IL-10/HMOX1 signaling modulates cochlear inflammation via negative regulation of MCP-1/CCL2 expression in cochlear fibrocytes.

Cochlear inflammatory diseases, such as tympanogenic labyrinthitis, are associated with acquired sensorineural hearing loss. Although otitis media is extremely frequent in children, tympanogenic labyrinthitis is not commonly observed, which suggests the existence of a potent anti-inflammatory mechanism modulating cochlear inflammation. In this study, we aimed to determine the molecular mechanism involved in cochlear protection from inflammation-mediated tissue damage, focusing on IL-10 and hemoxygenase-1 (HMOX1) signaling. We demonstrated that IL-10Rs are expressed in the cochlear lateral wall of mice and rats, particularly in the spiral ligament fibrocytes (SLFs). The rat SLF cell line was found to inhibit nontypeable Haemophilus influenzae (NTHi)-induced upregulation of monocyte chemotactic protein-1 (MCP-1; CCL2) in response to IL-10. This inhibition was suppressed by silencing IL-10R1 and was mimicked by cobalt Protoporphyrin IX and CO-releasing molecule-2. In addition, IL-10 appeared to suppress monocyte recruitment through reduction of NTHi-induced rat SLF cell line-derived chemoattractants. Silencing of HMOX1 was found to attenuate the inhibitory effect of IL-10 on NTHi-induced MCP-1/CCL2 upregulation. Chromatin immunoprecipitation assays showed that IL-10 inhibits NTHi-induced binding of p65 NF-κB to the distal motif in the promoter region of MCP-1/CCL2, resulting in suppression of NTHi-induced NF-κB activation. Furthermore, IL-10 deficiency appeared to significantly affect cochlear inflammation induced by intratympanic injections of NTHi. Taken together, our results suggest that IL-10/HMOX1 signaling is involved in modulation of cochlear inflammation through inhibition of MCP-1/CCL2 regulation in SLFs, implying a therapeutic potential for a CO-based approach for inflammation-associated cochlear diseases.

The diagnosis of autoimmune inner ear disease: evidence and critical pitfalls.

The purpose of this paper is to review the current diagnostic work-up for patients with suspected Autoimmune Inner Ear Disease (AIED). AIED is a rare disease accounting for less than 1% of all cases of hearing impairment or dizziness, characterized by a rapidly progressive, often fluctuating, bilateral SNHL over a period of weeks to months. While specific tests for autoimmunity to the inner ear would be valuable, at the time of writing, there are none that are both commercially available and proven to be useful. Thus far, most of the identified antigens lack a clear association with localized inner ear pathology and the diagnosis of AIED is based either on clinical criteria and/or on a positive response to steroids. For clinical practice, we recommend an antigen-non-specific test battery including blood test for autoimmune disorders and for conditions that resemble autoimmune disorders. Nevertheless, if financial resources are limited, a very restricted work-up study may have a similar efficiency.

Sjögren's syndrome: an autoimmune disorder with otolaryngological involvement.

Sjorgen's syndrome (SS) is an autoimmune exocrinopathy characterized by lymphocyte infiltration of salivary and lacrimal glands that leads to progressive xerostomia and xerophtalmia. One-third of patients suffer of systemic manifestations including arthritis, fever, fatigue and mucosal dryness whereas those with major salivary involvement show an increased risk to develop low-grade non-Hpdgkin lymphomas. In addition, a minority of patients show symptoms related to progressive hearing loss whose pathogenesis remains undefined. Both deposition of autoantibodies to antigens of the inner-ear structures and infiltration by autoreactive T-cells have been implicated in its pathogenesis. In this context, high levels of autoantibodies to both cardiolipin and M3 muscarinic receprtors as well as to ciliar epitopes of the cochlear cells have been recently described. Here we review recent advances on the pathodgenesis of SS with a particular focus to otolaryngological manifestations.

[Obliterated cochlea in Cogan's syndrome -- implications for cochlear implant surgery]. / Obliteration der Cochlea beim Cogan-Syndrom -- Bedeutung für die Cochlear-Implant-Chirurgie.

BACKGROUND: Acute, often bilateral deafness in Cogan's syndrome or other autoimmune diseases is caused by autoimmune mediated inflammatory attack on the membranous labyrinth. Auditory rehabilitation in case of bilateral deafness can be achieved by cochlear implant surgery. METHODS: A retrospective analysis of all patients suffering from Cogan's syndrome that had received a cochlear implant, was carried out. RESULTS: 6 of 295 adult patients (2.6 %) that had received a cochlear implant, had become deaf due to Cogan's syndrome. Partial obliteration or ossifikation was encountered in all cases and influenced surgical procedure. In one case a fibrous obliteration of the scala tympani was found 8 weeks after acute onset of complete deafness. CONCLUSIONS: The course of obliteration is unknown. With regard to our results a fibrous obliteration may occur as early as 8 weeks after complete deafness. This has to be considered in counseling of patients. Only early cochlear implant surgery facilitates best possible rehabilitation results.

