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Researchers at Johns Hopkins have evidence that curbed activity from several key

chemicals on the inner lining of the nose are linked to chronic sinusitis that fails to respondto the usual current treatments.

An estimated 32 million Americans know the misery of persistent inflammation of the

moist tissue that lines the nose and sinus cavities. The result is clogged passages andrecurring infections, according to the U.S. Centers for Disease Control and Prevention.

Because nearly one in 10 of those treated see symptoms return within weeks or monthsafter drugs or surgery fail to keep the sinus passages open, scientists have long suspected

that these resistant cases had some underlying problem with the immune system

contributing to the ailment.

In a study to be described on Sept. 19 at the annual scientific sessions of the American

Academy of Otolaryngology, Head and Neck Surgery, the Hopkins team found that in

chronic sufferers who failed to respond to treatment, the activity of at least four genes in

the body's nasal immune defense system were severely decreased, and their production oftwo proteins critical to this defense was 20 to 200 times less than normal.

Comparing nasal epithelial cell samples from nine patients who benefited from surgery

with nine who did not, the Hopkins team discovered suppressed levels of human beta

defensin 2 (HBD2) and mannose binding lectin (MBL) in those whose symptoms returned.The proteins are naturally produced in the nose whenever the immune system detects

foreign bacteria or fungi, binding to invading pathogens, inactivating them and making

them easily disposed of.

An earlier study published by the same team in the March-April issue of theAmerican

Journal of Rhinology also showed that sinus tissue from people with chronic sinusitis thatresisted treatment had 30 times lower than normal activity of a so-called toll-like receptorgene, TLR9.

Inside the nose, researchers say, toll-like receptor proteins (TLRs) detect invading bacteriaand other pathogens in the air by attaching to their trace byproducts. Once a threat is

identified, the receptors stimulate the epithelial cells to produce antibioticproteins, such as

HBD2 and MBL, to fight the invading organisms. This innate response helps preventairborne bacteria or fungi from settling in the nose and sinus cavities, causing infection.

"Colonization with microorganisms is a common problem in patients with chronic sinusitis

and polyps, but the reasons for this are incompletely understood," says Andrew Lane,M.D., an associate professor at The Johns Hopkins University School of Medicine and

director of its rhinology and sinus surgery center. "Now we are uncovering new clues as to

what might be wrong and perhaps, ultimately, how it might be treated.

"The nose's first line of defense is the epithelium, and when the local innate immune

function is curtailed, infections can get a head start, which might serve to worsen the sinusinflammation.

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"The potential is there to manipulate these chemical receptors and proteins to see if this

makes patients more responsive to conventional therapy," says Lane.

The study, led by Lane, was believed to be the first to determine levels of each TLR - there

are 10 - by directly measuring messenger RNA expression in sinusitis patients and thosemore fortunate to not have it. Scientists have known for more than a year that TLRs were

present in both the healthy and sinusitis-wracked nose, but not which receptors or proteins

were more important than others in the condition's chronic form. That study involved 30men and women, mostly from the Baltimore region, who had surgery for chronic sinusitis

at Hopkins. (Another 10 had no sinus problem and served as study controls.)

Those who underwent surgery did so after standard therapy using antibiotics, decongestantsand steroids had failed to stop their symptoms and keep their infections from coming back.

Indeed, 20 participants in the study had developednasal polyps, which have no known

cause and are especially hard to treat, researchers say. They note that polyps must often be

surgically removed to allow the sinuses to drain normally.

All patients were monitored for a minimum of six months to see if any symptoms or polypsreturned. Thirteen in the surgery group had recurrent inflammation within three months to

one year after surgery, while the rest remained symptom free.

The Hopkins team took samples during surgery of the mucous membrane lining the nose,and using real-time polymerase chain reaction, analyzed the samples for any genetic

differences between the groups.

"Surgically treating sinusitis is much like plumbing, in the sense that we try to restore

normal sinus cavity drainage pathways," adds study presenter Murugappan Ramanathan Jr.,

M.D., a resident in otolaryngology - head and neck surgery at Hopkins. "But for theintractable cases, surgery may fail because the problem is not so much about plumbing as it

is inflammation, and for this we need research at the molecular level to find a solution."

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Funding for this study was provided in part by the National Institutes of Health, including

the National Institute on Deafness and Other Communication Disorders, and the NationalInstitute of Allergy and Infectious Diseases, with additional funding coming from the

American Rhinologic Society.

Besides Lane and Ramanathan, other researchers involved in this research, conducted

solely at Hopkins, were Quynh Ai Truong-Tran, Ph.D., and Robert Schleimer, Ph.D.

Contact: David March

Johns Hopkins Medical Institutions

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