Jeffrey P. Harris

Inner ear autoantibodies in patients with rapidly progressive sensorineural hearing loss

Recognition of immune‐mediated sensorineural deafness that responds to immunosuppressive therapy has led to a search for a diagnostic assay to identify inner ear autoantibodies. Without a confirmed diagnosis of autoimmune disease, many patients have undergone inappropriate immunosuppressive treatment or developed irreversible inner ear damage.

Immunology of the Inner Ear: Evidence of Local Antibody Production

Previously we reported the capacity of the inner ear to respond immunologically by demonstrating a rise in perilymph antigen-specific antibody following inner ear sensitization. This rise in perilymph antibody was either the result of increased vascular permeability to serum immunoglobulins or the result of local antibody production. In order to determine if the inner ear was the source of antibody, a serum reference was established by systemically immunizing animals to bovine serum albumin (BSA). With anti-BSA as a serum marker during inner ear immunization with keyhole limpet hemocyanin (KLH), we were able to demonstrate an increase in anti-KLH perilymph antibody levels without a corresponding increase in anti-BSA levels. This suggested that increased vascular permeability was not responsible for the increased perilymph levels and that local production of antibody had occurred within the inner ear. The response was independent of the cerebrospinal fluid.

Intratympanic gentamicin therapy for Ménière's disease: a meta-analysis.

Objective: This study compared the effectiveness of five different techniques of intratympanic gentamicin administration for Ménière’s disease. Data Sources: A MEDLINE search of the English language literature from 1978 to 2002 was performed using the key words “intratympanic,” “gentamicin,” “therapy,” “Ménière’s,” and “disease.” Study Selection: Inclusion criteria to select articles for meta-analysis were clear description of gentamicin delivery technique, clearly reported vertigo control results, and report of hearing loss posttreatment. Seven studies (n = 218) describing the multiple daily dosing technique (delivery three times per day for =4 d), two studies (n = 84) describing the weekly dosing technique (weekly injections for four total doses), eight studies (n = 253) of the low-dose technique (one to two injections with retreatment for recurrent vertigo), four studies (n =156) of continuous microcatheter delivery, and six studies (n =269) of the titration technique (daily or weekly doses until onset of vestibular symptoms, change in vertigo, or hearing loss) were entered into the model. Data Extraction: Vertigo control results were stratified into complete, substantial, or poor control. Hearing results were separated by profound, partial, or no hearing loss. Individuals undergoing caloric testing were separated by degree of vestibular ablation (complete versus partial) and analyzed for vertigo control (n = 301) and hearing loss (n = 333) after treatment. Data Synthesis: Comparisons between the rates of complete vertigo control, effective vertigo control (complete plus substantial control), overall hearing loss (partial plus profound), and profound hearing loss by delivery method were based on a parametric empirical Bayes analysis using binomial generalized linear models and backward variable selection (joining). Relative risk for vertigo control and hearing loss by partial or complete ablation was examined study by study using residual maximum likelihood to carry out a parametric empirical Bayes analysis. Conclusion: The titration method of gentamicin delivery demonstrated significantly better complete (81.7%, p = 0.001) and effective (96.3%, p < 0.05) vertigo control compared with other methods. The low-dose method of delivery demonstrated significantly worse complete vertigo control (66.7%, p < 0.001) and trends toward worse effective vertigo control (86.8%, p = 0.05) compared with other methods. The weekly method of delivery trends toward less overall hearing loss (13.1%, p = 0.08), and the multiple daily method demonstrated significantly more overall hearing loss (34.7%, p < 0.01) compared with other groups. No significant difference in profound hearing loss was found between groups. Degree of vestibular ablation after gentamicin therapy is not significantly correlated with the resulting vertigo control or hearing loss status.

The endolymphatic sac: its importance in inner ear immune responses†

The present study investigated the role of the endolymphatic sac in the generation of inner ear immune responses. The inner ear immune response to KLH antigen challenge was examined in animals whose endolymphatic sac was surgically obliterated and in a sham operated control group. In primary inner ear immune responses, endolymphatic sac obliteration resulted in reduced serum anti-KLH levels, compared to controls, while no difference was observed for perilymph anti-KLH levels. In secondary inner ear immune responses, endolymphatic sac obliteration resulted in significantly suppressed perilymph anti-KLH levels and greatly reduced cellular infiltration within the cochlea. In contrast, the sham operated animals showed a greatly increased number of plasma cells and lymphocytes in the perisaccular space and the endolymphatic sac lumen. These findings suggested that the endolymphatic sac must play an integral role in the generation of both systemic and local antibody responses following inner ear antigen challenge. The endolymphatic sac, like the gut, appears to have an immunological as well as a resorptive role in the host.

