Accepted Article
Article Type: Review Article Current understanding of the pathogenesis of autoimmune inner ear disease: a review Andrew F. Goodall MRCS & M.A. Siddiq FRCSE (ORL-HNS) Department of Otolaryngology, St Helens & Knowsley Hospitals NHS Trust, UK Primary and correspondence author; Andrew F. Goodall MBChB MRCS Department of Otolaryngology, St Helens & Knowsley Hospitals NHS Trust, St Helens Hospital, Marshalls Cross Road, St Helens, WA9 3DA. Tel: 01744 646621. Fax 01744 646331. Email: [email protected].
Abstract Background: autoimmune inner ear disease (AIED) is a poorly understood form of sensorineural hearing loss that causes bilateral, asymmetric, progressive hearing loss, sometimes with vestibular symptoms, often associated with a systemic autoimmune disease, which is noteworthy as the only sensorineural loss responsive to medical therapy. Despite much research interest of the past 25 years, its aetiopathogenesis is still unproven. Objective of review: to succinctly consolidate research and opinion regarding the pathogenesis of autoimmune inner ear disease, in ongoing efforts to elucidate the molecular and intracellular pathways that lead to inner ear damage, which may identify new targets for pharmacotherapy. Type of review: systematic review Search strategy: Pubmed/MEDLINE search using key terms to identify articles published between January 1980 and Apr 2014. Additionally, any landmark works discussed in this body of literature were obtained and relevant information extracted as necessary. Evaluation method: Inclusion criterion was any information from animal or human studies with information relevant to possible aetiopathogenesis of AIED. Studies that focused on diagnosis, ameliorating symptoms, or treatment, without specific information relevant to mechanisms of immune-mediated injury were excluded from this work. Articles meeting the inclusion criteria were digested and summarised. Results: a proposed pathogenic mechanism of AIED involves inflammation and immunemediated attack of specific inner ear structures, leading to an excessive Th1 immune response with vascular changes and tissue damage in the cochlea. Studies have identified self-reactive T cells and immunoglobulins, and have variously implicated immune complex deposition, microthrombosis, and electrochemical disturbances causing impaired neurosignalling in the pathogenesis of AIED. Research has also demonstrated abnormalities in the cytokine milieu in subjects with AIED, which may prove a target for therapy in the future. Conclusion: Ongoing research is needed to further elucidate the aetiopathogenesis of AIED and discern between various mechanisms of tissue injury. Large-cohort clinical studies employing IL1 receptor blockade are warranted to determine its potential for future therapy.
Key points Proposed pathogenesis of immune-mediated attack of specific inner ear structures begins with recognition of self-antigens by cochlear innate immune cells, which release the inflammatory mediator ICAM-1. This increases vascular permeability and facilitates chemotaxis of activated lymphocytes. The effector functions of activated cytotoxic lymphocytes and immunoglobulins from plasma cells pursue an excessive Th1 response (signaling pathways involving IL-1β, IFNγ and IL-17), and immune-mediated tissue injury. Several self-reactive immunoglobulins and T cells have been identified in animal models, and the presence in human subjects of excessive immune-complexes correlated with inner ear disease, followed by recovery with their elimination.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/coa.12432 This article is protected by copyright. All rights reserved.
Accepted Article
Studies have implicated cochlear vascular injury due to both immune-complex deposition (type III hypersensitivity) and autoantibody-related microthrombosis (as occurs in antiphospholipid syndrome), whilst other studies have suggested a mechanism of vascular changes involving electrochemical disturbances and impaired neurosignalling which can be similarly ameliorated with glucocorticoids (the accepted gold-standard treatment) and mineralocorticoids. Research evidence of the cytokine environment in AIED has demonstrated abnormal expression of pro-inflammatory cytokines involving the IL-1 family, which may be susceptible to treatment with IL-1 receptor blockade.
Conflicts of interest None declared.
