By
Peter Rickards D.P.M.
1stungun@gmail.com
ABSTRACT
Background –
At issue is whether exposure to ionizing radiation is a significant factor for induction of autoimmune diseases in humans. The present focus on trying to detect a linear dose –response, in just the direct dose to the thyroid, may obscure the full array of
autoimmune responses. In animals, irradiation of the thymus and lymph nodes, but not thyroid, induces thyroiditis.
Methods –
A review of literature was conducted.
Results –
Studies of downwinders exposed to radioactive fallout from Japan, Hanford, Chernobyl, and Nevada Test Site have reached varying conclusions, mainly concerning autoimmune thyroiditis. Autoimmune health effects from radiation were dismissed
because no linear-dose response to the thyroid was detected.
This dismissal is inappropriate. It is contradicted by the Journal of Immunology article titled “Ionizing radiation and autoimmunity. Induction of autoimmune disease in
mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells,” by N. Sakaguchi.
The Sakaguchi study found that direct irradiation of the thyroid in mice never induced thyroid autoimmunity. Radiation could induce autoimmune responses, to many different organs, including the thyroid, but only by irradiating the thymus and lymph organs.
Important cure related updates reveal the role of FoxP3+ regulatory T-Cells (Treg), that function as natural inhibitors for preventing escape of autoreactive T cells, normally present in even healthy individuals
Implications include Gulf War veteran’s elevated rate of amyotrophic lateral sclerosis, and depleted uranium in weapons.
Conclusions –
Understanding the varied autoimmune reactions to irradiation of the thymus and
lymph nodes is key to progress.
Acknowledgement -
The author would like to thank the valued advice of Multiple Sclerosis researcher,
Arthur A. Vandenbark, in editing and reviewing this article. (Neuroimmunology research scientist at the Portland Veterans Affairs Medical Center and a professor in the departments of Neurology and Microbiology and Immunology at Oregon Health and Science University.)
Introduction –
The New England Journal of Medicine recently covered the updates on genetic markers of Multiple Sclerosis (MS), and their interactions with treg cells,[1]. This paper explores the possibility that ionizing irradiation of the thymus and lymph nodes is a
precipitating factor, that disturbs the immune system, which then manifests in many autoimmune diseases, depending on the different genetic predispositions.
Background details –
The present focus on trying to detect a linear dose –response, in just the direct dose to the thyroid, may obscure the full array of autoimmune responses. In animals, irradiation of the thymus and lymph nodes, but not the thyroid, induces thyroiditis. A linear doseresponse means that increasing radiation doses to an organ, cause increasing disease rates.
The National Academy of Sciences (NAS), in 2005, studied the status of knowledge about radiation effects on downwinders [2]. The NAS stated, "Conclusion There are no convincing epidemiological data from which to calculate radiation risk estimates for autoimmune diseases and thereby to justify their inclusion as a new compensable category of disease under RECA." This NAS dismissal is based on the lack of linear-dose
response from estimates of dose to the thyroid, as can be seen when they clearly stated, "The different studies of irradiated populations rarely provide data adequate to support a definitive diagnosis. And a positive correlation with dose is rarely demonstrated. Of the many published studies on irradiated populations, the only one in which many of those considerations were addressed involved 27 cases of autoimmune thyroiditis that were
observed in 2,587 members of the Adult Health Study (atomic-bomb survivors). A positive correlation was found with doses up to about 0.7 Gy; the correlation inexplicably decreased at higher doses (much below cell-killing levels). None of the studies of other irradiated populations (Chornobyl (sic), Marshall Islands, Southern Utah, and Hanford)
has demonstrated a positive correlation between autoimmune thyroiditis and thyroid dose."
