STANFORD, Calif. — The nervous system and the immune system havesomething in common. Each has evolved to react quickly to environmentalcues. Because the nervous system is able to detect some of these cues -say, a characteristic odor signaling a pathogen's presence - at adistance, it sometimes can sense trouble earlier than the immune system,which has to wait until the pathogen invades the organism.
So it makes sense that the two systems might talk to one another.Stanford University School of Medicine geneticists have shown that,indeed, they do.
In a study to be published online Oct. 14 by the journal NatureImmunology, Man-Wah Tan, PhD, assistant professor of genetics and ofmicrobiology and immunology, and postdoctoral scholar Trupti Kawli haveshown that a change in the secretion patterns of nerve cells in theminuscule soil-dwelling worm, Caenorhabditis elegans, induces a changein the worm's susceptibility to a bacterial pathogen, Pseudomonasaeruginosa. In humans, P. aeruginosa is an important pathogen amongcystic fibrosis patients and can cause pneumonia.
Importantly, the Stanford investigators have nailed down the connectionbetween the two systems. They identified a particular molecule that,secreted by nerve cells, binds to receptors in the worm's gut cells.When the levels of the secreted molecule fall, this sets off acomplicated chain reaction that activates the powerful immune defenseagainst bacterial infection. Since bacteria are what C. elegans mainlyeats, this is a handy defense to have.
The notion of crosstalk between our nervous and immune systems is hardlysurprising, said Tan. "A person who is undergoing prolongedpsychological stress - say, because they're taking care of someone whois sick - is more likely to have reactivation of a latent infection orbecome more susceptible to new ones," he said. "That stressful situationcannot be changed. But by identifying the pathways through which thenervous system alters immune function in this simple creature C.elegans, we can perhaps start to think about how we can intervene inhumans."
The very complexity of the nervous and immune systems would make anyinteractions between them exceedingly tough to tease out in humans. SoKawli and Tan used C. elegans, because both its nervous and immunesystems have been entirely mapped out. This enabled the researchers tomanipulate the former, then watch what happened to the latter.
C. elegans has nerve cells that ordinarily secrete bioactive moleculescontained within tiny membrane-wrapped bundles, called dense-corevesicles. The rate at which these molecules are secreted is governed bythe activity of the nervous system. One of those secreted bioactivemolecules is called ins-7. The Stanford team obtained or generatedvarious C. elegans mutants that lacked the ability either to produce orto secrete ins-7, or secreted it excessively.
By using these and other advanced laboratory tools to manipulate theworm's ability to secrete ins-7, the researchers were able tocorrespondingly alter the readiness of the minuscule creature's innateimmune system: a primitive but potent piece of the immune system sharedby C. elegans and higher organisms including humans.
People often associate "immune response" with antibodies and rovingT-cells dispatched to combat a particular viral or bacterial infection -the so-called adaptive immune response. But that response takes a weekor two to develop, said Tan. In contrast, all of our cells havereceptors that can recognize molecular patterns common to whole classesof pathogens (for example, characteristic viral DNA snippets, orbacterial cell-wall constituents), immediately triggering cascades ofintracellular reactions, such as the activation of batteries of genesthat code for antimicrobial proteins.
Both the innate and adaptive branches of the immune system have tofunction optimally in order for us to leave a healthy life. "The innateimmune system is our first line of defense," said Tan. "If not for theinnate immune system, we'd be dead by the time the adaptive immunesystem raises antibodies to a pathogenic invader we have not encounteredbefore."
It is still a matter of speculation as to how crosstalk between thenervous and immune systems of humans regulates innate immune responses.But now that a clear pathway has been identified in the worm, it will beeasier to conduct focused research on higher organisms to see if thephenomenon is universal, Tan said.
Tan acknowledged that it has not yet been proven that the signaling ofthe nervous system to the immune system of C. elegans, as shown in thisexperiment, occurs in nature. But there's very good reason to believe itdoes.
In a separate paper set to be published online on Oct. 17 by anotherjournal, PLoS-Pathogens, Tan and other Stanford associates demonstratethat P. aeruginosa - which is often isolated from the same soil samplesin which C. elegans is found and, presumably, co-evolved with C. elegans- has a way of subverting this defense against it. The pathogen inducesexcess production of ins-7 by the worm to dull its immuneresponsiveness. In contrast, other human bacterial pathogens such asSalmonella typhimurium and Enterococcus fecalis have no such capability.Nor do abiotic stresses, such as heat or heavy metals.
This suggests to Tan that the fine-tuning of the innate immune responseby the nervous system is effective enough in the natural state that somepathogens with which C. elegans coexists have evolved strategies tosubvert this system.
An inducible immune response makes more sense - in worms and people -than a state of constantly hyper-elevated immune vigilance. People withhyperactive immune systems suffer from autoimmune and inflammatoryconditions. Although worms with downregulated secretion from dense-corevesicles are better at combating infection, they don't move well, whichwould probably prove lethal in the wild. One of the ins-7-deficient C.elegans mutants used in the Nature Immunology study is called unc, saidKawli, the paper's first author. "That stands for 'uncoordinated,'" shesaid.