Hearing Restoration and the Stria Vascularis: Evidence for the Role of the Immune System in Hearing Restoration

Abstract

Purpose of review:

This article reviews the current literature regarding the pathogenesis of immune-mediated sensorineural hearing loss, utilizes previously published single-nucleus transcriptional profiles to characterize cytokine and cytokine receptor expression in the adult stria vascularis (SV) cell types to support immune system interaction with the SV, and reviews the current literature on immunomodulatory agents currently being used for hearing-restoration treatment.

Recent findings:

The literature review highlights recent studies that elucidate many cytokines and immune markers which have been linked to various immune-mediated disease processes that have been observed with sensorineural hearing loss within the stria vascularis and highlights recent publications studying therapeutic targets for these pathways.

Summary:

This review highlights the current literature regarding the pathogenesis of immune-mediated hearing loss. The role of cochlear structures in human temporal bones from patients with immune-mediated sensorineural hearing loss are highlighted, and we review cytokine signaling pathways relevant to immune-mediated sensorineural hearing loss and localize genes encoding both cytokine and cytokine receptors involved in these pathways. Finally, we review immunomodulatory therapeutics in light of these findings and point to opportunities for the application of novel therapeutics by targeting these signaling pathways.

Introduction:

There is a growing body of literature that supports the role of immune-mediated pathways in hearing loss, suggesting that there may be contributions from both autoimmune and auto-inflammatory disease processes[1–4]. Autoimmune disease refers broadly to conditions where the adaptive immune system (largely mediated by B- and T-cells) does not function properly, while autoinflammatory disease refers to conditions where the innate immune system, which acts through an array of cell types (i.e., macrophages) and mediators (i.e. cytokines), does not function properly. Immune-mediated sensorineural hearing loss broadly refers to both autoimmune and autoinflammatory mechanisms that result in sensorineural hearing loss (SNHL). Patients with immune-mediated hearing loss demonstrate hearing instability, which can manifest as sudden sensorineural hearing loss initially and more typically as hearing fluctuation over time[5]. The existence of autoimmune phenotypes for Meniere’s disease (MD), a disease characterized by hearing fluctuation that sometimes goes unrecognized as a presumed sudden SNHL, further complicates this picture[6–7,8*]. Diseases with hearing instability, including MD and autoimmune inner ear disease (AIED), have recently been associated with radiologic evidence of endolymphatic hydrops, which is an expansion of the endolymph-containing scala media[9–12]. While the mechanism of the hearing loss in immune-mediated hearing loss remains incompletely understood, there have been attempts to characterize this process in both in-vivo and in-vitro models as reviewed previously[1]. Nonetheless, knowledge of which cells are targeted and the mechanisms by which hearing loss occurs is poorly understood.

One region in cochlea that is potentially susceptible to interaction with the immune system is the stria vascularis (SV) (Figure 1), which represents a natural confluence between the immune system and major SV cell types (marginal, intermediate, and basal cells). The SV is a stratified non-sensory epithelium situated in the lateral wall of the cochlea that is responsible for generating the endocochlear potential (EP), for maintaining ion homeostasis in the cochlea, and is ultimately necessary for proper hair cell mechano-transduction and hearing. Radiologic evidence of endolymphatic hydrops in the cochlea in diseases that demonstrate hearing fluctuation suggest ion homeostatic dysfunction in the cochlea to which SV dysfunction may contribute. This article will review the literature regarding the pathogenesis of the immune-mediated sensorineural hearing loss, utilize previously published single-nucleus transcriptional profiles to characterize cytokine and cytokine receptor expression in the adult SV cell types to support immune system interaction with the SV, and review the current literature on immunomodulatory agents currently being used for hearing-restoration treatment.

Figure 1. Stria vascularis cellular heterogeneity and organization.

Schematic of the stria vascularis (SV) and its relationship to structures in the cochlea. The SV is composed of three layers of cells and is responsible for generating the +80mV endocochlear potential (EP) and the high potassium concentration in the endolymph-containing scala media. The relationship between the marginal, intermediate and basal cells are demonstrated with the marginal extending basolateral projections to interdigitate with intermediate cells, which have bidirectional cellular projections that interdigitate with both marginal and basal cells. In addition to these cell types, other cell types, including spindle cells (yellow), endothelial cells, pericytes, and macrophages (not shown) are present in the SV. Used with permission from Korrapati and colleagues.

