The diagnosis of idiopathic sudden sensorineural hearing loss (ISSNHL) still heavily relies on clinical evaluation in many cases, with only limited markers available to assist and confirm the diagnosis. The immunopathological mechanisms underlying this condition remain elusive. Due to the impracticality of biopsying the inner ear, which would result in its destruction, alternative investigative methods have been explored, such as MRI studies utilizing intratympanic gadolinium 20. However, the ultimate pathophysiological or immunopathological mechanism has yet to be fully elucidated.
In recent years, several articles have proposed the correlation and potential involvement of certain interleukins as immunopathological mechanisms in this condition 21. However, currently, there are no cytokines identified to definitively support the diagnosis of this disease. The findings across published studies remain controversial. (Table 3)
Table 3
Previous research on the correlation and potential involvement of interleukins in immune mediated inner ear disease
Study | Molecules | Results |
Amor Dorado JC et al | HLA DRA1∗04 | Marker of autoimmune middle ear disease, worse prognosis associated. |
Psillas G. et al | HLA DRA1∗04 | favorable response to treatment (non statistically significant) |
SW Gorthey et al | IL-6 | Elevated IL6 levels are associated with a worse response to treatment. |
Moleon MDC et al | IL-1β, CCL3, CCL4, CXCL1, CCL22, CCL8 | Cytokine levels do not allow distinguishing between late-onset or early-onset Meniere's disease. |
There have been studies examining the association between HLA and IMIED, although they are limited in number 22. Certain HLA types, such as HLA DRB104, have been identified as potential markers for autoimmune inner ear diseases 23. HLA DRB104 has demonstrated prognostic significance in patients experiencing sudden sensorineural hearing loss, being linked to a poorer treatment outcome.
However, in the study conducted by Psillas et al. 24, was examined the correlation between HLA and response to corticosteroid treatment. In this instance, a favorable response to treatment was observed, although the outcome did not reach statistical significance.
Gorthey et al. conducted an analysis investigating the correlation between IL-6 levels and the efficacy of corticosteroid treatment in individuals with autoimmune-related hearing loss. Their findings demonstrated that heightened IL-6 levels corresponded with a reduced response to treatment, offering significant insights for timely therapeutic interventions in such patients 12. In our current study, IL-6 levels were observed to be higher in controls compared to patients. However, it is noteworthy that all patients exhibited a positive response to treatment, as the diagnosis was established in the early stages, and positive treatment response was a criterion for diagnosis.
In 2020, Moleon et al. employed multiplex technology to quantify various cytokine levels in Meniere's disease, with the objective of delineating the cytokine profile based on the age of disease onset. The study did not yield statistically significant differences overall. However, when stratifying by gender, notable distinctions emerged: levels of ILB were found to be higher in men than in women during early onset, whereas levels of CXCL1 were higher in women compared to men.4
In the present study, elevated levels of IL-10 were observed in individuals with autoimmune hearing loss. Moreover, given the favorable response to corticosteroid therapy exhibited by the study participants, this biomarker may serve as a predictive indicator for treatment response. IL-10 serves as a crucial anti-inflammatory cytokine with significant effects on antigen-presenting cells. It operates by impeding the synthesis of proinflammatory cytokines such as IL1-β, TNF-α, and IL-6, along with Th2 cell-derived cytokines like IL-4 and IL-5. Additionally, IL-10 exerts a direct regulatory influence on T cell differentiation by suppressing IL-2 and IFN-γ.25–28
This observation offers a potential explanation for the elevated IL-10 levels in our patients alongside the comparatively lower levels of other analyzed cytokines in comparison to control subjects. Likewise, IL-10 also demonstrates higher expression in patients with idiopathic ulcerative colitis during remission. This upregulation is attributed to its anti-inflammatory properties within the intestine, where it acts to inhibit antigen presentation and the subsequent release of proinflammatory cytokines.27. In this context, the administration of recombinant IL-10 and gelatin microspheres incorporating IL-10 in ulcerative colitis has been suggested.26.
Based on this finding, we propose a novel treatment strategy with IL-10 (transtympanic or systemically administrated) for corticosteroids non-responder IMIED patients.
Since the inner ear lacks a lymphatic system the endolymphatic sac could potentially function as a mucosa-associated lymphoid tissue (MALT) organ within the inner ear 10, transtympanic injection of IL-10 may represent a new therapeutic strategy in IMIED patients.
Recently, Xinyuan Tan et al.29 delve into the significance of the interplay between inflammatory and anti-inflammatory cytokines in the pathogenesis of sudden hearing loss, as well as our proposed theory on autoimmune hearing loss. This elucidates the favorable response to corticosteroid treatment, attributed to their anti-inflammatory properties.
The findings from the experimental study conducted in mice by Zhou et al. provide support for the theory behind this novel treatment approach. Their results indicate that a deficiency in IL-10 worsens hearing loss, while the exogenous administration of IL-10 enhances hearing function. These outcomes underscore the pivotal role of IL-10 as a key regulator of inflammation in vivo. 30
Due to the extended duration of IMIED, which may lead to hearing fluctuations unresponsive to corticosteroids, there's a need to explore the role of cytokines in later stages. This prompts our ongoing research into the rationale behind IL-10 treatment for non-responders.