http://www.medpagetoday.com/InfectiousDisease/Vaccines/dh/2900

Review
DAVIS, Calif., March 21 - Thimerosal, a mercury-containing organic no
longer used as a preservative in many pediatric vaccines, can disrupt
certain antigen presenting cells and may affect the immune response to
external factors, reported investigators here.

Although far from the smoking gun that proponents of a
thimerosal-autism link seek, the finding suggested that thimerosal
exposure could cause dendritic cells to activate "aberrant and harmful
immune responses," according to Isaac N. Pessah, Ph.D., and colleagues
of the University of California at Davis. They reported the research
online in Environmental Health Perspectives.

"This is the first time that thimerosal has been shown to selectively
alter the normal functions of dendritic cells," said Dr. Pessah, a
toxicologist and director of the Children's Center for Environmental
Health and Disease Prevention at Cal Davis.

He added that dendritic cells "play pivotal roles in overcoming viral
and bacterial invaders by coordinating the immune system's overall
combat response."

Yet, Dr. Pessah emphasized, "Our findings do not directly implicate
thimerosal as a single causative agent for triggering
neurodevelopmental disorders such as autism."

"There is growing evidence that autism is several disorders that we
now refer to as just one," he added. "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."

Dendritic cells are antigen-presenting cells that are potent
activators of T-cells. But as Dr. Pessah and colleagues demonstrated
in their study of cultured mouse cells, exposure to thimerosal
disrupts calcium-channel signaling within dendritic cells, thereby
altering growth patterns, maturation, and activation.

They determined this by exposing both mature and immature dendritic
cells cultured from murine bone marrow to thimerosal at varying
concentrations. The authors used immunocytofluorescence to visualize
the effect of thimerosal exposure on calcium channels. Thimerosal
contains approximately 50% ethylmercury by weight.

They found that at concentrations of 20 parts per billion, exposure of
the dendritic cells to thimerosal altered the normal cross-talk
between the calcium channels RyR12 and IP3R1, thereby "garbling the
normal signaling system between them."

In addition, exposure to the compound resulted in irregular secretion
by the dendritic cells of the pro-inflammatory cytokine interleukin-6.

When they ramped up thimerosal concentrations to 200 parts per
billion, they found that it induced apoptosis of dendritic cells
before they had fully matured, thereby preventing T-cell activation.

The finding suggests that in addition to its known neurotoxic
properties, ethylmercury may also be an immunotoxicant, the authors
said.

"A practical implication of the present findings has relevance to the
commercial uses of thimerosal as an antimicrobial agent in vaccines
and consumer products since they identify dendritic cells as sensitive
targets for thimerosal and ethylmercury-mediated dysfunction," they
wrote. "Given the importance of dendritic cells as a front line in
regulating lymphocyte mediated immunity and tolerance, altering
dendritic cell functions by forms of ethylmercury should be considered
when assessing contributions to altered immune function."

They stopped short, however, of fingering thimerosal as a cause of
autism. Thimerosal is still used in some commercial vaccines.

Other experts also advised drawing no final conclusions regarding
thimerosal and autism on the basis of on this research.

"These findings should be interpreted cautiously. Although they
suggest that thimerosal may affect dendritic cell function, the
pathophysiological consequences of thimerosal remain unclear," said
David A. Schwartz, M.D., director of the National Institute of
Environmental Health Sciences, who was not involved in the study.

Primary source: Environmental Health Perspectives
Source reference:
Goth SR et al. Uncoupling of ATP-mediated Calcium Signaling and
Dysregulated IL-6 Secretion in Dendritic Cells by Nanomolar Thimerosal
Environmental Health Perspectives. doi:10.1289/ehp.8881

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