Methods:

Systematic Reviews

Systematic reviews were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses[13] (PRISMA) reporting guidelines. The following databases were searched from inception through March 10, 2021: PubMed-NCBI, MEDLINE, Embase and Cochrane Library. PRISMA flow charts detailing search results are provided in Figures 2–3. The following search terms for immune signaling and cytokine involvement in immune-mediated sensorineural hearing loss were utilized: autoimmune AND hearing loss AND cytokine (text words), autoinflammatory AND hearing loss AND cytokine (text words), inner ear AND immune (text words), inner ear AND inflammasome, stria vascularis (text words), inner ear AND cytokine receptor (text words). The primary outcome of interest was cytokines investigated in relation to autoimmune or autoinflammatory sensorineural hearing loss (Figure 2). The following search terms for immunomodulatory agents for hearing preservation in the setting of immune-mediated sensorineural hearing loss were utilized: hearing loss AND autoinflammatory AND treatment (text words), hearing loss AND autoimmune AND treatment (text words), and hearing loss AND steroids AND immune (text words). The primary outcome of interest was immunomodulatory agents utilized for hearing restoration in relation to autoimmune or autoinflammatory sensorineural hearing loss (Figure 3). Article titles and abstracts were screened for eligibility before full-text articles were obtained and assessed for possible inclusion. Additional relevant articles were identified through the reference lists of included studies or through manual searches and were used to contextualize our findings. Data from included studies was extracted and compiled in a standardized electronic data collection sheet. The strength of clinical data was graded independently by two authors according to the following rating scheme for individual studies, modified from the Oxford Centre for Evidence-Based Medicine levels of evidence as previously described[14*].

Figure 2. PRISMA Flow Chart on Immune Signaling.

PRISMA flow chart on immune signaling and cytokine involvement in immune-mediated sensorineural hearing loss.

Figure 3. PRISMA Flow Chart on Immunomodulatory Agents.

PRISMA flow chart on immunomodulatory agents in immune-mediated sensorineural hearing loss.

Bioinformatics

Data and Software Availability

Previously published single nucleus RNA-Seq datasets of postnatal day 30 (P30) mouse stria vascularis[15*] were utilized (GEO Accession ID: GSE152551) which can be found at the following link (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152551) and are available through the gene Expression Analysis Resource (gEAR), a website for visualization and comparative analysis of multi-omic data, with an emphasis on hearing research (https://umgear.org/p?l=58911b5d) [16].

Data Visualization

P30 MethFix and RNAlater SV snRNA-Seq datasets

snRNA-Seq data normalization and annotation of MethFix and RNAlater samples have been previously described[15*]. Briefly, genes were filtered based on number of cells. Only genes detected in at least 3 cells are kept. Low-quality cells were filtered out when: (1) less than 200 genes were detected; (2) more than 8000 counts in total; and (3) more than 10% of mitochondria genes were detected. Predicted doublets by Scrublet (v0.2.1) with default settings were also filtered. Preprocessed data were normalized by total with parameter exclude_highly_expressed set as “True” and scaled by the function pp.log1p(). Cell clustering and annotation was performed using modularity-based clustering with Leiden algorithm implemented in Scanpy (v1.4.5). Normalized MethFix and RNAlater datasets are concatenated and scaled between 0 and 1 by min-max scaling. Heatmap were plotted by Seaborn (v0.10.1).

Discussion:

Overview of Immune-Mediated Hearing Loss

Although limited, there have been multiple human temporal bone studies of immune-mediated hearing loss (Table 1). These studies have highlighted histopathologic changes to the cochlea, including fibro-osseous reaction[17], destruction of hair cells[18], IgG deposition within the SV[19] with loss or atrophy of the SV[20, 21], and spiral neuron degeneration[21].

Table 1.

