Innate Immune Recognition of Molds and Homology to the Inner Ear Protein, Cochlin, in Patients with Autoimmune Inner Ear Disease

Abstract

Autoimmune Inner Ear Disease (AIED) is characterized by bilateral, fluctuating sensorineural hearing loss with periods of hearing decline triggered by unknown stimuli. Here we examined whether an environmental exposure to mold in these AIED patients is sufficient to generate a pro-inflammatory response that may, in part, explain periods of acute exacerbation of disease. We hypothesized that molds may stimulate an aberrant immune response in these patients as both several Aspergillus species and penecillium share homology with the LCCL domain of the inner ear protein, cochlin. We showed the presence of higher levels of anti-mold IgG in plasma of AIED patients at dilution of 1:256 (p=0.032) and anti-cochlin IgG 1:256 (p=0.0094 and at 1:512 p=0.024) as compared with controls. Exposure of peripheral blood mononuclear cells (PBMC) of AIED patients to mold resulted in an up-regulation of IL-1β mRNA expression, enhanced IL-1β and IL-6 secretion, and generation of IL-17 expressing cells in mold-sensitive AIED patients, suggesting mold acts as a PAMP in a subset of these patients. Naïve B cells secreted IgM when stimulated with conditioned supernatant from AIED patients’ monocytes treated with mold extract. In conclusion, the present studies indicate that fungal exposure can trigger autoimmunity in a subset of susceptible AIED patients.

Toll-like receptor 4 modulates the cochlear immune response to acoustic injury

“…28, 29, 30, 31, 32, 33 These cells have been linked to the production of pro-inflammatory mediators under stress, but their contributions to the cochlear inflammatory response are unclear. Here, we observed a discrepancy in the timing of monocyte infiltration and immune molecule production.…”

“…The organ of Corti lacks professional immune cells, 7, 37 whereas the lateral wall and the basilar membrane are rich in professional and non-professional immune cells. 28, 29, 30, 31, 32, 33 This difference could contribute to the difference in the production of immune mediators between the two tissue types. Although the organ of Corti lacks immune cells, it does have an immune capacity, which has been linked to its resident cells, particularly supporting cells.…”

Cochlin in autoimmune inner ear disease: Is the search for an inner ear autoantigen over?

“…Cross-reactivity between cochlin and fungal and bacterial antigens is an attractive hypothesis [17]. Antibodies to cochlin may also be generated following exposure of inner ear cochlin to the immune system as may occur with inner ear trauma/ surgery, infections.…”

“…AIED patients were found to have significantly higher serum levels of anti-cochlin antibodies compared to healthy controls and patients with noise and/or age-related hearing loss by Baek et al [16]. Further evidence for a humoral immune response to cochlin in AIED has been presented recently by Pathak et al [17]. Cochlin has been shown to share homology with several Aspergillus and Penicillium species.…”

“…Moreover, peripheral mononuclear cells from AIED patients also produced high levels of inflammatory cytokines interleukin-6 (IL-6) and IL-1b upon stimulation with fungal antigens. The authors suggested that autoimmune responses to fungal antigens can contribute to the pathogenesis of AIED [17].…”