COCH5B2 Is a Target Antigen of Anti-Inner Ear Antibodies in Autoimmune Inner Ear Diseases

Boulassel, Mohamed-Rachid; Tomasi, Jean-Paul; Deggouj, Naïma; Gersdorff, Michel

doi:10.1097/00129492-200109000-00009

Cited by 35 publications

(21 citation statements)

References 24 publications

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“…Cochlin has also been implicated in autoimmune hearing loss in humans (Boulassel et al 2001;Baek et al 2006) and in experimental immune-mediated hearing loss in mice (Solares et al 2004). Similarly, CTL2 has been implicated in autoimmune hearing loss (Zeitoun et al 2005) and experimental antibodymediated hearing loss (Nair et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Cochlin Isoforms and Their Interaction with CTL2 (SLC44A2) in the Inner Ear

Kommareddi

Nair

Raphael

et al. 2007

JARO

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Choline transporter-like protein 2 (CTL2) is a multitransmembrane protein expressed on inner ear supporting cells that was discovered as a target of antibody-induced hearing loss. Its function is unknown. A 64 kDa band that consistently co-precipitates with CTL2 from inner ear extracts was identified by mass spectroscopy as cochlin. Cochlin is an abundant inner ear protein expressed as multiple isoforms. Its function is also unknown, but it is suspected to be an extracellular matrix component. Cochlin is mutated in individuals with DFNA9 hearing loss. To investigate the CTL2-cochlin interaction, antibodies were raised to a cochlin-specific peptide. The antibodies identify several cochlin polypeptides on western blots and are specific for cochlin. We show that the heterogeneity of the cochlin isoforms is caused, in part, by in vivo posttranslational modification by N-glycosylation and, in part, caused by alternative splicing. We verified that antibody to CTL2 co-immunoprecipitates cochlin from the inner ear and antibody to cochlin coimmunoprecipitates CTL2. Using cochlear crosssections, we show that CTL2 is more widely distributed than previously described, and its prominent expression on cells facing the scala media suggests a possible role in homeostasis. A prominent but previously unreported ribbon-like pattern of cochlin in the basilar membrane was demonstrated, suggesting an important role for cochlin in the structure of the basilar membrane. CTL2 and cochlin are expressed in close proximity in the inner sulcus, the spiral prominence, vessels, limbus, and spiral ligament. The possible functional significance of CTL2-cochlin interactions remains unknown.

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Section: Discussionmentioning

confidence: 99%

Cochlin Isoforms and Their Interaction with CTL2 (SLC44A2) in the Inner Ear

Kommareddi

Nair

Raphael

et al. 2007

JARO

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“…Moreover, our prior work has shown that immunization of SWXJ mice with the p131-150 peptide derived from mouse cochlin results in a significant loss of hearing that may be passively transferred into naive recipients with peptide-activated CD4 ϩ T cells (21,22). Cochlin antigenicity has also been shown in ASNHL since many patients have elevated serum levels of cochlin Abs (23).…”

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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“…These early studies showed antibody recognition of inner ear tissues in patients suffering from hearing loss. Further characterization of antibodies from patients with SNHL using inner ear tissues from different mammalian species by Western blot analysis showed immune reactivity with several antigens of varied molecular weights [4,[10][11][12][13][14][15][16][17]. Several putative antigens have been identified as markers of AIED, but their role in the pathogenesis as well as relevance in disease-specific diagnosis remains undefined.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, antibodies against microbial pathogen and mammalian HSPs are present in healthy individuals as well as in various diseases, arguing against the significance of HSP antibodies in the serological diagnosis of AIED [18,19]. Other antigens of great potential include the cochlin protein, identified initially by Boulassel et al [12] as a candidate autoantigen for SNHL, myelin protein Po [15], choline transporter-like protein 2 [17] as well as b-tectorin [20,21]. The hypothesis of a pathogenic role for either cochlin or b-tectorin is supported by experimental induction of hearing loss following adoptive transfer of T cell lines specific for these proteins [21].…”

Section: Introductionmentioning

confidence: 99%

Antibody reactivity to heat shock protein 70 and inner ear-specific proteins in patients with idiopathic sensorineural hearing loss

Tebo

Szankasi

Hillman

et al. 2006

Clinical and Experimental Immunology

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SummaryDeafness is attributable to autoimmunity in a subset of adult patients with sensorineural hearing loss (SNHL) of unknown aetiology. To determine the roles of self-antigens in the pathogenesis of idiopathic SNHL, we analysed antibody responses to the inner ear-specific proteins, cochlin and b-tectorin as well as the non-specific heat shock protein 70 (HSP70). Recombinant cochlin and b-tectorin proteins were used in a qualitative Western blot assay for the detection of antigen-specific IgG antibodies in 58 patients with idiopathic SNHL and 28 healthy blood donors. In the same study cohort, we also used a Western blot assay to assess IgG antibody responses to the recombinant human HSP70. Of the 58 patient samples analysed, 19 tested positive to the HSP70, eight to cochlin and one to b-tectorin, giving a prevalence of 33, 14 and 2%, respectively. Only one patient sample was reactive for HSP70, cochlin and b-tectorin, seven of the remaining eight cochlin IgG antibody-positive samples were monospecific. Thus, cochlin-specific antibodies were observed predominantly in HSP70 IgG-negative patients demonstrating an additive value for testing this antibody response in patients with idiopathic SNHL.

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COCH5B2 Is a Target Antigen of Anti-Inner Ear Antibodies in Autoimmune Inner Ear Diseases

Abstract: These findings indicate that the 58-kDa target protein of antibodies in serum samples of patients with autoimmune inner ear diseases is the COCH5B2 protein, a molecule that is highly and specifically expressed in the cochlea and vestibule.

Cited by 35 publications

References 24 publications

Cochlin Isoforms and Their Interaction with CTL2 (SLC44A2) in the Inner Ear

Cochlin Isoforms and Their Interaction with CTL2 (SLC44A2) in the Inner Ear

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

Antibody reactivity to heat shock protein 70 and inner ear-specific proteins in patients with idiopathic sensorineural hearing loss

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