Contradiction to present assumptions from animal organ irradiation data –
The present approach insists we must find a linear dose-response to the direct radiation dose to the thyroid. This assumption is contradicted by the Journal of Immunology article titled “Ionizing radiation and autoimmunity. Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells,” by N. Sakaguchi [3]. In this study, direct irradiation of the thyroid never caused autoimmune thyroiditis. However, many different autoimmune organ responses, including thyroiditis, were caused only by irradiating the immune organs, the thymus and
peripheral lymph nodes. Changing the radiation dose to the thymus and lymph nodes changed which organ received the autoimmune response. The exact same dose would give mice, with different genetics, a completely different organ autoimmune reaction..
This demonstrates the dose of radiation to the thyroid, in downwinder cohorts, is irrelevant to the thyroiditis created. No amount of radiation to the thyroid can induce thyroiditis.
This warrants reconsideration of this fundamental flaw in the approach of the National Academy of Sciences and approach of the studies of autoimmunity on irradiated people. Focusing on just the thyroid, and basing their conclusion on the lack of detected linear dose-response, to the direct dose to the thyroid, is not appropriate.
Despite that, if we take liberty, and estimate the cohort that got higher doses to the thyroid also got higher doses to the nearby thymus and lymph nodes, the lack of more thyroiditis at higher doses, in Nagasaki’s concave dose-response, does make sense. The autoimmune response should target a different organ, at the higher dose, like it did in the
animal irradiation. The concave dose-response is not inexplicable, if you understand the variety of organs that developed autoimmune reactions, from irradiation of the thymus and lymph nodes.
Another 1996 study found Addison’s disease in dogs that inhaled plutonium, stating, “Although the pathogenesis of adrenal cortical atrophy in these dogs is unclear, there is evidence to suggest an autoimmune disorder linked to damage resulting from alpha particle irradiation to the lymphatic system.”, [4].
An earlier 1986 study for the government’s Defense Nuclear Agency, [5] actually studied irradiation effects of the thymus during pregnancy in animals, in a report titled “Radiation injury to the canine thymus lympho-hematopoietic stem cells – Correlation with functional deficits.” They stated, “These data show that prenatally and neonatallyirradiated dogs have significant postnatal and immunologic and hematopoietic defects..”
They also noticed the important thymus did not grow as much, stating, “evaluation of individual tissue weights and neasurements showed significant radiation-induced reductions in prenatally and neonatally-irradiated dogs.” This study was not published, but was later declassified, and I retrieved it through the archive.
This all warrants much deeper studies into the full array of autoimmune organ responses, beyond thyroiditis, that should be expected in an irradiated population, from understanding Sakaguchi's study.
Important updates on Sakaguchi’s study provide potential cures –
While the 1994 Sakaguchi study was definitive, that no amount of radiation to the thyroid ever created an autoimmune reaction, equally important was that he was also able to block the radiation induced autoimmune response. By inoculating the mice with normal T cells, he prevented the autoimmune cascade of cellular responses, that was
induced from irradiation.
Important updates on T-cells have since been advanced, as noted by The National Academy of Sciences stated in 2006, “Thymus-derived regulatory T cells (Tregs) expressing CD4, CD25, and the transcription factor Foxp3 play major roles in preventing autoimmunity,” [6].
The Multiple Sclerosis research team from Oregon Health and Sciences University has been exploring these links. In 2005 they published that, [7]. “Autoimmune diseases such as multiple sclerosis (MS) may result from the failure of tolerance mechanisms to prevent expansion of pathogenic T cells. Our study is the first to establish that MS patients have abnormalities in FOXP3 message and protein expression levels in peripheral CD4+
CD25+ T cells (Tregs) that are quantitatively related to a reduction in functional suppression induced during suboptimal T-cell receptor (TCR) ligation. Of importance, this observation links a defect in functional peripheral immunoregulation to an
established genetic marker that has been unequivocally shown to be involved in maintaining immune tolerance and preventing autoimmune diseases. Diminished FOXP3 levels thus indicate impaired immunoregulation by Tregs that may contribute to MS.
Future studies will evaluate the effects of therapies known to influence Treg cell function
and FOXP3 expression, including TCR peptide vaccination and supplemental estrogen.”