Temporal Bone Studies in Immune-mediated Hearing Loss

Publication	Disease	Number of Temporal Bones (#)
Schuknecht et al. (1994)	Polyarteritis Nodosa	4
	Relapsing Polychondritis	1
	Cogan’s Syndrome	4
	Autoimmune Inner Ear Disease (AIED)	1
Sone et al. (1999)	Systemic Lupus Erythematosus (SLE)	7
Calzada et al. (2012)	Sjogren’s Syndrome	4
Kariya et al. (2015)	Systemic Lupus Erythematosus (SLE)	8
Di Stadio et al. (2017)	Systemic Lupus Erythematosus (SLE)	52
	Granulomatosis with Polyangiitis (GPA)	22
	Sjogren’s Syndrome	20
	Cogan’s Syndrome	8
	Autoimmune (unspecified)	7

While the pathophysiology of immune-mediated sensorineural hearing loss is poorly understood, it is suggested that both autoimmune and autoinflammatory disease may play prominent roles in these processes. Autoimmune diseases are various dysfunctions of the adaptive immune system that lead to loss of tolerance against the body’s own tissues or organs. These processes may lead to hearing loss through both humoral-mediated and cell-mediated responses results in reactive B- and T-cells that generate autoantibodies against tissues of the auditory pathway in the presence of IL-17, INF-g, and TNF[1, 22]. Alternatively, autoinflammatory diseases involve innate immune reactions. In this setting, damage to the hearing organs occurs through the production of both humoral-mediated and cell-mediated responses including autoantibodies by monocytes in the presence of IL-1, which results in acute episodes of inflammation[1, 22].

There are many challenges to study the effect of immune responses on hearing loss. To begin, the low incidence of these diseases, which can be hampered by underdiagnosis, presents a challenge to the systematic study of these diseases. Furthermore, there are few standardized diagnostic criteria or reliable diagnostic tests with the diagnosis often being one of exclusion. Additionally, the presence of autoantibodies in these patients is inconsistent, lacking a single dominant diagnostic or prognostic autoantibody[1].

Clinical Investigations of Immune-Mediated Sensorineural Hearing Loss

With this in mind, correlating immunological characterization of patients with immune-mediated sensorineural hearing loss with cytokine and cytokine receptor expression in the inner ear could provide new insights into the underlying pathogenesis and provide opportunities to evaluate novel hypotheses related to mechanisms underlying hearing instability. We performed a systematic review of immune signaling and cytokine involvement in immune-mediated sensorineural hearing loss to identify cytokines detected in peripheral circulation that might be relevant to disease in the human inner ear.

Sensorineural hearing loss (SNHL) is seen in many diseases with underlying systemic inflammation. In our systematic review, the diseases identified included AIED[23, 24**, 25–30], MD[3, 4, 31, 32*], Cogan’s syndrome[33, 34], NLRP3-related Autoinflammatory Disorders (AID) – formerly known as Cryopyrin-associated periodic syndrome (CAPS) (including Muckle-Wells syndrome, neonatal-onset multisystem inflammatory disease or NOMID, and familial cold autoinflammatory syndrome or FCAS)[35–41], systemic lupus erythematosus (SLE)[21, 42], Sjogren’s syndrome (SS)[19, 21, 43, 44], rheumatoid arthritis (RA)[45, 46], Vogt-Koyanagi-Harada syndrome[47, 48], Melkersson-Rosenthal syndrome[49], cerebrovascular disease[50], mixed connective tissue disease (MCTD)[51], H syndrome[52], fetal inflammatory response syndrome[53], and Behcet’s disease[54]. Many cytokines and immune markers have been linked to these diseases and observed in the setting of sensorineural hearing loss, which are summarized in Table 2.

Table 2.