1 Introduction Autoimmune inner ear disease (AIED) usually causes bilateral, asymmetric and progressive sensorineural hearing loss (SNHL)1, sometimes with vestibular symptoms2, that is associated with a systemic autoimmune disease in 15-30% of patients3,4. AIED is the only form of SNHL that responds to medical therapy5 but delays in treatment beyond three months lead to profound and permanent hearing decline6 that may necessitate the provision of hearing aids or cochlear implantation5. Human and animal studies have variously implicated self-reactive T cells and antibodies, circulating immune complexes, and vasculitis in its pathogenesis7. Corticosteroids remain the sole proven treatment3 but only 70% of patients respond to therapy with this benefit curtailing over time8. Additionally, the harmful side effect profile of Corticosteroids makes longterm usage impractical. It is important to elucidate the molecular and intracellular pathways that participate in inner ear damage as this may identify new targets for pharmacotherapy of immune-mediated hearing loss9,10 to supplant the unsatisfactory use of long-term corticosteroids.
2 Method A Medline/Pubmed search was undertaken using the terms ‘autoimmune’, ‘immune-mediated’, ‘pathogenesis’, ‘sensorineural’, ‘hearing loss’ and ‘inner ear disease’, initially limiting the study period to include January 1980 through to Apr 2014. This generated a variety of publication types, including animal studies, case reports, pilot studies, clinician’s experiences, treatment outcomes, and reviews. These were assessed, digested and summarised for content and relevance. Additionally any important or landmark works that had been referenced in these articles were also obtained and the relevant information extracted. Whilst the large bulk of the literature pertaining to AIED discusses diagnosis, clinical importance of recognition, or reports improvement with immune suppression, this review seeks to discuss the potential aetiopathogenesis with a specific discussion of the immune processes that would be involved. Laboratory and clinical studies in humans and animals with information regarding the aetiopathogenesis of AIED were included in this review. Articles pertaining specifically to treatment or ameliorating symptoms, making a diagnosis, or other off-topic subjects were excluded from this work.
3 Animal models of AIED Unfortunately, an autoimmune mechanism for AIED has not yet been proven as tissue specimens for histopathologic analysis have not (and cannot) come from living patients15. Whilst postmortem temporal bone studies have shown osteoneogenesis in keeping with prior inflammation16 this cannot be proven to have occurred concurrently with the onset of disease. The vast majority of our understanding of possible mechanisms of injury comes from animal models of AIED, including genetically-modified research mice, Lewis rats and guinea pigs. The inner ear expresses many antigens that may be targets for immune surveillance, with their recognition by innate immune cells (neutrophils, macrophages and dendritic cells) stimulating the release of IL-1β that promote an ongoing adaptive immune response where activated circulating leukocytes are drawn into the inner ear by chemotaxis and cause irreversible tissue damage17. Studies have proven that the endolymphatic sac contains immunocompetent tissues capable of immune responses6. Immune challenge of a sensitised animal by delivery of antigen to the inner ear results in substantial inner ear inflammation and associated hearing loss18, 19.
This article is protected by copyright. All rights reserved.
Accepted Article
52. Harris J, Sharp P (1990), Inner ear autoantibodies in patients with rapidly progressive SNHL, Laryngoscope, 100, 516-524
53. Trune D, Kempton J, Mitchell C, et al. (1998), Failure of elevated heat shock protein 70 antibodies to alter cochlear function in mice, Hear Res, 116, 65-70
54. Yeom K, Gray J, Nair T, et al. (2003), Antibodies to HSP-70 n normal donors and autoimmune hearing loss patients, laryngoscope, 113, 1770-1776
55. Moscicki R, San Martin J, Quintero C, et al. (1994), Serum antibody to inner ear proteins in patients with progressive hearing loss. Correlation with disease activity and response to corticosteroid treatment, J Am Med Assoc, 272, 611-616
56. Sutton C, Brereton C, Keogh B, et al., (2006), A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis, J Exp Med, 203,1685-91
57. Pathak S, Goldofsky E, Vivas E, et al., (2011), IL-1β is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease, Journal of Immunology, 186, 1870-1879
58. Koitschev A, Gramlich K, Hansmann S, et al., (2012), Progressive familial hearing loss in Muckle-Wells syndrome, Acta Otolaryngol, 132, 756-62
59. Mirault T, Launay D, Cuisset L, et al., (2006), Recovery from deafness in a patient with Muckle-Wells syndrome treated with anakinra, Arthritis Rheum., 1697-700
This article is protected by copyright. All rights reserved.