Many scientific teams are advancing our knowledge of cellular autoimmune interactions, [8&9]. The 2007 update from Nomura and Sakaguchi states, “The transcriptional regulators Foxp3 and Aire have key functions in self-tolerance. New
studies emphasize potential links between Aire-expressing thymic stromal cells and the
development of Foxp3-expressing regulatory T cells,”, [10].
While radiation is well known for it's ability to mutate cells, it is noteworthy that they also wrote, “Mutations in AIRE in humans result in the autoimmune disease 'APECED' (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy) or 'APS-1' (polyglandular syndrome type 1). Evidence suggests that Aire deficiency affects the thymic negative selection of self-reactive T cells.”
These updates need to be integrated into our approach toward exposure to ionizing
radiation.
Longevity of the thymus revisited –
While the thymus starts to atrophy after puberty, recent studies have shown that despite this involution, the thymus “functions well into adult life,” [11]. The updates reported “support the notion that the human thymus is functional well into the sixth decade.”
Radiation doses to the thymus and lymph from transuranics, and the potential link
to Gulf War veteran’s elevated rate of amyotrophic lateral sclerosis-
Many veterans of the Gulf Wars complain of a wide variety of health problems, cancers and autoimmune diseases. The first Gulf War veteran health effect acknowledged by the government is, amyotrophic lateral sclerosis (ALS) [12 & 13], although no exact
cause has been isolated. Depleted Uranium (DU) is one of the suspected toxins. Brain cancer is now the second elevated disease rate acknowledged.
While ALS is known as a degenerative disease of the nerves, there has long been a question of the autoimmune aspects of ALS, since the 1989 article “Amyotrophic lateral sclerosis: an unconventional autoimmune disease?”, in The Annals of Neurology [14].
The latest article published in 2007, called “Are multiple sclerosis and amyotrophic lateral sclerosis autoimmune disorders of endogenous vasoactive neuropeptides?” reveals the latest links in autoimmune cellular responses that holds hope for cures, [15].
While not exposed to I-131, nor plutonium, like atomic fallout downwinders, the use of DU in weapons that explode, exposes our Gulf War soldiers to embedded DU shrapnel of this alpha emitter, as well as inhalation exposure and absorption, [16].. One study of Gulf War veterans noted, after tracking urine samples of DU eight years after exposure,
“The persistence of elevated urine uranium suggests ongoing mobilization of the DU fragments and result in chronic systemic exposure,” [17].
Recent articles on the toxicity of DU show it can affect the immune system. One 2006 study of DU stated,” Lymphoproliferation analysis indicated that macrophage accessory cell function was altered with 200 microM DU after exposure times as short as 2 hr. Microarray and real-time reverse-transcriptase polymerase chain reaction analyses
revealed that DU alters gene expression patterns in both cell types. The most differentially expressed genes were related to signal transduction, such as c-jun, NFkappa Bp65, neurotrophic factors (e.g., Mdk), chemokine and chemokine receptors (e.g.,
TECK/CCL25), and interleukins such as IL-10 and IL-5, indicating a possible involvement of DU in cancer development, autoimmune diseases, and T helper 2
polarization of T cells.”, [18].
The study following shrapnel bearing veterans noted, [17], “Sister chromatid exchange frequency, a measure of mutation in peripheral lymphocytes, was related to urine uranium level (6.35 sister chromatid exchanges/cell in the high uranium exposure
group vs 5.52 sister chromatid exchanges/cell in the low uranium exposure group; P = 0.03).”
The article summarizing “Health effects of embedded Depleted Uranium,” from the Armed Forces Radiobiological Research Institute, [19], stated, “Results indicate that uranium from implanted DU fragments distributes to tissues distant from implantation sites, including bone, kidney, muscle, and liver. Despite levels of uranium in kidney that would be nephrotoxic after acute exposure, no histological or functional kidney toxicity was observed with embedded DU, indicating that the kidney adapts when exposed
chronically. Nonetheless, further studies of the long-term health impact are needed. DU is mutagenic and transforms human osteoblastic cells into a tumorigenic phenotype. It alters neurophysiological parameters in rat hippocampus, crosses the placental barrier, and enters fetal tissue. Preliminary data also indicate decreased rodent litter size when
animals are bred 6 months or longer after DU implantation.”
