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Friendly FireMichael Glenwood

Friendly Fire (continued)

AMONG THE THINGS that both cause and react to system imbalances are messenger proteins called cytokines. The immune system communicates through these versatile factors that float around in the bloodstream. Unlike neurons in the hard-wired nervous system, cells in the immune system are not physically connected to one another.

"If you think of the nervous system as a landline, then the immune system is a cell phone," says Jay Bream, PhD, an MMI associate professor. "Different cocktails of cytokines, in various abundances, play a central role in determining immune responses."

A phenomenon known as a "cytokine storm" can occur if the reaction of the immune system to a pathogen is wildly exaggerated and stimulates too many of the messenger molecules, which in turn activate the same cells that stimulated them, resulting in a dangerous feedback loop. For example, cytokine storms are associated with severe bacterial infections and the onset of septic shock as well as avian influenza (H5N1) infection. Likewise, infection with the deadly Ebola virus is associated with a cytokine storm leading to uncontrolled inflammation.

Cytokine storms can happen in tissues throughout the body. That's because the component parts of the immune system spread far and wide, from the top layer of skin to the deepest recesses of the bowels.

Bream, whose mission is linking cytokines with disease outcomes, studies Interleukin-10 (IL-10): "a lynchpin" he says, "at the nexus of inflammation."

When the volume of IL-10 is turned down low, inflammation happens. When it's blasting, inflammation is tamped down. Bream, co-director of the Becton Dickinson Immune Function Laboratory at the Bloomberg School, has shown that mice prone to express higher levels of IL-10 are susceptible to certain types of persistent infections because they can't mount appropriate inflammatory responses. If there's an under-abundance of IL-10, they are susceptible to immunopathology caused by collateral damage from the excessive immune response. In this scenario, the original infections clear, but the animals' inflammatory responses set them up for autoimmune diseases and cancers. Animals whose IL-10 gene has been knocked out have extremely compromised anti-inflammatory responses. For example, under conditions that mimic septic shock, 100 percent die within 48 hours due to the cytokine storm, Bream says.

"One of the main roles of IL-10 is to control expression of pro-inflammatory cytokines," Bream explains. "That's how it tries to right the ship, by reducing inflammation to acceptable levels."

If inflammation, which dictates how we respond to vaccines and infectious pathogens, is not under stringent genetic control, the result is disease.

"In terms of public health, I see all these diseases—from heart disease to autoimmune disease to cancer to schizophrenia—as gene regulation issues, related to inflammation," he says. "Some people who get influenza end up hospitalized and die while others recover. Some people get colds and can go to work while others are bedridden. It's this diversity in the human population of response to disease threats that is at the center of my research program."

To find out why some individuals control inflammation better than others, he's looking at tiny genetic variations (known as single nucleotide polymorphisms, or SNPs) that make each human a unique individual, and noting how they affect the levels of IL-10 in various tissues, ultimately exerting control over inflammation and disease.

Because he wants to know how IL-10 works in people, Bream has inserted chunks of DNA containing the human IL-10 gene into the mice he's using. Some mice get human genes with variations associated with high IL-10 expression, and some get human genes with variations associated with low IL-10 expression.

Among other things, he's discovered that location is all-important: Where he manipulates IL-10—that is, which tissue type—matters. If, for instance, Bream turns down the IL-10-producing ability of a subset of cells in a very specific area of the colon, just below the surface cell layer, those mice end up with severe colitis.

"IL-10 is an attractive target for therapeutic interventions that either add back or neutralize IL-10," says Bream, who's now testing different expression levels of the human gene across various tissue types in response to different kinds of infectious pathogens in mice. "By identifying the triggers and genetic variations that regulate IL-10 levels, it will be feasible to develop more personalized therapies that restrict or enhance IL-10 in tissues where inflammation is occurring. But it's extremely complicated."

Another group of researchers at the Bloomberg School is looking at the anti-inflammatory IL-10 cytokine in the context of frailty in older adults. Some elderly people get frail in a clinical sense, meaning they spiral into a vicious cycle of decline characterized by exhaustion, slowness, weakness and muscle loss.

"It's hypothesized that there's at least a subset of older adults in whom inflammation essentially gets turned on all the time," says Karen Bandeen-Roche, PhD, the Frank Hurley and Catharine Dorrier Professor and Chair of Biostatistics, and co-principal investigator of the Older Americans Independence Center. "It's associated with muscle wasting and other adverse outcomes."

Bandeen-Roche is collaborating with Jeremy Walston, MD, a Johns Hopkins professor of Medicine and co-director of the Biology of Healthy Aging Program, who has developed a frail mouse model by knocking out expression of the IL-10 gene.

"In human studies, again and again, associations of high inflammation and adverse outcomes have been revealed, with frailty prominently among them," says Bandeen-Roche. "Pro-inflammation is thought by many to be one of the key hallmarks in a cycle of multisystem dysregulation that leads to frailty."

Human studies designed to discover how inflammation works and reveal its links to diseases require not only big funding and endless approvals but also plenty of participants, willing subjects who are healthy, as well as those who are sick.

People like Patricia Mabe, for instance.

"When there's imbalance in one thing, it's like a wave that pushes on other things and you get a whole cluster of effects."
—Josef Coresh


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