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16-02-2012 | Genetics | Article

Body clock linked to immune response



MedWire News: People's body clocks may dictate the best time to give them immunomodulatory therapies, research suggests.

"Our findings unveil a direct molecular link between the circadian system and the innate immune system," say Erol Fikrig (Yale University School of Medicine, New Haven, Connecticut, USA) and colleagues.

The researchers studied Toll-like receptor 9 (TLR9), which is a protein that recognizes conserved pathogen-associated molecular patterns (PAMPs) and the only one found to date that recognizes both bacterial and viral DNA.

Using macrophages isolated from mice, they show that expression of Tlr9 fluctuates in line with that of the circadian cycle gene Per2, and that the immune response to PAMPs recognized by TLR9 is dependent on the presence of functional Per2.

By contrast, expression of the Tlr4 and Tlr7 genes were unaffected by circadian rhythms, and the immune response to PAMPs recognized by molecules other than TLR9 did not depend on Per2.

Fikrig et al also found that the major circadian transcription factors Clock and Bmal1 were able to bind to the Tlr9 promoter.

Mice used to a cycle of 12 hours of light and 12 hours of dark displayed daily fluctuations in Tlr9 expression in splenic tissue, but as with the in vitro experiments, there were no circadian-related differences in expression of Tlr4 and Tlr7. Circadian control of Tlr9 was evident in macrophages and B cells, but not in dendritic cells.

All circadian variations in Tlr9 expression persisted when the mice were kept in constant darkness. The researchers note that "a defining feature of circadian rhythms is that the rhythm persists in the absence of an environmental cue."

The team then vaccinated mice with PAMPs recognized by TLR9 and found a significantly increased immune response if vaccination took place at the time of highest Tlr9 expression, relative to the point of lowest expression.

"Several TLR9 agonists are undergoing extensive clinical evaluation as adjuvants and immunomodulators that could be useful for treatment of important conditions such as multiple sclerosis, asthma, and cancer," Fikrig et al write in Immunity.

"Considering not only the dosing and immunization timing but also the degree of proper circadian entrainment in patients may be critical for assessing and maximizing the prophylactic and therapeutic efficacy of these agents."

Circadian rhythm also affected outcomes in a mouse model of sepsis. In sepsis, infection causes systemic inflammatory response syndrome, which can be fatal. In the current study, when sepsis in mice was triggered at the time of highest Tlr9 expression the immune response was greater than if sepsis was triggered at the time of lowest Tlr9 expression. Consequently, outcomes were worse, with mice dying sooner (31 vs 45 hours) and having worse disease scores, more severe hypothermia, and higher serum levels of creatine kinase.

The researchers note that patients with sepsis have a particularly high risk for mortality between the hours of 02:00 and 06:00, suggesting that circadian rhythms may also influence sepsis outcomes in humans.

"If this proves to be the case, septic patients might benefit from receiving immunomodulatory therapies during the hours when they are most vulnerable," they conclude.

By Eleanor McDermid

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