A team of cell biologists, toxicologists and molecular bioscientists
at UC Davis 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 Davis 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 Davis 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. The UC Davis study
indicates that in addition to being a direct neurotoxicant,
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
David 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 Davis M.I.N.D.
Institute. Joining Pessah on the scientific team were molecular
bioscientists Samuel R. Goth, Ruth A. Chu and Gennady Cherednichenko
and pathologist Jeffrey P. Gregg.