It is noteworthy that the autopsy data at the National Repository shows the thymus, lymph nodes, and brain can retain plutonium from atomic testing fallout, and uranium particles, [20]. These particles provide an ongoing radiation source of destructive alpha emitters to these immune organs.
Recent studies have been able to isolate a single alpha particle, that cross only one cell, and have found an additional mutagenic “alpha bystander effect,” [21 & 22]. Zhou demonstrated for every cell damaged by an alpha particle, cellular communication damages 10 neighboring cells. Thus, we may be greatly underestimating the biological
damage of alpha emitters.
While the separate Parkinson’s Disease advocates, and the National Multiple Sclerosis Society have voiced their concerns tracking GW veterans with MS on their volunteer list, it appears the downind Kuwaiti people share the concern, and apparently some genes. A 2006 study noted the rapid rise in native Kuwait people stating, [23] “In conclusion, the
incidence and prevalence of MS in Kuwait has increased between the early and late 1990s with no signs of leveling off. In a geographic area that was previously associated with low prevalence, local environmental factors may be responsible for these dramatic changes.”
Could this relate to radon, as a precipitating factor in autoimmune disease? -
Radon is an alpha emitter, as are most it’s many heavy metal daughter isotopes. While suspected as a cause of lung cancer, it is also absorbed by the entire body, and can decay in any organ. Two published studies did report a significant positive correlation between MS and radon levels,[24 & 25].
While not looking at treg cells, a recent study on chronic radon exposure in rats found immune and lymphocyte damage, reporting, “The results showed that radon-exposed lymphocytes were significantly lower and granulocytes higher in BALF compared to
blood in exposed groups,” [26].
A 2005 study in Mutagenisis documented immune suppression from breathing in a high radon environment, called “Incidence of cytogenetic damage in lead-zinc mine workers exposed to radon.”, [27] They tracked workers when the mine closed and found improvement stating, “We used peripheral blood lymphocytes as the target material. The total share of structural chromosome aberration (SCA) decreased significantly over the 3 years of monitoring, from 5.08/200 analyses of metaphases in 1995 to 3.28 in 1997, owing to the decrease in exposure during the process of mine closure.”.
Cellular immune responses to radiation found in cancer research –
The damaging effects of ionizing radiation to the immune system has long been studied, leading to better understanding the cellular damage. A 2007 report titled “Effect of Tinospora Cordifolia on Gamma ray-induced Perturbations in Macrophages and Splenocytes,” [28], confirmed earlier results, that an old herb extract allowed mice to survive lethal doses of radiation.
Increasing communication between the many specialties may accelerate insights and solutions.
Re-evaluating The Hanford Thyroid Dose Study conclusion of “no health effects.” -
Have we already documented an elevated autoimmune health effect?
The Hanford Thyroid Disease Study (HTDS) stated in their conclusion that no health effects were found, but used a different, very broad definition of
autoimmune thyroiditis for their conclusion. The HTDS conclusion's definition of autoimmune thyroiditis used mainly asymptomatic people, with an 18.3% of the cohort qualifying, at the “normal rate”, [29].
However, within their report, the clinical autoimmune hypothyroid cohort of 4.7%, of
people needing ongoing medical care and thyroid supplement, is quite high, according to their report. The HTDS actually notes this cohort is "considerably higher”, compared to the Nagasaki atomic bomb survivors that had a "significantly increased" cumulative incidence rate of autoimmune hypothyroidism of 2.5%, reported, [30]. The HTDS did not find a linear dose-response for this clinical cohort, using that as justification to say no health effect was found.