Cytokine Signaling Implicated in Immune-Mediated Sensorineural Hearing Loss

Disease	Immune Mediators	Publication
Autoimmune Inner Ear Disease (AIED)	IL-1	Strum et al. (2020)
	IL-1β, IL-6, TNF-α, CCL3	Pathak et al. (2020)
	IL-1β, TIMP-1, MMP-9	Eisner et al. (2017)
	IL-1R2	Peters et al. (2013)
	IL-1β, IL-1R1, IL-17, IFN,	Goodall et al. (2015)
	IL-1β, IL-6, IL-17	Pathak et al. (2013)
	IL-1β	Zhao et al. (2013)
	TNF-α, MPO, IL-8	Pathak et al. (2015)
Meniere’s Disease	TNF-α, INF-γ	Gazquez et al. (2011)
	IL-1β, IL-1RA, IL-6, TNF-α	Frejo et al. (2018)
	IL-1β, CCL3, CCL22, CXCL1	Flook et al. (2019)
	IL-1β, TNF-α, IL-6, NF-κB	Lopez-Escamez et al. (2018)
Cogan’s Syndrome	TNF-α, IL-1β, ICAM-1	Tayer-Shifman et al. (2014)
	IL-1β, ICAM-1	Shamriz et al. (2018)
NLRP3-AID *	IL-1 (NLRP3)	Ahmadi et al. (2011)
		Hui et al. (2019)
		Fingerhutova et al. (2019)
		Marchica et al. (2018)
	IL-1β (NLRP3)	Nakanishi et al. (2017)
		Kuemmerle-Deschner et al. (2015)
		Goldbach-Mansky et al. (2011)
Systemic Lupus Erythematous (SLE)	Anti-DNA antibodies	Di Stadio et al. (2017)
	High titer anticardiolipin antibodies	Mancini et al. (2018)
Sjogren’s Syndrome	IFN-α, IFN-γ, TNF-α, IL-1, IL-6, IL-18	Kiripolsky et al. (2017)
		Ziavra et al. (2000)
Rheumatoid Arthritis	MMP-3	Nasution et al. (2019)
Idiopathic Sensorineural Hearing Loss	TNF-α, IL-2, IL-6, IL-8	Tsinaslanidou et al. (2016)
	TNF-α, IL-10, IL-12	Demirhan et al. (2013)
Vogt-Koyanagi-Harada (VKH)	IFN-γ, IL-2, IL-17, TNF-α	Abad et al. (2014)
	IL-6, IL-8, IFN-γ	Couto et al. (2010)
Melkersson-Rosenthal Syndrome	TNF-α,	Stein et al. (2014)
Cerebrovascular Disease	TNF-β	Um et al. (2010)
Mixed Connective Tissue Diseaese	TNF-α, INF-γ	Osnes et al. (2013)
H Syndrome	IL-6	Cagdas et al. (2020)
Fetal Inflammatory Response Syndrome	IL-6, CRP	Jung et al. (2020)
Behcet’s Disease	IL-21	Greco et al. (2018)

^*NLRP3-related Autoinflammatory Disorder (AID), formerly known as Cryopyrin-Associated Periodic Syndrome (CAPS), which includes Muckle-Wells Syndrome, NOMID, and FCAS

Broadly speaking, immune-mediated sensorineural hearing loss has been defined by autoimmune and/or autoinflammatory mechanisms. In practice, these diseases may represent a disease continuum model combining elements of both autoimmune and autoinflammatory disease with elements of both adaptive and innate immunity[55*, 56]. Systemic autoimmune disease, which are classically thought to be mediated by the adaptive immune system resulting in the generation of autoantibodies and immune complex deposition, have been linked to sensorineural hearing loss in a variety of disease settings. Gazquez and colleagues show that MD appears to be associated with autoimmunity and MD individuals display a high prevalence of systemic autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematous, and ankylosing spondylitis[4]. The NF-kb inflammatory pathway appears to be activated in MD which leads to the production of pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6[3]. More generally, IL-1β appears to play a critical role in the progression of autoimmune disease and is involved in the pathogenesis of rheumatic diseases, uveitis, autoimmune thyroid diseases (AITD), insulin-dependent diabetes mellitus (IDDM), AIED, multiple sclerosis (MS), myocarditis, hepatitis and kidney diseases[29].

Autoinflammatory diseases, which are thought to be mediated by maladaptive innate immunity, have been connected to mutations in genes involved in the inflammasome. Inflammasomes are innate immune system multi-protein complexes that activate inflammatory responses. They have been shown to activate inflammatory caspases and induce IL-1β and IL-18, leading to pyroptosis, an inflammatory form of cell death, under certain conditions[57]. The dysregulation of pyroptosis and necroptosis, another form of inflammatory cell death, has been implicated in autoimmune and autoinflammatory diseases[58]. Nakanishi and colleagues showed that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome[2]. As noted in Table 2, NLRP3-AID [57] results from NLRP3 inflammasome mutations that lead to constitutive NLRP3 inflammasome activation and resulting higher IL-1β levels[2, 35–38, 40, 41]. Nakanishi and colleagues demonstrated that constitutive activation of the NLRP3 inflammasome through a missense mutation in p.Arg918Gln resulted in sensorineural hearing loss associated with elevated IL-1β levels in two unrelated families[2]. Several studies have confirmed the involvement of IL-1β in SNHL through the use of IL-1 receptor antagonists including Anakinra and consequently observed improvements in hearing[2, 59].

