Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides
C. Arturo Solares, … , Gordon B. Hughes, Vincent K. Tuohy
C. Arturo Solares, … , Gordon B. Hughes, Vincent K. Tuohy
Published April 15, 2004
Citation Information: J Clin Invest. 2004;113(8):1210-1217. https://doi.org/10.1172/JCI18195.
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Article Autoimmunity

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

Abstract

Autoimmune sensorineural hearing loss (ASNHL) is characterized typically by bilateral, rapidly progressive hearing loss that responds therapeutically to corticosteroid treatment. Despite its name, data implicating autoimmunity in the etiopathogenesis of ASNHL have been limited, and targeted self-antigens have not been identified. In the current study we show that the inner ear–specific proteins cochlin and β-tectorin are capable of targeting experimental autoimmune hearing loss (EAHL) in mice. Five weeks after immunization of SWXJ mice with either Coch 131–150 or β-tectorin 71–90, auditory brainstem responses (ABR) showed significant hearing loss at all frequencies tested. Flow cytometry analysis showed that each peptide selectively activated CD4+ T cells with a proinflammatory Th1-like phenotype. T cell mediation of EAHL was determined by showing significantly increased ABR thresholds 6 weeks after adoptive transfer of peptide-activated CD4+ T cells into naive SWXJ recipients. Immunocytochemical analysis showed that leukocytic infiltration of inner ear tissues coincided with onset of hearing loss. Our study provides a contemporary mouse model for clarifying our understanding of ASNHL and facilitating the development of novel effective treatments for this clinical entity. Moreover, our data provide experimental confirmation that ASNHL may be a T cell–mediated organ-specific autoimmune disorder of the inner ear.

Authors

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

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Figure 1

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Immunogenicity of cochlin and β-tectorin peptides containing the KXXS MH...
Immunogenicity of cochlin and β-tectorin peptides containing the KXXS MHC class II–binding motif. Female SWXJ mice were immunized with selected peptides containing the KXXS motif and derived from the sequences of inner ear–specific proteins. Eight to 10 days after immunization, LN cells were tested for recall proliferative responses to each peptide immunogen. (A) Coch 131–150 and β-tectorin 71–90 elicited marked dose-response reactivity compared with several other cochlin and β-tectorin peptides that were relatively nonimmunogenic. (B) ELISA analysis of 48-hour culture supernatants showed that recall responses to Coch 131–150 involved the proinflammatory Th1-like phenotype with elevated production of IFN-γ and virtually no production of IL-4. (C) Recall responses to β-tectorin 71–90 showed a similar Th1-like cytokine profile. Error bars show ± SE.