Sensorineural hearing loss (SNHL) is a common otologic problem that typically is not amenable to medical intervention. Potentially reversible SNHL can be divided into two sub-groups: (1) Autoimmune Inner Ear Disease (AIED) and (2) sudden SNHL (SSNHL). Timely administration of glucocorticoids in these two conditions may result in hearing preservation. While SSNHL is usually an isolated, unilateral and single event, patients with AIED usually experience multiple episodes of rapid hearing loss in both ears. This disorder can be an isolated process affecting the ear only, or it may be part of a systemic autoimmune disorder in approximately 30% of those afflicted 
. Further characterization of AIED has been hampered by limited access to the inner ear, and by the absence of a reliable biomarker that distinguishes AIED from patients with other forms of SNHL 
. Thus, the incidence and prevalence of AIED is unknown, however an initial response to glucocorticoids may assist to define this clinical disorder 
. In patients with AIED, hearing preservation with glucocorticoids is often only maintained short term 
. Of the 60 
to 70% 
of patients who are initially steroid responsive, only 14% remain so after 34 months 
. It is unknown whether these patients who initially respond, and then become refractory to steroid therapy, have undergone a change in immune response that precludes continued response to corticosteroids. Moreover, on a molecular level, it is unknown how steroids induce a clinical response.
Medical therapy for AIED patients refractory to corticosteroids is limited. Methotrexate has been shown to be beneficial in several small series; however, in a large prospective trial, methotrexate was comparable to placebo in maintaining hearing in AIED patients 
. In animals, suppression of TNFα by Etanercept was helpful in treating AIED, however, a recent human clinical trial failed to confirm this 
. When medical therapy fails to restore hearing, and hearing aids are no longer beneficial, cochlear implantation is often used to restore hearing in patients with AIED who develop bilateral, severe to profound SNHL. Identification of a more effective medical therapy for AIED is contingent on developing a better understanding of the mechanism(s) that cause this disorder.
A much more common entity treated with corticosteroid therapy is sudden sensorineural hearing loss (SSNHL). A fraction of patients with SSNHL are considered to have AIED 
, as the majority of these patients are thought to have either viral or vascular pathophysiologic causes of their disease. Nonetheless, therapy for all patients with a sudden decline in hearing is similar and usually treatment entails the prompt use of corticosteroids. Evidence of an autoimmune mechanisms being important in SSNHL has been reported, and includes an increased prevalence of antibodies specific for a HSP70 (a heat shock protein), commonly found in the blood of a cohort of SSNHL patients 
, and an increased frequency of the HLA-DRB1*04 allele in SSNHL, which is associated with a poor response to glucocorticoids 
. HLA-DRB1*04 has also been associated with other autoimmune disorders such as autoimmune thyroiditis and rheumatoid arthritis 
Many autoantibodies to cochlear and other self-antigens in human serum have been shown to be enriched in AIED patients. Presumptive markers for AIED that has been identified include autoantibodies to: ANA (18–43%), HSP70 (22–89%) and others (recently reviewed 
). However, no single antibody is present in all patients with this disease 
. An increased prevalence of several autoantibodies have correlated with glucocorticoid-responsive AIED, including antibodies to both HSP70 
and CTCL2, recently suggested to be a biomarker for this disease 
. HSP 70 garnered a great deal of attention because of its high specificity for AIED 
; however its pathogenic role is controversial 
, since mice immunized with bovine HSP 70 failed to experience hearing loss 
Animal models of AIED have demonstrated that the inner ear is accessible from the peripheral circulation and no strict anatomic barrier exists within the cochlea. Immunocytes have been shown to traffic into the inner ear from the peripheral circulation 
, and radiolabeled lymphocytes have been shown to enter the scala tympani of the cochlea 
. Furthermore, T cells from the systemic circulation have been shown to proliferate in the endolymphatic sac, and perilymph proteins of the cochlea can activate immunocytes in the endolymphatic sac 
. These passive transfer experiments suggest that there is no anatomic barrier to trafficking lymphocytes from the systemic circulation into the inner ear.
Recent animal studies suggest that macrophages (MФ), which are part of the innate immune response, can augment adaptive T-cell responses made in AIED 
. In these experiments, re-exposure to KLH antigen in the presence of systemic lipopolysaccharide (LPS) caused upregulation of Interleukin-1β (IL-1β) expression in the cochlea, leukocyte entry into the cochlea, and subsequent hearing loss. As anticipated, LPS induced Toll Like Receptor 4 (TLR4) signaling and augmented IL-1β expression and was associated with hearing loss. These experiments suggest that the innate immune system may participate in the development of AIED 
. In addition, the production of IL-1β by MФ, likely causes T-cell polarization to Th1-like response that might perpetuate AIED. A critical role of pro-inflammatory CD4+, Th1-like T-cells has been shown in the cochlin peptide-murine model 
. Interferon-gamma (IFNγ)-producing, Th1-like T cells have been identified in the peripheral blood of AIED patients 
. Modulation of interleukin-1β levels has resulted in IFN-γ expression by T-cells in other autoimmune disorders. In murine autoimmune encephalomyelitis, blockade of the IL-1 receptor antagonist (IL-1RA) permits soluble IL-1β to bind the IL-1 receptor type 1 (IL-1R1), augmenting the development of clinical encephalomyelitis and T-cells expression of IFN-γ 
. Thus, the absence of IL-RA expression, or other molecules that oppose the IL-1β inflammatory cascade, during an immune response, can promote the development of autoimmune disease, including AIED.