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New lab research may help those deafened by immune system attack

16.08.2005


Study may one day lead to test that could show which patients may be helped by immediate steroid treatment

Our immune system protects us from disease, destroying invading microbes with a swarm of attacking cells. But it can also go haywire for no apparent reason, ganging up on normal tissues in our body and wreaking havoc.

In thousands of people each year, the immune system attacks the inner ear, home to the tiny, delicate structures that allow us to hear. Without warning, in days or weeks, patients lose the ability to hear in one or both ears. Some might get part or all of their hearing back if they take steroid medicines, but many are left to cope with partial or total deafness without knowing what caused it. And no one knows why it happens.



Now, new research based at the University of Michigan’s Kresge Hearing Research Institute may help more patients find out quickly if steroids could help them, or if they can be spared the drugs’ harsh side effects. It may also expand the definition of the condition, known as autoimmune sensorineural hearing loss or AISNHL, and help more people get a firm diagnosis of what’s causing their mysterious hearing loss.

In the August issue of the Archives of Otolaryngology – Head and Neck Surgery, researchers reports results from a study of 63 people with rapidly progressing hearing loss in Michigan, Pennsylvania and Indiana, and 20 people with normal hearing. The patients were suspected of having an auto-immune cause for their hearing loss, and all received steroids, but they hadn’t been formally diagnosed.

The researchers found that more than half of the hearing-loss patients had antibodies against a protein found in the inner ear, called IESCA for inner-ear supporting cell antigen. This is a sign their immune systems recognized it as foreign.

"In all, 28 of the 63 patients experienced improvement in their hearing after steroid treatment, and 35 did not. But the vast majority, 89 percent, of those who improved had a positive immunofluorescence test for an antibody to IESCA that we have studied at U-M for years," says senior author Thomas Carey, Ph.D., a professor and distinguished research scientist at the U-M Medical School and department chair in the School of Dentistry. "The results strongly suggest that a direct test for antibodies could accurately predict which patients will regain hearing with steroid treatment." Such a test, he notes, is still several years away from being available to patients.

The new findings also may be important to people with systemic autoimmune disorders such as lupus or rheumatoid arthritis. Such people may be prone to losing all or part of their hearing due to an overzealous autoimmune reaction. All eight study participants who had systemic autoimmune diseases showed signs of antibodies against IESCA. Six of them regained hearing after steroid treatment.

U-M researchers have been studying IESCA for several years in animals and have found that it may be a main target of the immune system’s deafening attack on the inner ear. IESCA is found in the supporting cells that help make up the organ of Corti, a tiny but crucial structure inside the cochlea, or inner ear.

Inside the organ of Corti are the ultra-sensitive hair cells, whose movement in response to vibrations creates the nerve signals that are fed to the brain and interpreted as sounds and speech. Damage to the organ of Corti and hair cells, whether due to immune system attack, loud noise, trauma or medications, can diminish or destroy hearing.

The U-M team has developed a monoclonal antibody, called KHRI-3, that attaches to IESCA in the inner ear, and can be detected in living animal systems and cell cultures. It has allowed them to study IESCA’s role in hearing loss in animal models, and show that damage to the inner ear caused by antibodies to IESCA can destroy hearing. The KHRI-3 antibody creates a staining pattern that resembles a line of tiny wine glasses when it binds to IESCA in the organs of Corti of guinea pigs.

The U-M has patent applications pending in the U.S. and abroad pertaining to KHRI-3, IESCA and AISNHL. The University, Carey and several colleagues stand to profit if tests or treatments based on these patents are developed. The development of a clinical test for patient antibody to IESCA will take time, Carey says.

In previous papers, Carey and his colleagues have shown that IESCA has about the same molecular weight as -- but is distinct from -- a protein that serves as the basis for a currently available commercial AISNHL test. That test, based on a protein-separation test known as Western blot, is known to give accurate results only some of the time. The U-M team reported in previous paper in the Journal of Neuroscience that IESCA is identical to a protein called CTL2, or choline transport-like protein 2.

In the new study, the researchers tested blood from the 63 patients and 20 normal controls with two tests: a Western blot test and an immunofluorescence (IF) test based on KHRI-3. They correlated the results of those two tests with patients’ response to steroid treatment, based on standard criteria and the results of hearing tests performed before and after treatment. They also considered patients’ other autoimmune diseases, the length and pace of hearing loss progression before treatment, and age and gender.

Thirty of the patients were female, and 33 male; their average age was 47, reflecting the young age at which AISNHL typically begins. Twenty-six had lost hearing in both ears, the rest in the left or right ear. They had no known cause for hearing loss, and most had lost their hearing gradually over weeks, though eight had lost it over hours or days. Many also had dizziness, ringing or a sensation of fullness in their ears. In all, half regained some or all of their hearing after steroid treatment.

Seventy-five percent of the patients had "wine glass" staining with IF testing, and 68 percent had positive Western blot results for the same size protein as is used in the commercial test.

The two different blood tests weren’t always consistent - - results were the same in 47 patients (both positive or both negative) but different in 16. But the IF test appeared give a more specific response to steroid treatment: patients who had a positive IF test result were three times more likely to improve after steroid treatment than those with negative IF results.

The two tests combined were even more predictive: 54 percent of those who had positive results on both tests improved after steroid, compared with 10 percent of those who had two negative results.

Interestingly, Carey notes, nearly all of the patients who had sudden hearing loss over hours or days had antibodies, and nearly all improved with steroids.

Since this kind of rapid-onset hearing loss has historically been excluded from the formal definition of AISNHL, Carey suggests the definition may need re-examining in light of this strong evidence for an immune-system cause in these patients.

In addition to Carey, who is associate chair for research of the Department of Otolaryngology at the U-M Medical School, the paper’s other U-M authors are Otolaryngology/Kresge members Hisham Zeitoun, MPhil., FRCS, the lead author; H. Alexander Arts, M.D.; Dawn E. Denny; Michael J. Disher, M.D.; Hussam El-Kashlan, M.D.; David S. Lee, M.D.; Thankam S. Nair, M.S.; Anna Ramakrishnan, M.S.; and Steven Telian, M.D. Co-authors from outside U-M are Jennifer Gray Beckman, JD; Christopher D. Lansford, M.D.; Robert Sataloff, M.D.; and Susan G. Fisher, Ph.D.

Kara Gavin | EurekAlert!
Further information:
http://www.umich.edu

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