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UC Study With Mice Links Thimerosal With Immune System Dysfunction

From a UC announcement.

Note: Thimerosal is a form of mercury widely used as a

preservative in pediatric vaccines. Mercury, particularly

the organic form of mercury such as thimerosal, is known for

its harmful effect on the nerve systems. Some studies linked

thimerosal with autism while some others disproved any link.

Autism or not, thimerosal is toxic and causes damage to

the nerve system. The only thing uncertain is whether such

damage would manifest itself clinically.

A team of cell biologists, toxicologists and molecular bioscientists

at the University of California, , has published a study connecting

thimerosal with disruptions in antigen-presenting cells known as dendritic

cells obtained from mice.

The study provides the first evidence that dendritic cells show

unprecedented sensitivity to thimerosal, resulting in fundamental changes in

the immune system's ability to respond to external factors.

The study was published online today and will be available in the July

print edition of Environmental Health Perspectives, the peer-reviewed

scientific publication of the National Institute of Environmental Health

Sciences.

" This is the first time that thimerosal has been shown to selectively

alter the normal functions of dendritic cells, " said Isaac Pessah, a

toxicologist with the UC School of Veterinary Medicine, director of

the Children's Center for Environmental Health and Disease Prevention and

senior author of the study. " Dendritic cells play pivotal roles in

overcoming viral and bacterial invaders by coordinating the immune system's

overall combat response. " One dendritic cell can activate as many as 300

T-cells white blood cells that help find and kill external agents that

attack the immune system making them the most effective immune system

activators.

The study shows how intricate connections between calcium channels in

dendritic cells change when exposed to thimerosal. " The slightest

fluctuation in how calcium channels `communicate' can alter the growth,

maturation and activation of dendritic cells, " explained Pessah. " Thimerosal

dramatically alters how two key calcium channels, code-named RyR1 and IP3R1,

found in dendritic cells function as a team by `garbling' the normal

signaling system between them. "

When thimerosal at a concentration as low as 20 parts per billion

alters the fidelity of normal calcium signals, dendritic cells show abnormal

secretion of IL-6 cytokine a potent chemical signal that initiates

inflammatory responses. Higher concentrations 200 parts per billion

causes programmed death of dendritic cells, preventing them from maturing

and doing their primary job of activating T-cells.

Without proper feedback to guide its response, a normal dendritic cell

can quickly become " a rogue, producing misinformation that could activate

aberrant and harmful immune responses, " Pessah explained.

" Even one rogue dendritic cell can activate many inappropriate immune

responses. "

The research team conducted the study on cells cultured from a strain

of mouse not particularly susceptible to immune dysregulation. Using

fluorescent stains and powerful microscopes to study both immature and

mature dendritic cells from bone marrow cultured under normal physiological

conditions, the researchers discovered that extremely small levels of

thimerosal interfere significantly with calcium channel function after just

a few minutes of exposure. They also observed that immature dendritic cells

are particularly sensitive to thimerosal.

Thimerosal is a cheap and effective mercury-based preservative. Its

potential effects on embryonic neuron development led to its removal from

many pediatric vaccines, however it is still used in influenza, diphtheria

and tetanus vaccines, blood products and many over-the-counter

pharmaceuticals. The concentrations of thimerosal used by the UC

researchers were comparable to those attained in childhood vaccinations

containing the preservative.

Researchers and parents have previously proposed links between

childhood vaccines and autism, a neurodevelopmental disorder that affects

language skills and social interactions. In addition to being a direct

neurotoxicant, the UC study indicates that thimerosal may also be an

immunotoxicant, leaving the immune system vulnerable to microbes and other

external influences.

" Our findings do not directly implicate thimerosal as a single

causative agent for triggering neurodevelopmental disorders such as autism, "

Pessah said. " There is growing evidence that autism is several disorders

that we now refer to as just one. There is also growing evidence that some

children with autism have unique immune cell composition and responses to

antigens. The results of our work provide a framework to test the hypothesis

that the genetic background of some individuals may render them especially

susceptible to thimerosal. "

Other experts also advise drawing no final conclusions regarding

thimerosal and autism based on these outcomes.

" These findings should be interpreted cautiously. Although they

suggest that thimerosal may affect dendritic cell function, the

pathophysiological consequences of thimerosal remain unclear, " said A.

Schwartz, a physician and director of the National Institute of

Environmental Health Sciences.

Since cell functions can differ across organisms, Pessah will next

study dendritic cells isolated from the blood of children with and without

autism to confirm if the intercellular changes are the same in humans. The

initial mouse study was funded by the National Institute of Environmental

Health Sciences and the UC M.I.N.D. Institute.

Joining Pessah on the scientific team were molecular bioscientists

R. Goth, Ruth A. Chu and Gennady Cherednichenko and pathologist

P. Gregg.

A copy of " Uncoupling of ATP-mediated Calcium Signaling and

Dysregulated IL-6 Secretion in Dendritic Cells by Nanomolar Thimerosal " can

be downloaded at http://www.ehponline.org/docs/2006/8881/abstract.html.