Failure of elevated heat shock protein 70 antibodies to alter cochlear function in mice

Trune, Dennis R.; Kempton, J. Beth; Mitchell, Curtin R.; Hefeneider, Steven H.

doi:10.1016/s0378-5955(97)00198-6

Cited by 46 publications

(25 citation statements)

References 20 publications

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“…If such antibodies do cause hearing loss, identification of the target antigen and elucidation of the mechanism by which the antibody causes hearing loss would be useful in the diagnosis and management of autoimmune hearing loss (AHL). Two groups identified heat shock protein 70 (HSP70) as a candidate target antigen Bloch et al, 1995); however, HSP70 has not held up as a high-probability inner ear target antigen (Billings et al, 1998;Trune et al, 1998;Yeom et al, 2003). We developed monoclonal antibodies to cells isolated from the guinea pig (GP) organ of Corti (Zajic et al, 1991) and observed that hearing loss developed in mice carrying the Kresge Hearing Research Institute-3 (KHRI-3) hybridoma (Nair et al, 1995), provoking us to study this antibody and its antigen in more depth.…”

Section: Introductionmentioning

confidence: 99%

Identification and Characterization of Choline Transporter-Like Protein 2, an Inner Ear Glycoprotein of 68 and 72 kDa That Is the Target of Antibody-Induced Hearing Loss

Nair¹,

Kozma²,

Hoefling³

et al. 2004

J. Neurosci.

108

133

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The Kresge Hearing Research Institute-3 (KHRI-3) antibody binds to a guinea pig inner ear supporting cell antigen (IESCA) and causes hearing loss. To gain insight into the mechanism of antibody-induced hearing loss, we used antibody immunoaffinity purification to isolate the IESCA, which was then sequenced by mass spectroscopy, revealing 10 guinea pig peptides identical to sequences in human choline transporter-like protein 2 (CTL2). Full-length CTL2 cDNA sequenced from guinea pig inner ear has 85.9% identity with the human cDNA. Consistent with its expression on the surface of supporting cells in the inner ear, CTL2 contains 10 predicted membrane-spanning regions with multiple N-glycosylation sites. The 68 and 72 kDa molecular forms of inner ear CTL2 are distinguished by sialic acid modification of the carbohydrate. The KHRI-3 antibody binds to an N-linked carbohydrate on CTL2 and presumably damages the organ of Corti by blocking the transporter function of this molecule. CTL2 mRNA and protein are abundantly expressed in human inner ear. Sera from patients with autoimmune hearing loss bind to guinea pig inner ear with the same pattern as CTL2 antibodies. Thus, CTL2 is a possible target of autoimmune hearing loss in humans.

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Section: Introductionmentioning

confidence: 99%

Identification and Characterization of Choline Transporter-Like Protein 2, an Inner Ear Glycoprotein of 68 and 72 kDa That Is the Target of Antibody-Induced Hearing Loss

Nair¹,

Kozma²,

Hoefling³

et al. 2004

J. Neurosci.

108

133

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“…Recently, the 68-kDa protein was confirmed to be a heat shock protein (HSP) by Billings et al [14]. Several authors [15,16] have suggested that HSP-70 may not be related to autoimmune inner ear diseases. We have observed our patients with unilateral juvenile deafness for at least 15 years, and have noted no symptoms with the exception of unilateral deafness.…”

Section: Discussionmentioning

confidence: 99%

Autoantibodies against inner ear proteins in patients with delayed endolymphatic hydrops and unilateral juvenile deafness

Suzuki

Hanamitsu

Kitanishi

et al. 2006

Acta Oto-Laryngologica

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“…Heat shock protein 70 (HSP70) has been implicated as a possible target Ag in ASNHL (5-7) but its ability to target inner ear-specific pathology is questionable in light of its expression in a variety of noninner ear tissues and its failure to target hearing loss in immunized mice (8). Collagen II has also been proposed as a target Ag in ASNHL (9,10).…”

Section: A Utoimmune Sensorineural Hearing Loss (Asnhl)mentioning

confidence: 99%

Increased Frequencies of Cochlin-Specific T Cells in Patients with Autoimmune Sensorineural Hearing Loss

Baek

Park

Johnson

et al. 2006

The Journal of Immunology

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Autoimmune sensorineural hearing loss (ASNHL) is the most common cause of sudden hearing loss in adults. Although autoimmune etiopathogenic events have long been suspected in ASNHL, inner ear-specific Ags capable of targeting T cell autoreactivity have not been identified in ASNHL. In this study, we show by ELISPOT analysis that compared with normal hearing age- and sex-matched control subjects, ASNHL patients have significantly higher frequencies of circulating T cells producing either IFN-γ (p = 0.0001) or IL-5 (p = 0.03) in response to recombinant human cochlin, the most abundant inner ear protein. In some patients, cochlin responsiveness involved both CD4+ and CD8+ T cells whereas other patients showed cochlin responsiveness confined to CD8+ T cells. ASNHL patients also showed significantly elevated cochlin-specific serum Ab titers compared with both normal hearing age- and sex-matched control subjects and patients with noise- and/or age-related hearing loss (p < 0.05 at all dilutions tested through 1/2048). Our study is the first to show T cell responsiveness to an inner ear-specific protein in ASNHL patients, and implicates cochlin as a prominent target Ag for mediating autoimmune inner ear inflammation and hearing loss.

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Failure of elevated heat shock protein 70 antibodies to alter cochlear function in mice

Cited by 46 publications

References 20 publications

Identification and Characterization of Choline Transporter-Like Protein 2, an Inner Ear Glycoprotein of 68 and 72 kDa That Is the Target of Antibody-Induced Hearing Loss

Identification and Characterization of Choline Transporter-Like Protein 2, an Inner Ear Glycoprotein of 68 and 72 kDa That Is the Target of Antibody-Induced Hearing Loss

Autoantibodies against inner ear proteins in patients with delayed endolymphatic hydrops and unilateral juvenile deafness

Increased Frequencies of Cochlin-Specific T Cells in Patients with Autoimmune Sensorineural Hearing Loss

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