The HTDS conclusion compared the broader, mainly asymptomatic thyroiditis cohort, to an age-adjusted control group, that was then properly adjusted for the increased incidence rates, that comes from screening for diseases. That comparison to a normal rate was done for thyroid cancer, and was the protocol for assessing other thyroid disease listed in the conclusion. The elevated Hanford clinical autoimmune hypothyroid cohort, that was nearly double the high Nagasaki clinical cohort, was never compared to
an expected normal rate.
CDC and NAS should reconsider their conclusion no health effects were found at Hanford, for what appear to be very high rates of this burdensome health effect, that requires thyroid supplement, and ongoing medical care. They should use their regular
protocol, and compare it to an age-adjusted, expected normal, which would enhance our
understanding of their work on this cohort.
It is noteworthy that, although the different specialties gathered by the NAS to review
the HTDS, were not aware of the Sakaguchi study’s contradiction on thyroid irradiation, their advise was to include more autoimmune responses than just thyroiditis. The NAS stated, “The public has expressed concerns that the HTDS analysis of the data has ‘missed the forest for the trees’; that is, examining the fine categories of diagnosis might
have caused the data analyst to miss trends, that occur in broader categories of thyroid disease. In as much as autoimmune thyroiditis, Grave’s Disease, otherwise unexplained hypothyroidism, and ultrasonographic texture changes all are associated with autoimmune processes, one could score a person, with any or all of these, as positive for
a new global variable of autoimmune thyroid disease (a broader category than the one by that name in the HTDS),”[31]. This advice is another good reason to re-evaluate Hanford.
An alternative approach to assessing downwind cohorts -
There has long been a public outcry from irradiated downwind people, like at Hanford, concerning the apparent overall high autoimmune diseases rates, beyond the thyroid. Of course, people's possibly flawed, subjective observations of their family, friends, and neighbors, need scientific examination.
The government approach to assessing irradiated cohorts seems an inappropriate way to determine the full autoimmune response to radiation.
Why not conduct a full health exam, with Medical Doctors, for all autoimmune diseases, and all diseases, in the diet-documented downwinder cohorts from Hanford, Utah, Marshall Islands, Chernobyl, and Japan? Gathering the many specialists in autoimmunity may also provide the latest anti-body cellular indicators, to add to this
medical exam profile.
Government studies focus on the thyroid and take many years. The Utah CDC study funding has now been cut, before completion of the study on these children of atomic testing. Gulf War veterans deserve a similar full approach, unique to their circumstances.
Allowing people from these cohorts to use their own Medical Doctors, using an approved, peer-reviewed, full medical exam format and fee voucher, would be a faster and more thorough approach than the present government studies.
Have we already documented implications of a simple therapy, that addresses the
underlying immune problem, to supplement the fight against autoimmune diseases and cancer? Does removing plutonium from the immune organs allow the immune system to do its job? Is avoiding concentrated radon more important than we
thought? -
While Sakaguchi and others have detailed the role of the thymus and lymph nodes in autoimmunity, many organs play many roles in our overall immune system. The immune system's fight against cancer has many overlapping features with the fight against
autoimmune diseases. Please remember the conclusion of the report on DU immune effects, that stated, "...indicating a possible involvement of DU in cancer development, autoimmune diseases, and T helper 2 polarization of T cells.”, [18].
The government studies acknowledged worldwide fallout from atomic testing has deposited plutonium everywhere, and is in everybody's body, humans and all animals, in varying amounts. Mother's pass on their body burden of plutonium to their children, just
like the DU study noticed that DU "crosses the placenta."
From inhalation of DU, even Gulf War veterans who don't have embedded shrapnel, have urine samples detecting DU, from the body's attempt to excrete this unwanted body burden. Youths who were never exposed to bomb testing still are excreting detectable plutonium from atomic fallout, in their urine, [32].
If uranium in Gulf War veterans have disturbed their immune systems, what has the
hyper- radioactive plutonium done to the immune systems of the world's children?