Accepted Article
treatment restores electrochemical gradients allowing adequate neurosignalling 34. Ruckenstein et al.33 treated MRL/lpr mice (which reliably develop autoimmune disease by age 12 weeks) with Dexamethasone from age 6 weeks until their destruction aged 20 weeks at which time a necropsy was performed. Dexamethasone treatment had yielded reduced levels of circulating immune complexes, and reduced lymphoproliferation and antibody deposition in stria, but critically no difference in levels of cochlear disease between treated and control animals. This does not support a postulated pathogenic mechanism for AIED involving immune complex deposition.
4 Studies in humans Abnormal expression of T cells has been demonstrated in patients with immune-mediated SNHL37, with low numbers of CTLs, CD4+ and naïve T cells at the onset of hearing loss. After corticosteroid treatment, the T cell population normalised in steroid-responders, but nonresponders showed fewer naïve cells and larger populations of Memory T cells. Garcia-Berrocal et al.37 attributed this to persistent immune activation (since the vestibulocochlear self-antigens cannot be cleared), with transformation of naïve T cells to Memory cells, which stimulate strong effector functions in B and T cells. Studies have correlated the presence of autoantibodies against vestibulocochlear proteins (see figure 2) with SNHL38, 39 and demonstrated hearing recovery and clearance of these antibodies with corticosteroid therapy39, implicating a pathogenic role. However, the mechanism by which autoantibodies cause damage has not been established. Quaranta et al.40 demonstrated that initially elevated levels of circulating autoantibodies and immune complexes in AIED patients responded to treatment with corticosteroids or Cyclophosphamide. After immunosuppressive treatment, these patients experienced a hearing recovery with improvement in mean pure tone audiometry from 32.5 to 12.5 dB, evoked otoacoustic emissions were present in all ears (absent in 40% prior to treatment), and all patients had normal levels of circulating immune complexes. The auditory dysfunction was attributed to immune complex deposition in the stria vascularis (type III hypersensitivity), causing damage to the capillary endothelium which increased vascular permeability leading to endolymphatic hydrops and disruption of the outer hair cells40. This postulated mechanism is supported by histopathologic findings from temporal bone studies of humans41 and animals42 which found vasculitis in the internal auditory artery, capillary damage in the stria vascularis, spiral ganglion degeneration, atrophy of the Organ of Corti, collapse of Reissner’s membrane, distortion of the tectorial membrane with endolymphatic hydrops, and atrophy of the surface epithelium of the endolymphatic duct41, 42. These findings can be produced experimentally by sudden interruption of cochlear blood flow. However evidence also exists to suggest a pathologic role for microthromboses affecting the cochlear. Antiphospholipid syndrome is an autoimmune hypercoagulable state characterized by anticardiolipin antibodies and lupus anticoagulant, which damage platelet membranes and endothelium and so reduce the levels of prostacyclin, leading to microthrombosis43, 44. Antiphospholipid syndrome has previously been associated with SNHL in SLE44, 9 and this hearing loss was successfully treated using low molecular weight heparin9. Mora et al.9 demonstrated improved hearing thresholds, enhanced oto-acoustic emissions (primary cochlear testing) and all patients reported subjective improvements in vestibular symptoms with daily Enoxaparin, which exerts its effect by reducing antiphospholipid activity, thrombocyte aggregation and capillary blood viscosity45. 4.1 Cytokine environment The release of cytokines from activated immune cells initiates a downstream immune cascade. IL-1β is the crucial mediator; it binds with the IL-1 receptor type I (IL-1R1) to signal T cell switching, propagation of a Th1 response and downstream expression of IL-17, which is critical to autoimmune disease55. Molecules that regulate the immune response by opposing this pathway include IL-1R antagonist (IL-1RA) which non-productively binds IL-1R as a competitive inhibitor, and the membrane-bound type of the IL-1R type II (mIL-1R2) which acts as a decoy and sequesters IL-1β without initiating downstream signaling or inflammation56. Autoimmune diseases can result from over-expression of IL-1β or the absence of these opposing molecules, most notably in Muckle-wells syndrome where excess IL-1β leads to SNHL, amyloidosis and arthralgia57. Importantly, the immune-mediated SNHL in Muckle-Wells syndrome has been successfully treated with a water-soluble IL-1R antagonist called Anakinra58.
