Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides

Solares, C. Arturo; Edling, Andrea E.; Johnson, Justin M.; Baek, Moo-Jin; Hirose, Keiko; Hughes, Gordon B.; Tuohy, Vincent K.

doi:10.1172/jci200418195

Cited by 66 publications

(40 citation statements)

References 50 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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“…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%

Section: Introductionmentioning

confidence: 99%

“…7,8,14,15 Transfer studies indicate that Ag-specific CD4 + T cells with a T-helper type 1 (Th1)-like phenotype mediate the development of EAHL by showing significantly increased auditory brain stem thresholds after adoptive transfer of autoantigen-activated CD4 + T cells into naïve recipients. 7,8,16,17 Recently, accumulating evidence has suggested that regulatory T (Treg) cells have a critical role in maintaining peripheral homeostasis and establishing controlled immune responses. [18][19][20] There are two classes of Treg cells within CD4 + T cells: (1) the naturally occurring, thymus-selected CD4 + CD25 + Foxp3 + Treg cells, 19 which develop in the thymus and are present in normal naïve mice and healthy individuals from birth; and (2) the inducible Treg cells including Tr1 and Th3 cells, which are generated in the periphery under various tolerogenic conditions.…”

Section: Introductionmentioning

confidence: 99%

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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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“…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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Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides

Cited by 66 publications

References 50 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

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

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

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