ANN ARBOR, Mich. -- Our immune system protects us from disease,destroying invading microbes with a swarm of attacking cells. But itcan also go haywire for no apparent reason, ganging up on normaltissues in our body and wreaking havoc.
In thousands of people each year, the immune system attacks theinner ear, home to the tiny, delicate structures that allow us to hear.Without warning, in days or weeks, patients lose the ability to hear inone or both ears. Some might get part or all of their hearing back ifthey take steroid medicines, but many are left to cope with partial ortotal deafness without knowing what caused it. And no one knows why ithappens.
Now, new research based at the University of Michigan's KresgeHearing Research Institute may help more patients find out quickly ifsteroids could help them, or if they can be spared the drugs' harshside effects. It may also expand the definition of the condition, knownas autoimmune sensorineural hearing loss or AISNHL, and help morepeople get a firm diagnosis of what's causing their mysterious hearingloss.
In the August issue of the Archives of Otolaryngology -- Headand Neck Surgery, researchers reports results from a study of 63 peoplewith rapidly progressing hearing loss in Michigan, Pennsylvania andIndiana, and 20 people with normal hearing. The patients were suspectedof having an auto-immune cause for their hearing loss, and all receivedsteroids, but they hadn't been formally diagnosed.
The researchers found that more than half of the hearing-losspatients had antibodies against a protein found in the inner ear,called IESCA for inner-ear supporting cell antigen. This is a signtheir immune systems recognized it as foreign.
"In all, 28 of the 63 patients experienced improvement in theirhearing after steroid treatment, and 35 did not. But the vast majority,89 percent, of those who improved had a positive immunofluorescencetest for an antibody to IESCA that we have studied at U-M for years,"says senior author Thomas Carey, Ph.D., a professor and distinguishedresearch scientist at the U-M Medical School and department chair inthe School of Dentistry. "The results strongly suggest that a directtest for antibodies could accurately predict which patients will regainhearing with steroid treatment." Such a test, he notes, is stillseveral years away from being available to patients.
The new findings also may be important to people with systemicautoimmune disorders such as lupus or rheumatoid arthritis. Such peoplemay be prone to losing all or part of their hearing due to anoverzealous autoimmune reaction. All eight study participants who hadsystemic 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 inanimals and have found that it may be a main target of the immunesystem's deafening attack on the inner ear. IESCA is found in thesupporting cells that help make up the organ of Corti, a tiny butcrucial 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 thatare fed to the brain and interpreted as sounds and speech. Damage tothe 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, calledKHRI-3, that attaches to IESCA in the inner ear, and can be detected inliving animal systems and cell cultures. It has allowed them to studyIESCA's role in hearing loss in animal models, and show that damage tothe inner ear caused by antibodies to IESCA can destroy hearing. TheKHRI-3 antibody creates a staining pattern that resembles a line oftiny wine glasses when it binds to IESCA in the organs of Corti ofguinea pigs.
The U-M has patent applications pending in the U.S. and abroadpertaining to KHRI-3, IESCA and AISNHL. The University, Carey andseveral colleagues stand to profit if tests or treatments based onthese patents are developed. The development of a clinical test forpatient antibody to IESCA will take time, Carey says.
In previous papers, Carey and his colleagues have shown thatIESCA has about the same molecular weight as -- but is distinct from --a protein that serves as the basis for a currently available commercialAISNHL test. That test, based on a protein-separation test known asWestern blot, is known to give accurate results only some of the time.The U-M team reported in previous paper in the Journal of Neurosciencethat IESCA is identical to a protein called CTL2, or cholinetransport-like protein 2.
In the new study, the researchers tested blood from the 63patients and 20 normal controls with two tests: a Western blot test andan immunofluorescence (IF) test based on KHRI-3. They correlated theresults of those two tests with patients' response to steroidtreatment, based on standard criteria and the results of hearing testsperformed before and after treatment. They also considered patients'other autoimmune diseases, the length and pace of hearing lossprogression before treatment, and age and gender.
Thirty of the patients were female, and 33 male; their averageage 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 rightear. They had no known cause for hearing loss, and most had lost theirhearing gradually over weeks, though eight had lost it over hours ordays. Many also had dizziness, ringing or a sensation of fullness intheir ears. In all, half regained some or all of their hearing aftersteroid treatment.
Seventy-five percent of the patients had "wine glass" stainingwith IF testing, and 68 percent had positive Western blot results forthe 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 specificresponse to steroid treatment: patients who had a positive IF testresult were three times more likely to improve after steroid treatmentthan those with negative IF results.
The two tests combined were even more predictive: 54 percentof 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 hadsudden hearing loss over hours or days had antibodies, and nearly allimproved with steroids.
Since this kind of rapid-onset hearing loss has historicallybeen excluded from the formal definition of AISNHL, Carey suggests thedefinition may need re-examining in light of this strong evidence foran immune-system cause in these patients.
In addition to Carey, who is associate chair for research ofthe Department of Otolaryngology at the U-M Medical School, the paper'sother 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; ChristopherD. Lansford, M.D.; Robert Sataloff, M.D.; and Susan G. Fisher, Ph.D.
The research was funded by the Autoimmune Sensorineural Hearing LossResearch Fund, the Ruth and Lynn Townsend Fund, a gift from the HoldenFoundation, the Deafness Research Foundation and the NationalInstitutes of Health.
Special note for hearing-loss patients: The new findings, whileexciting, are laboratory results and cannot be immediately applied tohuman treatment. It will take several years to develop a test thatcould be used in patients who have recently developed hearing loss. Ifyou have recently begun to experience hearing loss that is progressing,seek immediate attention from an otolaryngologist, sometimes called anear, nose and throat (ENT) doctor. He or she can advise you onimmediate and long-term treatment options.
If you would like to help support U-M research into autoimmune sensorineural hearing loss, visit https://cgi.www.umich.edu/cents-bin/cents-open/mcado2to make a secure on-line donation; please note that you would like thedonation to go to the Autoimmune Hearing Loss Research Fund of theKresge Hearing Research Institute.
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