This article is protected by copyright. All rights reserved.
Accepted Article
Corticosteroids remain the mainstay of AIED treatment although not all patients respond; 70% may respond initially but this curtails over time, with some estimates of sustained response being only 14%8. Differences have been identified in the cytokine environment of serum from responders and non-responders57. Pathak et al.56 demonstrated increased IL-1R2 expression and reduced IL-1β expression with corticosteroid treatment. Interestingly, differences were noted between steroid responders and non-responders; Steroid responders had low basal (unstimulated) levels of mIL-1R2 in peripheral immune cells, which dramatically increased after Dexamethasone treatment. Contrastingly, non-responders had high basal (unstimulated) levels of mIL-1R2 which were minimally changed after Dexamethasone treatment. This suggests a role for mIL-1R2 in reducing immune damage in AIED. Additionally, responders showed reduced expression of IL-1β mRNA whilst non-responders showed a paradoxical increase in IL-1β mRNA levels after Dexamethasone. This may explain the inability of corticosteroids to suppress inflammation in a subset of AIED patients56. Vambutas et al.10 used microarray analyses to similarly show that patients with end-stage AIED (undergoing cochlear implantation) failed to express mRNA for mIL-1R2, further suggesting a protective effect of mIL-1R2. RT-PCR analyses of immune cells stimulated with autologous perilymph showed that patients with immune-mediated hearing loss failed to exhibit m-IL-IR2 whilst patients with a non-immunologic hearing loss strongly expressed mIl-1R2 (p
Article Type: Review Article Current understanding of the pathogenesis of autoimmune inner ear disease: a review Andrew F. Goodall MRCS & M.A. Siddiq FRCSE (ORL-HNS) Department of Otolaryngology, St Helens & Knowsley Hospitals NHS Trust, UK Primary and correspondence author; Andrew F. Goodall MBChB MRCS Department of Otolaryngology, St Helens & Knowsley Hospitals NHS Trust, St Helens Hospital, Marshalls Cross Road, St Helens, WA9 3DA. Tel: 01744 646621. Fax 01744 646331. Email: [email protected].
Abstract Background: autoimmune inner ear disease (AIED) is a poorly understood form of sensorineural hearing loss that causes bilateral, asymmetric, progressive hearing loss, sometimes with vestibular symptoms, often associated with a systemic autoimmune disease, which is noteworthy as the only sensorineural loss responsive to medical therapy. Despite much research interest of the past 25 years, its aetiopathogenesis is still unproven. Objective of review: to succinctly consolidate research and opinion regarding the pathogenesis of autoimmune inner ear disease, in ongoing efforts to elucidate the molecular and intracellular pathways that lead to inner ear damage, which may identify new targets for pharmacotherapy. Type of review: systematic review Search strategy: Pubmed/MEDLINE search using key terms to identify articles published between January 1980 and Apr 2014. Additionally, any landmark works discussed in this body of literature were obtained and relevant information extracted as necessary. Evaluation method: Inclusion criterion was any information from animal or human studies with information relevant to possible aetiopathogenesis of AIED. Studies that focused on diagnosis, ameliorating symptoms, or treatment, without specific information relevant to mechanisms of immune-mediated injury were excluded from this work. Articles meeting the inclusion criteria were digested and summarised. Results: a proposed pathogenic mechanism of AIED involves inflammation and immunemediated attack of specific inner ear structures, leading to an excessive Th1 immune response with vascular changes and tissue damage in the cochlea. Studies have identified self-reactive T cells and immunoglobulins, and have variously implicated immune complex deposition, microthrombosis, and electrochemical disturbances causing impaired neurosignalling in the pathogenesis of AIED. Research has also demonstrated abnormalities in the cytokine milieu in subjects with AIED, which may prove a target for therapy in the future. Conclusion: Ongoing research is needed to further elucidate the aetiopathogenesis of AIED and discern between various mechanisms of tissue injury. Large-cohort clinical studies employing IL1 receptor blockade are warranted to determine its potential for future therapy.