Etanercept therapy for immune-mediated cochleovestibular disorders: preliminary results in a pilot study.

OBJECTIVE: Immune-mediated cochleovestibular disorders (IMCVDs) continue to present a management challenge to the otolaryngologist. Antirheumatic agents, commonly used for IMCVDs, are associated with variable efficacy and sometimes with serious side effects. The authors describe the preliminary result of their experience in patients with IMCVDs who have been treated with etanercept, a tumor necrosis factor alpha receptor blocker, recently approved by the United States Food and Drug Administration for the treatment of rheumatoid arthritis. STUDY DESIGN: Retrospective case series. SETTING: Tertiary care hospital. PATIENTS: Twelve patients suspected of having IMCVD who did not respond to conventional therapies or experienced side effects of the conventional therapies. INTERVENTION: Etanercept 25 mg by subcutaneous injection twice per week. MAIN OUTCOME MEASURES: The main outcome measurement was assessment of hearing change by air conduction pure tone audiograms and/or word discrimination. When present, vertigo, tinnitus, and aural fullness were assessed as well. RESULTS: Follow-up of more than 5 months was available for all patients (range, 5-12 months). Eleven (92%) of 12 patients had improvement or stabilization of hearing and tinnitus, seven (88%) of eight patients who had vertigo and eight (89%) of nine patients who had aural fullness had resolution or significant improvement of their symptoms. The benefit persisted until the last visit (5-12 months after etanercept was begun). The condition of one patient improved dramatically at first but deteriorated after 5 months. The patient's hearing was rescued and stabilized with the addition of leflunomide to etanercept. Similarly, three other patients required a second antirheumatic agent to stabilize their hearing. There were no significant side effects from the etanercept therapy. CONCLUSIONS: Our limited data suggest that etanercept therapy is safe and may be efficacious in carefully selected patients with IMCVDs, at least on a short-term basis. These preliminary efficacy and safety results appear encouraging enough to warrant further follow-up and studies for better determination of the potential clinical utility of etanercept for IMCVDs.

Effects of immunosuppression on the development of cochlear disease in the MRL-Fas(lpr) mouse.

OBJECTIVES: The MRL-Fas(lpr) mouse, an animal that spontaneously develops multisystemic autoimmune disease, has been proposed as model of immune-mediated inner ear disease. Previous studies revealed that this mouse manifested elevated auditory brainstem response thresholds, hydropic degeneration of strial cells, and antibody deposition within strial capillaries. As the etiology of the observed strial disease may be immune, genetic, or uremic, a study was designed to attempt to delineate between these possible etiologic factors. STUDY DESIGN: Prospective, controlled animal study. METHODS: Dexamethasone, which is known to suppress autoantibody production and glomerulonephritis in these animals, was administered systemically on a daily basis to experimental animals, beginning at 6 weeks of age. Control animals received no treatment. Animals were allowed to age, with control animals predictably manifesting systemic disease at 20 weeks of age, at which point all animals were sacrificed. RESULTS: Animals receiving dexamethasone treatment manifested a significant reduction in serum immunoglobulin levels, lymphoid hyperplasia, and a significant improvement in the level of renal function. However, morphologic analysis revealed a persistence of strial disease despite the elimination of strial antibody deposition. CONCLUSION: The results of this experiment support the hypothesis that genetic mechanisms may be responsible for the observed strial disease. Further studies are under way to confirm these findings.

Changes in immunostaining of inner ears after antigen challenge into the scala tympani.

To study the mechanisms of immune responses and immune injuries in inner ears, labyrinthitis was induced by inoculation of keyhole limpet hemocyanin (KLH) into the scala tympani of systemically sensitized guinea pigs. Inner ears were then immunostained for KLH, immunoglobulin G (IgG), albumin, connexin26 (Cx26), and sodium-potassium adenosine triphosphate (Na,K-ATPase). Inflammatory cells containing KLH were observed in the scala tympani and in the collecting venule of the spiral modiolar vein (SMV). Spiral ligament, spiral limbus, and blood vessels including the SMV were diffusely positive for IgG and albumin. Immunoreactivity for Cx26 and Na,K-ATPase was decreased compared with the normal ears in the fibrocytes of the spiral ligament. These results suggest that inflammatory cells and blood constituents could extravasate into the cochlea from blood vessels and that fibrocyte damage in the spiral ligament could cause cochlear dysfunction.

