Animal Studies

Various experimental approaches have been used to gain insight into the pathogenesis of AIED. None of these studies has yielded an animal model that is definitively analogous to the human condition, however.

Harris and colleagues^6–8 have contributed significant information to the literature pertaining to the processes mediating inflammation in the inner ear. Using a sterile labyrinthitis, Harris and colleagues^6–8 showed in these studies that the inner ear does not represent an immune-privileged site, but can generate a local immune response after either local or systemic immunization of antigen. These immune responses depend on the presence of an intact endolymphatic sac.⁹ Cells that mediate the labyrinthitis enter the scala tympani via the spiral modiolar vein.¹⁰ The ensuing labyrinthitis results in physiologic dysfunction, loss of sensory cells, and, ultimately, fibrosis and osteoneogenesis within the cochlea.¹¹

Although these studies shed light on the mechanisms by which an immune-mediated response can be elicited within the cochlea, they do not specifically address the issues of an autoimmune response. To that end, a model of AIED was proposed in which heterologous (bovine) temporal bone antigen and immune adjuvant were used to immunize guinea pigs systemically.¹² This model showed modest changes in physiologic measures of hearing and cochlear morphology. The model has proven to be difficult to replicate, however. The main contribution of this work pertains to the detection of a specific antibody that binds to a 68-kD bovine inner ear antigen on Western blot analysis. This antibody has been found in the guinea pig model, and in humans with AIED.¹³ The same antibody also binds to the inducible form of bovine (but not human) heat shock protein 70 (HSP-70), although it does not seem that this antibody is primarily directed against HSP-70 in the in vivo setting. The primary antigenic epitope against which this antibody is directed is unknown, and its role in mediating AIED is unclear.

Another approach to understanding the etiology of this disorder was taken by Nair and coworkers.^14–18 They immunized mice with chick and guinea pig inner ear extracts and created monoclonal antibodies against inner ear cells. One particular antibody, KHRI-3, binds to supporting cells of the organ of Corti, creating a characteristic wine-glass staining pattern when observed through immunofluorescence.^15–18 Infusion of KHRI-3 into live guinea pigs produces hearing loss.^15,16 The KHRI-3 antibody also binds to a 68- to 72-kD antigen on a Western blot of inner ear extract.¹⁸ Sera from some humans with AIED strongly stained a 68- to 72-kD inner ear antigen immunoprecipitated from guinea pig inner ear extract with KHRI-3, and these same patient sera stained organ of Corti–supporting cells in a wine-glass pattern.¹⁹ This is strong evidence that KHRI-3 and human antibodies recognize the same inner ear–supporting cell antigen.

More recent data suggest that KHRI-3 targets multiple peptides similar to those present in the highly conserved protein CTL2, which is abundantly expressed in the guinea pig and human inner ear.¹⁴ CTL2 coprecipitates with the protein cochlin, which is one of the most expressed proteins in the inner ear. Cochlin is critical to the structure and function of the inner ear, and mutations are known to cause cochleovestibular pathology. More recent work reveals that cochlin-specific serum antibody titers are significantly elevated in individuals with AIED compared with age-matched controls.²⁰ The same study also implicates T-cell response to this specific protein, supporting cochlin as a possible target antigen susceptible to B-cell and T-cell influence.

A third approach has incorporated the study of animal models of multisystemic, organ-nonspecific autoimmune disease. These mouse models of systemic lupus erythematosus spontaneously develop autoimmune disease; they do not require any experimental manipulation. Various strains have been examined, with the most detailed studies focusing on the MRL-Fas^lpr and C3H-Fas^lpr mice. These strains develop elevations in auditory thresholds, degeneration of the stria vascularis, and antibody deposition within the strial capillaries.^5,21–25 These changes occur in the absence of inflammatory response. The etiology of the observed strial degeneration is unknown. The administration of corticosteroids improves cochlear function in these animals without impeding the development of the morphologic changes.^24,25 Studies have shown that there is similar efficacy in resolution of hearing loss with glucocorticoid and mineralocorticoid administration. These results suggest that the mechanism of reversal of hearing loss occurs as a result of alterations in local ion transport in the cochlea.^25–27

These studies illustrate that immune-mediated and autoimmune pathology can affect the inner ear. The various pathologies observed in these models do not correlate well, however, with the clinical entity known as AIED.

Human Temporal Bone Studies

A few studies have been performed on human temporal bones derived from patients with autoimmune disease, specifically Wegener’s granulomatosis, polyarteritis nodosa, Cogan’s syndrome, and systemic lupus erythematosus.^5,21–23 Morphologic changes show findings consistent with two different pathogenic mechanisms. Some bones show fibrosis and osteoneogenesis within the scalae, findings consistent with the end stages of inflammation, as described earlier. Other bones show changes more consistent with ischemia, including cellular atrophy in the absence of inflammation. In cases of ischemia, the vascular compromise is likely secondary to a nonspecific vasculopathy in which the labyrinthine artery becomes occluded in the absence of vascular inflammation and necrosis associated with vasculitis.