Key points Proposed pathogenesis of immune-mediated attack of specific inner ear structures begins with recognition of self-antigens by cochlear innate immune cells, which release the inflammatory mediator ICAM-1. This increases vascular permeability and facilitates chemotaxis of activated lymphocytes. The effector functions of activated cytotoxic lymphocytes and immunoglobulins from plasma cells pursue an excessive Th1 response (signaling pathways involving IL-1β, IFNγ and IL-17), and immune-mediated tissue injury. Several self-reactive immunoglobulins and T cells have been identified in animal models, and the presence in human subjects of excessive immune-complexes correlated with inner ear disease, followed by recovery with their elimination.
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/coa.12432 This article is protected by copyright. All rights reserved.
Accepted Article
Studies have implicated cochlear vascular injury due to both immune-complex deposition (type III hypersensitivity) and autoantibody-related microthrombosis (as occurs in antiphospholipid syndrome), whilst other studies have suggested a mechanism of vascular changes involving electrochemical disturbances and impaired neurosignalling which can be similarly ameliorated with glucocorticoids (the accepted gold-standard treatment) and mineralocorticoids. Research evidence of the cytokine environment in AIED has demonstrated abnormal expression of pro-inflammatory cytokines involving the IL-1 family, which may be susceptible to treatment with IL-1 receptor blockade.
Conflicts of interest None declared.
1 Introduction Autoimmune inner ear disease (AIED) usually causes bilateral, asymmetric and progressive sensorineural hearing loss (SNHL)1, sometimes with vestibular symptoms2, that is associated with a systemic autoimmune disease in 15-30% of patients3,4. AIED is the only form of SNHL that responds to medical therapy5 but delays in treatment beyond three months lead to profound and permanent hearing decline6 that may necessitate the provision of hearing aids or cochlear implantation5. Human and animal studies have variously implicated self-reactive T cells and antibodies, circulating immune complexes, and vasculitis in its pathogenesis7. Corticosteroids remain the sole proven treatment3 but only 70% of patients respond to therapy with this benefit curtailing over time8. Additionally, the harmful side effect profile of Corticosteroids makes longterm usage impractical. It is important to elucidate the molecular and intracellular pathways that participate in inner ear damage as this may identify new targets for pharmacotherapy of immune-mediated hearing loss9,10 to supplant the unsatisfactory use of long-term corticosteroids.
2 Method A Medline/Pubmed search was undertaken using the terms ‘autoimmune’, ‘immune-mediated’, ‘pathogenesis’, ‘sensorineural’, ‘hearing loss’ and ‘inner ear disease’, initially limiting the study period to include January 1980 through to Apr 2014. This generated a variety of publication types, including animal studies, case reports, pilot studies, clinician’s experiences, treatment outcomes, and reviews. These were assessed, digested and summarised for content and relevance. Additionally any important or landmark works that had been referenced in these articles were also obtained and the relevant information extracted. Whilst the large bulk of the literature pertaining to AIED discusses diagnosis, clinical importance of recognition, or reports improvement with immune suppression, this review seeks to discuss the potential aetiopathogenesis with a specific discussion of the immune processes that would be involved. Laboratory and clinical studies in humans and animals with information regarding the aetiopathogenesis of AIED were included in this review. Articles pertaining specifically to treatment or ameliorating symptoms, making a diagnosis, or other off-topic subjects were excluded from this work.