Antibodies to glycosphingolipid antigens in patients with immune-mediated cochleovestibular disorders.

HYPOTHESIS: To determine the presence of antibodies against the glycosphingolipid antigen sulfated glucuronic lactosominyl paragloboside (SGLPG) in the sera of patients suspected of immune-mediated cochleovestibular disorders (IMCVD). BACKGROUND: Glycospingolipids are molecules present on the surface of normal nerve cells and are considered antigenic. Previous studies have isolated these antigens in vestibular neuroepithelia, cochleovestibular nerves and endolymphatic sacs. METHODS: The sera of 22 patients suspected of IMCVD were tested for antibodies against the antigen SGLPG. Thin-layer chromatography-immunostaining method was used. RESULTS: Antibody titers were elevated in 63.6% of patients tested. Statistical significance (p < 0.0001) was achieved since reactivity was seen in only 7% of 43 age-matched healthy controls. CONCLUSIONS: Antibodies to SGLPG antigens are present in some patients with IMCVD. Because SGLPD antigens have been previously isolated in the inner ear and the cochleovestibular nerve, these structures can potentially become targets for anti-SGLPG antibodies.

Methotrexate management of immune-mediated cochleovestibular disorders.

Immune-mediated cochleovestibular disorders continue to present a management challenge to the otolaryngologist. The traditional treatment of these disorders, corticosteroids and/or cyclophosphamide (Cytoxan), has been associated with serious and occasionally life-threatening complications. In this study we report our experience in treating 25 patients with immune-mediated cochleovestibular disorders with methotrexate, a less toxic immunosuppressive agent that has been used extensively in patients with rheumatoid arthritis. Mean duration of treatment was 12.9 months, and adverse reactions were acceptable and reversible. Hearing improved in 69.6% of patients, and vestibular symptoms subsided or improved in 80% of patients. The results of this study suggest that methotrexate treatment is effective in a substantial number of patients with immune-mediated cochleovestibular disorders and has acceptable adverse reactions. A prospective, randomized study is needed to compare the efficacy of methotrexate with that of other immunosuppressive agents.

Altered immunoregulations in otosclerosis: presence of autoantibodies in otosclerotic sera samples.

A current concept of the etiopathogenesis of otosclerosis is an immune response. The purpose of this study was to determine if autoantibodies were present in sera samples from patients with known otosclerosis. Organ non-specific total antinuclear antibodies (tANA) were determined in 98 sera samples by the immunofluorescent method in 47.9% of otosclerotic patients versus 5% in controls. The most frequent specific antinuclear antibody was antibody to native deoxyribonucleinic acid and antibody to ribonucleoprotein. Tissue-specific antibodies to native-collagen type II molecule (ACA II) were determined by counter-immunoelectrophoresis in the same sera samples and were detected in 54% versus none in healthy sera. There was no correlation between the presence of these two autoantibodies. In patients with tANA present, a statistically significant depletion of cochlear function was noted. The presence of ACA II showed no connection with hearing loss. The present study showed some alteration in immunoregulatory markers in otosclerotic patients and the possibility that ANA may play a role in the pathogenesis of otosclerosis-induced perceptive deafness.

[Primary sclerosing cholangitis and autoimmune cochlear deafness: a new syndrome?]. / Cholangite sclérosante primitive et surdité endocochléaire auto-immune: nouveau syndrome?

Association of autoimmune cochlear hearing loss with primary sclerosing cholangitis is reported in two patients. Endocochlear sensorineural hearing loss was associated with the presence of anti-cochlear antibodies in the serum directed against the walls of vessels in the stria vascularis. The hearing loss appeared at the same time or shortly after the diagnosis of cholangitis. This association, which has never been described, may reinforce the theory of the role of immunologic factors in the pathogenesis of primary sclerosing cholangitis, possibly linked to or initiated by vasculitis.

[Application of an immunofluorescent technique on a guinea pig cochlear section for the study of endocochlear pathologies]. / Application d'une technique d'immunofluorescence sur coupe de cochlée de cobaye à l'étude de pathologies endocochléaires.

Experimental evidence suggests the existence of autoimmune mechanisms in the appearance of cochlear pathologies. Following a recall of studies made previously by different authors, we will present an immunofluorescent technique on a guinea pig cochlear section applied to the study of 22 serums of patients with endocochlear pathologies. The goal of this test is to identify the patients with immunologic disorders in order to adapt treatment using immunosuppressive medication. The findings show the existence of antibodies directed against the cell nuclei, or against the endothelium of the cochlear vessels, or against the endosteum of the inner ear. The importance of these findings has yet to be established.