Despite these distinctions, there is evidence that immune-mediated sensorineural hearing loss may possess both autoimmune and autoinflammatory features[1]. Implicated in both autoimmune and autoinflammatory settings are a vast array of pro-inflammatory cytokines including IL-1β, IL-6, TNF-a, IL-17, NF-kb, IFN-γ, as well as other inflammatory markers/immune mediators, including bcl2, Fas, FasL, TIMP-1 (related to IL-1b release), metalloproteases (MMP-9, MMP-3), adhesion molecules ICAM-1, and neutrophil enzyme myeloperoxidase (MPO) (Table 2). Furthermore, mutations in cytokine receptor genes may potentiate the effects of pro-inflammatory cytokines. For example, downregulation and alternate splicing of IL-1R2, a decoy receptor of IL-1β, enhances its inflammatory effects[26, 60]. Finally, mutations in the interferon lambda 1 receptor (IFNLR1) are associated with autosomal-dominant nonsyndromic hearing loss[61]. The mechanisms by which these proinflammatory cytokines and mediators interact with the cells in the cochlea to cause sensorineural hearing loss are poorly defined.

With this in mind, the recent availability of single-cell and single-nucleus RNA-Seq datasets from the adult mouse inner ear provide an opportunity to identify how cytokine signaling might interact in the inner ear, particularly in the SV, which serves as one location where the immune system and inner ear interact in close proximity. In particular, these datasets provide the opportunity to characterize cytokine and cytokine receptor gene expression in silico at the single cell level in the unperturbed adult mammalian SV and to identify potential target cell types. A list of cytokines and cytokine receptors encompassing both pro-inflammatory and anti-inflammatory cytokines is shown in the gene expression heatmap (Figure 4). The heatmap demonstrates cytokine and cytokine receptor genes along the vertical axis broken down by pro-inflammatory and anti-inflammatory properties, respectively. Major cell types in the SV including marginal, intermediate, and basal cells as well as some rare cell types (spindle and root cells) displayed along the horizontal axis of the heatmap. Expression is in normalized transcript counts with an increasingly dark purple color indicating a higher number of transcripts in a given cell. Prominent pro-inflammatory cytokine and cytokine receptor gene expression include Nfkb1, Mif, Il1rap, Il6ra, Il6st, Il17re, Tnfrsf19, Ifnar2, and Tnfrsf21. Prominent anti-inflammatory cytokine and cytokine receptor gene expression include Tgfb2, Il10rb, Il15ra, Tgfbr2, Tgfbr3, Il15, Jak1, Stat2, Stat3, and Stat5b. These data suggest that cytokine signaling through IL-1β, TNF-α, IL-6, TGF-β, IL-10, IL-15 and the JAK-STAT pathway may be mediated within the SV (Table 2).

Figure 4. Cytokines and Cytokine Receptors in Stria Vascularis.

Heatmap displays SV cell types along the horizontal axis with cell types grouped by color and cytokine and cytokine receptor genes along the vertical axis. The darker the bar, the more highly expressed the gene is in a given cell. Cell types include major SV cell types (marginal cells in pink, intermediate cells in green, and basal cells in light blue) as well as cells at the boundary of the SV (spindle cells in gold, root cells in dark green).

Therapeutic targeting of cytokine signaling pathways in the stria vascularis

Given the evidence for cytokine signaling within the adult mouse SV and in autoinflammatory and autoimmune disorders, we will now discuss therapeutic targeting of these signaling pathways. Given that treatment with steroids represents the first-line treatment of these disorders[34, 42, 62, 63*, 64–71, 72*, 73, 74*, 75, 76*], understanding cytokine signaling in patients with steroid-responsive and steroid-unresponsive disease offers an opportunity to identify critical entry points for therapeutic immunomodulation. Corticosteroids repress IL-6 expression via inhibiting the interaction between NF-IL6 and the p65 subunit of NF-κB[77]. These interactions result in repression of the effects of pro-inflammatory cytokines, including, but not limited to, IL-1, IL-6, IL-8, and TNF-α [78]. The need to identify novel alternative therapies is supported by the fact that, although approximately 70% of AIED patients are initially responsive to corticosteroids, this response appears to be lost in all but 14% of patients over time[79].

