New research shows that the success of host immune
defense depends in part on an organism's "body
clock." The study may lead to therapeutic strategies
designed to optimize the immune response and to
protect patients at the time when they are most
vulnerable.
The study may lead to therapeutic strategies
designed to optimize the immune response and to
protect patients at the time when they are most
vulnerable.
Many organisms have evolved an endogenous timing
system called a circadian clock that regulates a
wide variety of metabolic activities over a
twenty-four hour cycle.
"It is becoming increasingly evident that disruption
of daily rhythms, such as from sleep deprivation,
affects the immune response," explains senior study
author, Dr. Erol Fikrig from Yale University School
of Medicine.
"In our study, we were interested in investigating
whether the ability of the immune system to detect a
pathogen is under circadian control and whether
there are timing-associated consequences for the
subsequent immune response."
Dr. Fikrig and colleagues examined the expression
and function of Toll-like receptor 9 (TLR9), an
immune system protein that can sense bacterial and
viral DNA.
The researchers demonstrated that the circadian
clock controlled TLR9 expression and function and
that mice immunized when TLR9 was most responsive
exhibited an enhanced immune response.
Importantly, in a mouse model of sepsis, disease
severity was dependent on the timing of sepsis
induction, which directly correlated with cyclical
changes in TLR9.
The authors suggest that this observation may be
clinically significant as septic human patients are
known to be at increased risk of mortality between 2
and 6 am.
"These findings not only unveil a novel, direct
molecular link between circadian rhythms and the
immune system, but also open a new paradigm in the
biology of the overall immune response with
important implications for the prevention and
treatment of disease," concludes Dr. Fikrig.
"Furthermore, patients in the ICU often have
disturbed sleep patterns, due to noise, nocturnal
light exposure and medications; it will be important
to investigate how these factors influence TLR9
expression levels and immune responses."
For more information
The Circadian Clock Controls Toll-like Receptor
9-Mediated Innate and Adaptive Immunity
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Yale University School of Medicine
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