Evidence Linking the 68 Kilodalton Antigen Identified in Progressive Sensorineural Hearing loss Patient Sera with Heat Shock Protein 70

Immunoblotting against bovine inner ear extracts has previously identified a 68 kd antigen reactive with 22% to 58% of sera of patients with rapidly progressive sensorineural hearing loss (PSNHL) of suspected autoimmune causation. Efforts to purify and characterize this diagnostic antigen suggest that it is ubiquitous rather than inner ear-specific, and may represent the highly inducible heat shock protein (hsp) 70. The antigens identified by PSNHL sera and anti-hsp 70 monoclonal antibodies copurify on ion exchange and adenosine triphosphate affinity chromatography, and comigrate on one- and two-dimensional gel electrophoresis. Additionally, immunoblotting with positive patient sera shows dramatically increased expression of the 68 kd antigen by bovine kidney cells following heat shock in culture. Reactivity with stress proteins of various classes has been reported in a number of autoimmune diseases; however, anti—hsp 70 appears uniquely associated with ulcerative colitis and PSNHL.

Immunology of the inner ear: Response of the inner ear to antigen challenge:

The relationship of the inner ear to host immunity and the immunoresponsiveness of the inner ear to antigen challenge were investigated. A radioimmunoassay was used to quantitate antibody titers to keyhole-limpet hemocyanin generated in the serum, perilymph, and CSF of guinea pigs following systemic or inner ear immunizations. The results of these experiments demonstrate (1) the blood-labyrinth barrier is analogous to the blood-brain barrier with respect to immunoglobulin equilibrium, (2) the inner ear is capable of responding to antigen challenge, and (3) the inner ear is an effective route for systemic immunization.

Assessment of serum antibodies in patients with rapidly progressive sensorineural hearing loss and Menière's disease.

The immunoreactivity of sera from patients with rapidly progressive sensorineural hearing loss (SNHL) or Menieres disease with bovine inner ear material was determined using the Western blot technique. Patients with other otologic conditions, autoimmune disorders, or arthritic disorders and age‐matched randomly chosen patients with no hearing complaints served as controls. Twenty‐two percent of the patients with bilateral rapidly progressive SNHL and 30% of the patients with Menieres disease had antibodies that reacted with a 68 kd antigen in the inner ear material. In the control groups, the incidence of reactivity was 5.0% (P<.001).

Tumor Necrosis Factor-α, an Initiator, and Etanercept, an Inhibitor of Cochlear Inflammation†‡

Objectives/Hypothesis The inner ear rapidly mounts an immune response that can lead to cochlear degeneration and permanent hearing loss. Identification of proinflammatory cytokine expression during the initiation of the response should lead to rational therapeutic strategies that block the response, reducing damaging sequelae.

Experimental autoimmune sensorineural hearing loss

Alterations in host immunity result in a number of disorders affecting multiple organ systems, including the inner ear. The mechanism of injury is poorly understood; as such, this study investigated whether an experimental model of autoimmune sensorineural hearing loss (ASNHL) could be established. Animals were immunized with heterologous inner ear antigen and then evaluated for evidence of evolving inner ear autoimmunity. These animals uniformly developed antibodies to inner ear antigen in their sera and perilymph and 12 of 38 ears showed significant increases in action potential thresholds. Histopathological lesions consisted of loss of cochlear neurons, perivascular plasma cell infiltrates, edema, and extravasation of erythrocytes. These findings are characteristic of autoimmune injury and suggest the establishment of an experimental model of ASNHL in which to further investigate this clinical disorder.

Fundamental immune mechanisms of the brain and inner ear

Because of the blood-brain and blood-labyrinthine barriers, the brain and inner ear were once thought to be immunoprivileged sites. Although these barriers provide protection from inflammatory damage to the delicate structures of the organs, both sites have since been shown to be capable of active immune responses when appropriately stimulated. In the inner ear, perisacular tissue around the endolymphatic sac hosts resident lymphocytes and serves as a site of immunosurveillance. Lymphocytes also enter the inner ear from the circulation, and in the cochlea this occurs via the spiral modiolar vein. Immune responses can protect the labyrinth from infection, but they can also cause bystander injury. Moreover, the cochlea can itself become the target of immune responses that damage hearing. Such autoimmune sensorineural hearing loss can be site specific, with the primary manifestation of the disorder being hearing loss and dysequilibrium. Some of these cases can be diagnosed by antibody or lymphocyte responses to inner ear antigens. Alternately, systemic autoimmune disorders can result in inner ear dysfunction as part of a broader spectrum of disease. Both forms of immune-mediated inner ear dysfunction may respond to immunosuppressive therapies, including steroids, cytotoxic agents, and plasmapheresis.