3 Animal models of AIED Unfortunately, an autoimmune mechanism for AIED has not yet been proven as tissue specimens for histopathologic analysis have not (and cannot) come from living patients15. Whilst postmortem temporal bone studies have shown osteoneogenesis in keeping with prior inflammation16 this cannot be proven to have occurred concurrently with the onset of disease. The vast majority of our understanding of possible mechanisms of injury comes from animal models of AIED, including genetically-modified research mice, Lewis rats and guinea pigs. The inner ear expresses many antigens that may be targets for immune surveillance, with their recognition by innate immune cells (neutrophils, macrophages and dendritic cells) stimulating the release of IL-1β that promote an ongoing adaptive immune response where activated circulating leukocytes are drawn into the inner ear by chemotaxis and cause irreversible tissue damage17. Studies have proven that the endolymphatic sac contains immunocompetent tissues capable of immune responses6. Immune challenge of a sensitised animal by delivery of antigen to the inner ear results in substantial inner ear inflammation and associated hearing loss18, 19.
This article is protected by copyright. All rights reserved.
Accepted Article
52. Harris J, Sharp P (1990), Inner ear autoantibodies in patients with rapidly progressive SNHL, Laryngoscope, 100, 516-524
53. Trune D, Kempton J, Mitchell C, et al. (1998), Failure of elevated heat shock protein 70 antibodies to alter cochlear function in mice, Hear Res, 116, 65-70
54. Yeom K, Gray J, Nair T, et al. (2003), Antibodies to HSP-70 n normal donors and autoimmune hearing loss patients, laryngoscope, 113, 1770-1776
55. Moscicki R, San Martin J, Quintero C, et al. (1994), Serum antibody to inner ear proteins in patients with progressive hearing loss. Correlation with disease activity and response to corticosteroid treatment, J Am Med Assoc, 272, 611-616
56. Sutton C, Brereton C, Keogh B, et al., (2006), A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis, J Exp Med, 203,1685-91
57. Pathak S, Goldofsky E, Vivas E, et al., (2011), IL-1β is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease, Journal of Immunology, 186, 1870-1879
58. Koitschev A, Gramlich K, Hansmann S, et al., (2012), Progressive familial hearing loss in Muckle-Wells syndrome, Acta Otolaryngol, 132, 756-62
59. Mirault T, Launay D, Cuisset L, et al., (2006), Recovery from deafness in a patient with Muckle-Wells syndrome treated with anakinra, Arthritis Rheum., 1697-700
This article is protected by copyright. All rights reserved.
Accepted Article
treatment restores electrochemical gradients allowing adequate neurosignalling 34. Ruckenstein et al.33 treated MRL/lpr mice (which reliably develop autoimmune disease by age 12 weeks) with Dexamethasone from age 6 weeks until their destruction aged 20 weeks at which time a necropsy was performed. Dexamethasone treatment had yielded reduced levels of circulating immune complexes, and reduced lymphoproliferation and antibody deposition in stria, but critically no difference in levels of cochlear disease between treated and control animals. This does not support a postulated pathogenic mechanism for AIED involving immune complex deposition.
