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

Baek, Moo Jin; Park, Hyun Min; Johnson, Justin M.; Altuntas, Cengiz Z.; Jane‐wit, Dan; Jaini, Ritika; Solares, C. Arturo; Thomas, Dawn; Ball, Edward J.; Robertson, Nahid G.; Morton, Cynthia C.; Hughes, Gordon B.; Tuohy, Vincent K.

doi:10.4049/jimmunol.177.6.4203

Cited by 89 publications

(64 citation statements)

References 34 publications

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“…A role for cochlin in host defense is also possible. Loss-of-function mutations in DFNA9 cause increased susceptibility to infection (de Kok et al, 1999;Baek et al, 2006). Furthermore, a number of DFNA9 patients tend to develop cardiovascular disease .…”

Section: Cochlin and Extracellular Matrixmentioning

confidence: 99%

Cochlin in the eye: Functional implications

Picciani

Desai

Guduric-Fuchs

et al. 2007

Progress in Retinal and Eye Research

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Aqueous humor is actively produced in the ciliary epithelium of the anterior chamber and has important functions for the eye. Under normal physiological conditions, the inflow and outflow of the aqueous humor are tightly regulated, but in the pathologic state this balance is lost. Aqueous outflow involves structures of the anterior chamber and experiences most resistance at the level of the trabecular meshwork (TM) that acts as a filter. The modulation of the TM structure regulates the filter and its mechanism remains poorly understood. Proteomic analyses have identified cochlin, a protein of poorly understood function, in the glaucomatous TM but not in healthy control TM from human cadaver eyes. The presence of cochlin has subsequently been confirmed by Western and immunohistochemical analyses. Functionally, cochlin undergoes multimerization induced by shear stress and other changes in the microenvironment. Cochlin along with mucopolysaccharide deposits have been found in the TM of glaucoma patients and in the inner ear of subjects affected by the hearing disorder DNFA9, a late onset, progressive disease that also involves alterations in fluid shear regimes. In vitro, cochlin induces aggregation of primary TM cells suggesting a role in cell adhesion, possibly in mechanosensation, and in modulation of the TM filter.

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Section: Cochlin and Extracellular Matrixmentioning

confidence: 99%

Cochlin in the eye: Functional implications

Picciani

Desai

Guduric-Fuchs

et al. 2007

Progress in Retinal and Eye Research

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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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“…1 He described patients with progressive, bilateral, synchronous or sequential, sensorineural hearing loss who responded to immunosuppressive therapy and who also tested positive for laboratory tests, clinical manifestations and immunological tests prescribed for autoimmune hearing loss. 2 Baek et al 3 demonstrated that patients with AIED have higher frequencies of interferon (IFN)-g-producing T cells and higher serum antibody titers compared with both normal hearing control subjects and patients with noise-and/or age-related hearing loss. Many autoantigens have been implicated as possible causal antigens (Ags) in AIED: heat-shock protein 70, 4,5 collagen II, 6 cochlin 3,7 and, most recently, b-tubulin.…”

Section: Introductionmentioning

confidence: 99%

“…2 Baek et al 3 demonstrated that patients with AIED have higher frequencies of interferon (IFN)-g-producing T cells and higher serum antibody titers compared with both normal hearing control subjects and patients with noise-and/or age-related hearing loss. Many autoantigens have been implicated as possible causal antigens (Ags) in AIED: heat-shock protein 70, 4,5 collagen II, 6 cochlin 3,7 and, most recently, b-tubulin. [8][9][10][11][12][13] Yoo et al [9][10][11] demonstrated that 67 (59%) of 113 patients with Ménière's disease had antibodies to a 55-kDa protein b-tubulin in guinea-pig inner ear extract.…”

Section: Introductionmentioning

confidence: 99%

Experimental autoimmune hearing loss is exacerbated in IL-10-deficient mice and reversed by IL-10 gene transfer

et al. 2011

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Interleukin-10 (IL-10) has an important role in the homeostatic regulation of autoreactive T-cell repertoire. We hypothesized that endogenous IL-10 would regulate the severity of b-tubulin-induced experimental autoimmune hearing loss (EAHL) and that exogenous IL-10 would abrogate it. BALB/c wild-type (WT) and homozygous IL-10-deficient mice (IL-10 À/À ) underwent b-tubulin immunization to develop EAHL; some IL-10 mice with EAHL were administered IL-10 DNA at the peak of EAHL. Auditory brainstem responses were examined over time. EAHL developed progressively in both WT and IL-10 À/À mice. However, the severity of hearing loss in the IL-10 À/À mice was significantly greater than that in WT animals. Moreover, disease severity was associated with a significantly enhanced interferon-g level and loss of hair cells in IL-10 À/À mice. IL-10 administered to EAHL IL-10 À/À mice promoted IL-10 expression. Consequently, hearing significantly improved by protecting hair cells in established EAHL. Importantly, IL-10 treatment suppressed proliferation of antigen-specific T-helper type 1 (Th1) cells, and the suppression can be attributed to inducing IL-10-secreting regulatory T cells that suppressed autoreactive T cells. We demonstrated that the lack of IL-10 exacerbated hearing loss, and the exogenous administration of IL-10 improved hearing. Mechanistically, our results indicate that IL-10 is capable of controlling autoimmune reaction severity by suppressing Th1-type proinflammatory responses and inducing IL-10-secreting regulatory T cells.

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

Cited by 89 publications

References 34 publications

Cochlin in the eye: Functional implications

Cochlin in the eye: Functional implications

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

Experimental autoimmune hearing loss is exacerbated in IL-10-deficient mice and reversed by IL-10 gene transfer

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