Defect in Immune Memory May Cause Repeat Bladder Infections
DURHAM, N.C. – Recurrent bladder infections, which are especially common among women, may result from a defect among the bladder’s immune fighters that keeps them from remembering previous bacterial infections. The immune memory lapse can hamper a timely and effective attack, according to researchers at Duke Medicine and Duke-National University of Singapore.
Their study, which involved mice, may provide a new route to develop vaccines and treatments for urinary tract infections, which are the second-most common infection and account for more than 8 million health care visits a year in the United States, according to the National Institutes of Health.
“A third of recurring bladder infections are from the same strain of bacteria, so that suggested to us that there is some sort of defect in the bladder that is causing this,” said Soman N. Abraham, PhD, professor of pathology at Duke and Duke-NUS and senior author of the paper published Feb. 14, 2013, in the journal Immunity. “We have identified how a muted immune response to bacterial infections in the bladder occurs, making it unable to fully eradicate a persistent population of bacteria.”
Like the gut and the liver, the bladder is involved in waste treatment, and is frequently exposed to bacterial invasion. But it has not been among the organs considered “immune privileged,” in which the immune system operates under special strategies for tolerating certain pathogens to keep it from over-activating. Not much is understood about how the mucosal tissue in the bladder functions.
Abraham and colleagues examined mouse bladders under conditions that closely mimic human infections; infections remained in the bladder for some, and traveled to the kidneys in others. In both cases, they found that urinary tract infections were typically met with a robust inflammatory response from the innate immune system, which is the body’s first line of defense and attacks all pathogens in a generalized fashion.
After 21 days, both sets of mice were re-infected, and here the groups diverged. In the mice that originally had an infection in both the bladder and kidney, a strong antibody response arose, indicating that the immune system recognized the invader and could swiftly eradicate it. But among those that originally had just the bladder infection, the immune system showed no memory recall.
The cause was an unlikely source: Mast cells. Best known for fighting allergies, mast cells are responsible for triggering an early immune response against bacteria in the bladder, and in every instance, they sprung to action when confronted with the E. coli infection. But in some cases, they then began producing a molecule called interleukin-10, which suppresses the immune system. It was if the immune system slammed on brakes, so the adaptive immune system never kicked into action to form antibodies that would recognize a recurring invasion.
Abraham said this function of mast cells to limit the immune response may coincide with the shedding of the bladder’s lining cells – a sort of cleansing mechanism that keeps bacteria from accumulating in the epithelial lining – and may be part of the bladder’s form of immune privilege to temper the inflammatory response.
“It appears that the bladder, like the gut, has a highly specialized strategy for balancing tolerance and resisting infection,” Abraham said. “In most cases, muting the adaptive immune response in the bladder would not be a problem, because the infection would be cleared by the vigorous response of the early, innate immune response. But in some people, it’s causing recurrent infections, because the bacteria hide in the epithelium and are not recognized by the adaptive immune system."
Abraham said the findings could lead the development of vaccines against the bacteria, or better treatments that bolster the antibody response.
In addition to Abraham, study authors include Cheryl Y. Chan of Duke University Medical Center and Ashley L. St. John of Duke and Duke-NUS.
The study was support by grants from the NIH (R01 A135678, R01 DK077159, R01 A150021, R37 DK50814 and R21 A1056101).
GRAPHIC: Bladder infections that travel to the kidneys result in an immune response that builds antibodies to recognize and attack the pathogen. When the infection remains in the bladder, however, the immune response is led by mast cells, which initially fight the infection but also produce an immune suppressing molecule called interleukin-10 that disrupts the development of antibodies and thus stifles immune memory.