones as would happen in a person developing NSLE as a young adult. Other conceptual "psychological" realities are likely being perturbed from the begginning, as opposed to being altered after some "typical" progression in some cases. In autism Freud's concepts have little and probably no bearing usually, and in NSLE they may have some, but often incorrectly conceived applications of what are associated as attributes in such individuals such as splitting and transference. Everything in what you have written is part of what I had concluded as well and I am encouraged that this is being elevated in consideration.

Jen

"which suggests that children with a family history of thyroid disease or rheumatoid arthritis have a 1 in 7 and 1 in 8 chance of developing autism (5). "

is that before or after the vaccines? My girls both have autism and neither have ever had a vaccine, not even vitamin K.

BUT, i have thyroid disease, my mom has it, my aunt has it, my gran had it, my other aunt has RA, my 3 uncles and a cousin have Crohns, two aunts have Fibromyalgia, one has epilepsy, ... the list, frighteningly, goes on and on.

Is this the missing link, i wonder?

kathy blanco

I have been saying this forever. HLA DR4 also was seen in patients who had lyme and had bad reactions to the lyme vaccines, even neurological outcomes. HLA DR4 is also described by Dr Ron Torres from Utah State, google him, see his studies, they are at least ten years old, but no one listened or funds him as they should. No one wants to hear that some come into this world have less healing capitals than the other, no one. No one wants to hear there are susceptible populations, no one. All they want to do (PERRY) is vaccinate us like texas cattle.

Cassandra

In the age of personalized medicine the sensible choice would be to taylor vaccines to individuals. So far, the government has been extremely short-sighted on this issue.

@Bob: if there are two many children having a risk for adverse reactions it becomes imperative for the government to try to figure out what the problem is. Is it the adjuvant? Maybe this group of kids could tolerate vaccines without adjuvants and develop sufficient immunity. Do we even know how they decide on how much aluminum to put in to a vaccine? Is that based on actual dose studies on humans or did someone just waved the magic wand? As the number of vaccines increase, do they lower the adjuvant to account for synergistic affects? Unlikely. There are so many factors here and I don't think anyone in government or pharma is seriously interested in doing the right studies.

@Carol: From the close genetic overlap with autoimmunity, my guess is that somewhere around a hundred genes might be involved. The epigenetic variations could add to that but starting with the known risk factors such HLA-DR4 would be a good start.

Carol

How does this relate to the SNPs, microdeletions, CNVs on chromosomes 5, 6, 7, 11, 15, 16 we hear so much about? The last I heard there were hundreds, maybe thousands, of genes involved in autism, so many we'd never be able to figure it out.

Bob Moffitt

Excellent research information that gives hope that someday .. future generations .. will not have to suffer the chronically impaired autoimmune consequences of public health vaccine policies which are based upon a growingly suspect theory that the benefits of "one size fits all vaccines" outweighs the risks.

What happens to the concept of "herd protection" if too many children are identified as having pre-existing genetic markers that will prevent them receiving certain vaccines?

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