4 Studies in humans Abnormal expression of T cells has been demonstrated in patients with immune-mediated SNHL37, with low numbers of CTLs, CD4+ and naïve T cells at the onset of hearing loss. After corticosteroid treatment, the T cell population normalised in steroid-responders, but nonresponders showed fewer naïve cells and larger populations of Memory T cells. Garcia-Berrocal et al.37 attributed this to persistent immune activation (since the vestibulocochlear self-antigens cannot be cleared), with transformation of naïve T cells to Memory cells, which stimulate strong effector functions in B and T cells. Studies have correlated the presence of autoantibodies against vestibulocochlear proteins (see figure 2) with SNHL38, 39 and demonstrated hearing recovery and clearance of these antibodies with corticosteroid therapy39, implicating a pathogenic role. However, the mechanism by which autoantibodies cause damage has not been established. Quaranta et al.40 demonstrated that initially elevated levels of circulating autoantibodies and immune complexes in AIED patients responded to treatment with corticosteroids or Cyclophosphamide. After immunosuppressive treatment, these patients experienced a hearing recovery with improvement in mean pure tone audiometry from 32.5 to 12.5 dB, evoked otoacoustic emissions were present in all ears (absent in 40% prior to treatment), and all patients had normal levels of circulating immune complexes. The auditory dysfunction was attributed to immune complex deposition in the stria vascularis (type III hypersensitivity), causing damage to the capillary endothelium which increased vascular permeability leading to endolymphatic hydrops and disruption of the outer hair cells40. This postulated mechanism is supported by histopathologic findings from temporal bone studies of humans41 and animals42 which found vasculitis in the internal auditory artery, capillary damage in the stria vascularis, spiral ganglion degeneration, atrophy of the Organ of Corti, collapse of Reissner’s membrane, distortion of the tectorial membrane with endolymphatic hydrops, and atrophy of the surface epithelium of the endolymphatic duct41, 42. These findings can be produced experimentally by sudden interruption of cochlear blood flow. However evidence also exists to suggest a pathologic role for microthromboses affecting the cochlear. Antiphospholipid syndrome is an autoimmune hypercoagulable state characterized by anticardiolipin antibodies and lupus anticoagulant, which damage platelet membranes and endothelium and so reduce the levels of prostacyclin, leading to microthrombosis43, 44. Antiphospholipid syndrome has previously been associated with SNHL in SLE44, 9 and this hearing loss was successfully treated using low molecular weight heparin9. Mora et al.9 demonstrated improved hearing thresholds, enhanced oto-acoustic emissions (primary cochlear testing) and all patients reported subjective improvements in vestibular symptoms with daily Enoxaparin, which exerts its effect by reducing antiphospholipid activity, thrombocyte aggregation and capillary blood viscosity45. 4.1 Cytokine environment The release of cytokines from activated immune cells initiates a downstream immune cascade. IL-1β is the crucial mediator; it binds with the IL-1 receptor type I (IL-1R1) to signal T cell switching, propagation of a Th1 response and downstream expression of IL-17, which is critical to autoimmune disease55. Molecules that regulate the immune response by opposing this pathway include IL-1R antagonist (IL-1RA) which non-productively binds IL-1R as a competitive inhibitor, and the membrane-bound type of the IL-1R type II (mIL-1R2) which acts as a decoy and sequesters IL-1β without initiating downstream signaling or inflammation56. Autoimmune diseases can result from over-expression of IL-1β or the absence of these opposing molecules, most notably in Muckle-wells syndrome where excess IL-1β leads to SNHL, amyloidosis and arthralgia57. Importantly, the immune-mediated SNHL in Muckle-Wells syndrome has been successfully treated with a water-soluble IL-1R antagonist called Anakinra58.
This article is protected by copyright. All rights reserved.
Accepted Article
Corticosteroids remain the mainstay of AIED treatment although not all patients respond; 70% may respond initially but this curtails over time, with some estimates of sustained response being only 14%8. Differences have been identified in the cytokine environment of serum from responders and non-responders57. Pathak et al.56 demonstrated increased IL-1R2 expression and reduced IL-1β expression with corticosteroid treatment. Interestingly, differences were noted between steroid responders and non-responders; Steroid responders had low basal (unstimulated) levels of mIL-1R2 in peripheral immune cells, which dramatically increased after Dexamethasone treatment. Contrastingly, non-responders had high basal (unstimulated) levels of mIL-1R2 which were minimally changed after Dexamethasone treatment. This suggests a role for mIL-1R2 in reducing immune damage in AIED. Additionally, responders showed reduced expression of IL-1β mRNA whilst non-responders showed a paradoxical increase in IL-1β mRNA levels after Dexamethasone. This may explain the inability of corticosteroids to suppress inflammation in a subset of AIED patients56. Vambutas et al.10 used microarray analyses to similarly show that patients with end-stage AIED (undergoing cochlear implantation) failed to express mRNA for mIL-1R2, further suggesting a protective effect of mIL-1R2. RT-PCR analyses of immune cells stimulated with autologous perilymph showed that patients with immune-mediated hearing loss failed to exhibit m-IL-IR2 whilst patients with a non-immunologic hearing loss strongly expressed mIl-1R2 (p
