Letter to the Editor

Assessing the role of anti-hsp70 in cochlear impairment

Inner ear damage can be caused by viral infections, genetic mutations, trauma, toxic agents, neoplastic diseases, vascular damage, and immune mechanisms and is responsible for sensorineural hearing loss, a syndrome characterized by the rapid progression of hearing impairment that is frequently nonresponsive to medical treatment. Immune-mediated inner ear disease can be of an autoimmune origin either as an isolated process affecting only the ear, to be considered an organ-specific autoimmune disease (primary), or as part of a systemic autoimmune disorder in approximately 30% of the cases (secondary). The incidence and prevalence of autoimmune inner ear disease is unknown due to the lack of reliable diagnostic tests and of standardized diagnostic process and to the limited access to the site of an autoimmune aggression. Since the rapid administration of steroids and/or other immunosuppressive agents may result in hearing preservation, a great effort is needed in order to find both clinical and immunological features able to identify these patients. Animal models of autoimmune inner ear disease may help in this effort to clarify the largely unknown pathophysiology of the disease and the response to therapy.

The aim of this study was to examine the activities of hASCs (Human Adipose tissue Derived Stem Cells) on experimental autoimmune hearing loss (EAHL) and how human stem cells regenerated mouse cochlea cells. We have restored hearing in 19 years old white female with autoimmune hearing loss with autologous adipose tissue derived stem cells and we wish to understand the mechanism of restoration of hearing in animal model. BALB/c mice underwent to develop EAHL; mice with EAHL were given hASCs intraperitoneally once a week for 6 consecutive weeks. ABR were examined over time. The helper type 1 autoreactive responses and T-reg cells were examined. H&E staining or immunostaining with APC conjugated anti-HLA-ABC antibody were conducted. The organ of Corti, stria vascularis, spira ligament and spiral ganglion in stem cell group are normal. In control group, without receiving stem cells, the organ of Corti is replaced by a single layer of cells, atrophy of stria vascularis. Systemic infusion of hASCs significantly improved hearing function and protected hair cells in established EAHL. The hASCs decreased the proliferation of antigen specific Th1/Th17 cells and induced the production of anti-inflammatory cytokine interleukin10 in splenocytes. They also induced the generation of antigen specific CD4⁺CD25⁺Foxp3⁺T-reg cells. The experiment showed the restoration is due to the paracrine activities of human stem cells, since there are newly regenerated mice spiral ganglion cells, not human mesenchymal stem cells derived tissue given by intraperitoneally.

This article is part of a Special Issue entitled <IEB Kyoto>.

Inner ear damage can be caused by viral infections, trauma, vascular damage, and immune mechanisms, and is responsible for sensorineural hearing loss, a syndrome characterized by rapid progression of hearing impairment that is frequently non-responsive to medical treatment. Immune-mediated inner ear disease can be of autoimmune origin either as an isolated process affecting only the ear, to be considered as an organ-specific autoimmune disease, or as part of a systemic autoimmune disorder in approximately 30% of cases. The incidence and prevalence of autoimmune inner ear disease is unknown due to the lack of reliable diagnostic tests and to the limited access to the site of autoimmune aggression. Since the rapid administration of steroids and/or other immunosuppressive agents may result in hearing preservation, a great effort is needed in order to find both clinical and immunological features able to identify these patients. Animal models of autoimmune inner ear disease may help in this effort to clarify the largely unknown pathophysiology of the disease and the response to therapy.

Autoimmune inner ear disease is described as progressive, bilateral although asymmetric, sensorineural hearing loss and can be improved by immunosuppressive therapy. We showed that the inner ear autoantigen β-tubulin is capable of inducing experimental autoimmune hearing loss (EAHL) in mice. Immunization of BALB/c mice with β-tubulin resulted in hair cell loss and hearing loss, effects that were not seen in animals immunized with control peptide. Moreover, the EAHL model showed that β-tubulin responsiveness involved CD4⁺ T cells producing IFN-γ, and T cell mediation of EAHL was determined by significantly increased auditory brainstem response after adoptive transfer of β-tubulin-activated CD4⁺ T cells into naive BALB/c recipients. The potential mechanisms responsible for the observed pathology of EAHL can be attributed to decreased frequency and impaired suppressive function of regulatory T cells. Our study suggests that EAHL may be a T cell-mediated organ-specific autoimmune disorder of the inner ear.

It is now evident that the inner ear is not an “immunologically privileged” site and may mount an immune response against both foreign and self-antigens. This chapter focuses on sensorineural hearing loss (SNHL). This has been described and termed in different ways: autoimmune SNHL, immunemediated inner ear disease (IMIED), idiopathic progressive bilateral SNHL, sudden SNHL, and idiopathic SNHL, bilateral immune-mediated Menière's disease, autoimmune vestibulo-cochlear disorders, generating a great confusion in the identification of patients and in the evaluation of different studies. The association of IMIED with systemic autoimmune diseases provides evidence that autoimmunity can damage the inner ear, but it does not address organ-specific disease. Antibodies directed against different inner ear antigens have been identified in some patients. However, they are neither diagnostic nor correlate with disease state. In the future, the major goals for research in this field can be the identification of pathogenetically relevant autoantigens, development of a highly specific diagnostic test, and a better knowledge of the immunopathologic mechanisms in an organ as inaccessible as the inner ear.

Autoimmune sensorineural hearing loss (ASNHL) typically produces a bilateral rapidly progressive loss of hearing that may occur suddenly. The diagnosis is made by excluding ototoxicity, systemic disease, and other factors that mimic ASNHL and by showing a therapeutic response to corticosteroid treatment. Although autoantibodies and autoreactive T cells have been implicated in the etiopathogenesis of ASNHL, several central issues remain unresolved, including the relative prominence of B cell or T cell autoimmunity in the initiation and progression of ASNHL, the identity of the putative inner ear self-antigen(s) that target ASNHL, and the development and application of immunosuppressive therapies for preventing the progressive hearing loss which may be profound and require cochlear implantation. In this review, we will examine the seminal human and animal studies that have led to our current views regarding the autoimmune etiopathogenesis of ASNHL. In addition, we will address the need for developing an inner ear-specific mouse model for ASNHL that may define the stages leading to the development of ASNHL and may also provide new diagnostic markers and help develop novel and effective treatments for preventing progressive hearing loss in ASNHL.