There have been many immunomodulatory agents that have been investigated for off-label use for immune-mediated hearing loss. Inhibitors of IL-1 (anakinra, canakinumab, rilonacept)[36, 38, 68, 80*, 81, 82*, 83–84], IL-6 (tocilizumab)[85, 86], TNF-α (infliximab, etanercept, golimumab, adalimumab)[34, 42, 65, 67, 72*, 86, 87*, 88*, 89], and B-cells (rituximab)[34, 65, 67, 86, 90, 91] have demonstrated efficacy. Additionally, JAK inhibitors (tofacitinib) have recently been utilized in the treatment of autoimmune and autoinflammatory disorders[92*]. This review highlights additional therapeutic targets with the potential for improved specificity and fewer side effects (Table 3).

Table 3.

Therapeutic Targeting of Cytokine Signaling Pathways in Immune-Mediated Sensorineural Hearing Loss

Drug Class	Therapeutic Agent	Publication
Corticosteroids	Prednisone/Methylprednisolone	Shamriz et al. (2018)
		You et al. (2020)
		Liu et al. (2019)
		Das et al (2019)
		Penêda et al. (2019)
		Zou et al. (2019)
		Carre et al. (2020)
		Oz et al. (2019)
		Padoan et al. (2019)
		Tripathi et al. (2018)
		Perez-Carpena et al. (2020)
		Mancini et al. (2018)
		D’Aguanno et al. (2018)
		Lu et al. (2019)
IL-1 Inhibitors	Anakinra	Penêda et al. (2019)
		Kim et al. (2021)
		Hui et al. (2019)
		Mancini et al. (2018)
		Kareva et al. (2020)
		Welzel et al. (2021)
		Iida et al. (2019)
		Williams et al. (2019)
	Canakinumab	Hui et al. (2019)
		Kareva et al. (2020)
		Welzel et al. (2021)
		Iida et al. (2019)
		Williams et al. (2019)
	Rilonacept	Kareva et al. (2020)
		Welzel et al. (2021)
		Iida et al. (2019)
		Williams et al. (2019)
IL-6 Inhibitors	Tocilizumab	Yan et al. (2020)
		Espinoza et al. (2020)
TNF-α Inhibitors	Infliximab	Espinoza et al. (2020)
		Das et al (2019)
		Shamriz et al. (2018)
		Sakano et al. (2019)
		Padoan et al. (2019)
		Mata-Castro et al. (2020)
		Mancini et al. (2018)
	Etanercept	Shamriz et al. (2018)
		Orlando et al. (2021)
	Golimumab	Sakano et al. (2019)
		Mancini et al. (2018)
	Adalimumab	Shamriz et al. (2018)
		Liu et al. (2019)
		Utsunomiya et al. (2019)
		Mancini et al. (2018)
B-cell Inhibitors	Rituximab	Shamriz et al. (2018)
		Liu et al. (2019)
		Das et al (2019)
		Espinoza et al. (2020)
		San et al. (2019)
		Monferrer-Adsuara et al. (2020)
JAK Inhibitors	Tofacitinib	Jamilloux et al. (2019)

Conclusion:

In summary, we demonstrate that the organ of Corti and the SV are prominently affected cochlear structures in human temporal bones from patients with immune-mediated sensorineural hearing loss. Furthermore, we review cytokine signaling pathways relevant to immune-mediated sensorineural hearing loss identified from peripheral blood studies and localize these genes encoding both cytokine and cytokine receptors involved in these pathways to cell types within these structures utilizing recently published single-cell and single-nucleus transcriptional profiles. These data establish the relevance of these studies to the difficult to access inner ear. Finally, we review immunomodulatory therapeutics in light of these findings and point to opportunities for the application of novel therapeutics by targeting these signaling pathways.

Key Points:

• Prior Human temporal bone studies have highlighted the organ of Corti and the stria vascularis as prominently affected cochlear structures in immune-mediated sensorineural hearing loss.

• Recent publications have studied cytokine signaling pathways relevant to immune-mediated sensorineural hearing loss as well as localized affected cell types within the stria vascularis

• There is a growing body of literature investigating immunomodulatory therapeutics for immune-mediated sensorineural hearing loss by targeting these signaling pathways.