Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides
C. Arturo Solares, Andrea E. Edling, Justin M. Johnson, Moo-Jin Baek, Keiko Hirose, Gordon B. Hughes, Vincent K. Tuohy
C. Arturo Solares, Andrea E. Edling, Justin M. Johnson, Moo-Jin Baek, Keiko Hirose, Gordon B. Hughes, Vincent K. Tuohy
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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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Hearing loss occurs in SWXJ mice following adoptive transfer of activate...
Hearing loss occurs in SWXJ mice following adoptive transfer of activated T cells specific for Coch 131–150 or β-tectorin 71–90. Ten days after immunization of female SWXJ mice with either Coch 131–150 or β-tectorin 71–90, LN cells were activated in vitro and transferred (107 cells) into γ-irradiated (4.5 Gy) 8-week-old naive female recipients that had undergone ABR testing 1 day prior to cell transfer. Six weeks later, ABR testing showed significantly increased thresholds and hearing deficit in mice that had received activated T cells specific for either (A) Coch 131–150 (P = 0.018) or (B) β-tectorin 71–90 (P = 0.002). Untreated 14-week-old female SWXJ mice showed no spontaneous hearing loss and are provided in each figure as reference. Eight to 10 days after immunization with either Coch 131–150 or OVA, splenocytes were activated in vitro with 100 μg/ml immunogen, and CD4+ T cells were purified more than 95% by magnetic bead separation. CD4+ T cells (2 × 107) were injected i.v. into γ-irradiated (4.5 Gy) 8-week-old naive female recipients. (C) Six weeks after transfer of purified CD4+ T cells, ABR testing showed significantly increased thresholds and hearing deficit in recipients of Coch 131–150–specific CD4+ T cells when compared with either age- and sex-matched controls (P = 0.001) or with recipients of OVA-specific CD4+ T cells (P = 0.001). Age- and sex-matched control mice and mice transferred with CD4+ T cells specific for OVA showed no differences in ABR thresholds (P = 0.39). Thus, purified CD4+ T cells specific for Coch 131–150 are capable of mediating EAHL. Error bars show ± SE. LNC, LN cells.