EDTA chelation therapy is the treatment of choice for removing heavy metal poisoning from the body, which would also remove the majority of the plutonium, which is a heavy metal like uranium. When the Department of Energy workers are exposed to plutonium-238 inhalation, the protocol response is to put them on EDTA chelation
therapy as soon as possible, and researchers are looking at even better ways to remove
transuranics from the body, [33].
The basic question is, if internal alpha emitters are continually interfering with the treg cells, wouldn't that spoil the attempts of different disease therapies? If we remove the internally deposited plutonium, would that allow the immune system to function properly, and repair the body?
Searching pubmed, to see if anyone had worked on this revealed no direct article on the approach, but 2 articles revealed very hopeful indications that EDTA could cleanse the body burden of most alpha emitters, and allow the immune system to function
properly.
A 1992 study on a 33-year-old male, with lead poisoning, had put him on EDTA to help his impaired renal function. What surprised them was that his IgA immune deposits healed during the treatment, in this article titled, "Disappearance of immune deposits with EDTA chelation therapy in a case of IgA nephropathy," [34].
While removing the excess lead, they also, unknowingly, removed most his atomic fallout plutonium, just like the DOE workers do during EDTA therapy. It is fair to ask if the underlying improvement in his immune deposits was the removal of plutonium. Did the removal of the plutonium simply allow the immune system to do its job, and repair the body? Is removing the plutonium with EDTA like taking a knife out of the tregs? Do
they start to heal, and soon are back at work protecting the body?
A 2007 article on squamous cell carcinoma studied if calcium depletion helped nectin-1
expression and herpes oncolytic therapy, [35]. To achieve this calcium depletion, they used EDTA, but attributed the improvement to calcium depletion. It again appears fair to ask if the underlying event was the removal of plutonium and heavy metal radon decay isotopes, in the overall immune system, not just the tregs, in this cancer battle.
While EDTA chelation therapy is accepted treatment for heavy metal poisoning and
plutonium removal, many MD's, and Naturopathic Doctors, use it for alternatives to heart and circulation problems, which is properly questioned by many other MD's.
These alternative doctors also report helping most patients with all autoimmune diseases using chelation of heavy metals. However unpublished the results are, of the many happy patients, doctors who use EDTA for people with autoimmune diseases report a fairly good success rate. We need to document and publish if this approach is truly
helping, and integrate it with our mainstream approaches where appropriate.
When asked if those it did not help as much, had had their homes and work place checked for high radon, this had not been done. High radon homes have cracks in the foundation that concentrate continually in tightly weather-proofed homes, allowing radon to permeate the body and immune organs with alpha emitters like a miner.
If the alpha emitting radon continually mutates AIRE cells, that interfere with treg cells that control autoimmune reactions, is this why they are not in full remission yet?
Since plutonium and radon interfere with the immune system, should we check the homes and work places of people with cancer and autoimmune diseases? Should EDTA and anti-oxidant nutrition be used on cancer patients, BEFORE harsher treatments if time allows, to see if we can allow the immune system to attack the cancer, as it normally
would? If not successful, would the immune system not still be better prepared to recover from the cancer treatment, after EDTA and herbs that help survive lethal irradiation?
If EDTA is used for nuclear workers for accidents, and healthy urbanites for prevention, why not soldiers and the downwinders?
Implications -
The ongoing use of DU may be causing more harm than we are aware of, in our soldiers, and the Iraqi children.
It is possible that the largest health effect of low-level radiation exposure, especially internally deposited alpha emitters, is an overall autoimmune response, not cancer. This has implications for safety standards for exposure to radiation, which are currently based on cancer risks, extrapolated from the studies on downwinder cohorts, and animal data..
Conclusions -
We need to re-evaluate the irradiated populations, to get the clearest medical perspective on their exposure. We need to increase research funding for preventing and curing autoimmune diseases. We need to increase communication between the many
scientific specialties that work on these related issues.
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139Hhttp://books.nap.edu/catalog.php?record_id=9738#toc
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