Auris Nasus Larynx 41 (2014) 499–501

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Cochlin in autoimmune inner ear disease: Is the search for an inner ear autoantigen over? Paramita Baruah * Department of Otolaryngology, New Cross Hospital, Wolverhampton WV10 0QP, United Kingdom

A R T I C L E I N F O

A B S T R A C T

Article history: Received 9 June 2014 Accepted 18 August 2014 Available online 8 September 2014

Definition: Autoimmune inner ear disease (AIED) is characterised by a rapidly progressive, often fluctuating, bilateral sensorineural hearing loss over a period of weeks to months. It is an uncommon disease accounting for less than 1% of all cases of hearing impairment or dizziness. The diagnosis is often missed and this impacts on the prognosis as the condition responds well to steroids and immunosuppressants if recognised early. Lacuna in knowledge: No useful specific test for autoimmunity affecting the inner ear exists. Objective of study: To gather evidence regarding cochlin in AIED. Methodology: Systematic review of human studies and animal experimental studies on inner ear antigens was undertaken. Search strategy: We searched MEDLINE (1965–2012), and Pubmed for relevant studies. A combination of key words for inner ear, autoimmunity (autoimmune, immune mediated) and cochlin were used. Results: A number of antigens have been implicated in autoimmune inner ear disease. Cochlin is a major component of the extracellular matrix in the inner ear and a promising candidate. We present evidence in literature on the role of this protein in the pathogenesis of autoimmune inner ear disease. ß 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Autoimmune inner ear disease Cochlin

1. Introduction Autoimmune inner ear disease (AIED) is rare and accounts for less than 1% of hearing loss or vestibular pathology and was first described in 1979 by McCabe [1]. Clinically it is characterised by a rapidly progressive, fluctuating, commonly bilateral sensorineural hearing loss. The progression of the disease may be slower than the classic sudden onset sensorineural hearing loss but is faster than age-related hearing deterioration. Vestibular symptoms may be the presenting feature in up to 50% of AIED [2]. Autoimmune pathology of the inner ear is difficult to confirm due to an absence of specific test that could identify the inner ear antigen(s) at fault. As with other organ specific autoimmunity, inner ear antigens could become the target for the body’s immune response following events such as infections, trauma or vascular events. Current therapy includes steroids to dampen the inflammatory response and this is reported to improve hearing in up to 60% of patients. Other treatments include immunomodulation with cyclophosphamide and methotrexate or plasmaphereis to remove auto-antibodies and immune complexes from the blood.

* Tel.: +44 07540729971. E-mail address: [email protected] http://dx.doi.org/10.1016/j.anl.2014.08.014 0385-8146/ß 2014 Elsevier Ireland Ltd. All rights reserved.

Significant attempts have been made to elucidate the inner ear antigens that could be the target of the disease process. A candidate antigen in autoimmune pathology of the inner ear is cochlin. It is a major component of the extracellular matrix (ECM) of the inner ear [3]. Several studies have shown evidence of cochlin defects in inner ear degenerative processes as well as evidence of an autoimmune response to cochlin in patients with AIED. In this review we present the information available on cochlin’s role in the pathogenesis of AIED.

2. Cochlin – structure and expression Cochlin is the major component of the extracellular matrix (ECM) in the inner ear after collagen [3,4]. It is expressed in both the cochlea and the vestibule of the inner ear. Cochlin is encoded by the COCH (Coagulation factor C homology) gene. Cochlin is highly conserved among species with 94% aminoacid homology between human and mouse and 79% amino acid identity between human and chicken, suggesting that this protein has important functions in cellular processes. Cochlin is secreted via the endoplasmic reticulum/Golgi apparatus network, and is proteolytically processed and glycosylated in its mature form. In the inner ear three glycosylated

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isoforms of cochlin have been described with molecular weights of 40 kDa, 46 kDa and 60 kDa [3,5,6]. In addition, a smaller 16 kDa isoform called cochlin-tomoprotein has been identified in the perilymph. High levels of cochlin have been detected in the stromata of the maculae of otolithic organs and cristae of semicircular canals in the channels in the bony labyrinth that transmit the dendritic innervation to the cristae and maculae. In contrast, sensory cells, dark cells and acellular structures such as otolithic membrane and cupula do not express cochlin [7]. Although cochlin is the second most abundant protein in the extracellular matrix of the inner ear, its precise function remains poorly understood. It has been suggested that cochlin may have a role in the structural homeostasis of the vestibule by acting in concert with the bundles of fibrillar Collagen II. Indeed, immunoelectromicroscopy analysis revealed cochlin co-localised with Collagen II in the fibrillar substance underlying the supporting epithelium of the sensory cells and beneath the epithelial cells facing the endolymph in the semicircular canals in rat labyrinths [8]. 3. Cochlin and inner ear disease Defects in cochlin have been identified in the autosomal dominant non-syndromic auditory and vestibular disorder DFNA9, Meniere’s disease and in presbyacusis [3,9–11]. The DFNA syndrome is characterised by neurodegeneration of inner ear that results in hearing loss and vestibular symptoms. Pathologically DFNA is characterised by loss of cellularity and aggregation of abundant homogenous acellular eosiniphilic deposits in the cochlear and vestibular labyrinth similar to the aggregation of proteins that characterises neurodegenerative disorders. Of note, these acellular deposits were found to contain cochlin aggregates. Cochlin expression has been found to be increased in the vestibule of patients with Meniere’s disease compared to control subjects [12]. This was associated with a decrease in collagen IV and laminin b2 which are basement membrane proteins. Overexpression of cochlin was thus suggested to contribute to inner ear dysfunction. 4. Cochlin and the immune system The expression of Cochlin is highly selective – it is abundant in the inner ear [13], as described earlier, but is also present in the spleen. Cochlin has recently been shown to be expressed by follicular dendritic cells and localises in the fine extracellular networks of spleen and lymph nodes [14]. Follicular dendritic cells present antigens to B cells and have important roles in the production of antibodies and regulation of humoral immune responses. Cochlin shares homology with Factor C, a serine protease found in horseshoe crabs and that has been shown to have a role in antibacterial immune responses. Thus cochlin may have important roles in the immune defence against microbes. This has indeed been shown to be the case. Animal models with cochlin deficiency such as the cochlin knock-out (Coch / ) mice have decreased survival to infections with Pseudomonas aeruginosa and Staphylococcus aureus [14]. Thus, cochlin may very well be involved in inner ear immune responses to pathogens. 5. Cochlin and autoimmune inner ear disease Detection of cochlin specific antibodies has been reported in 14% of patients with idiopathic sensorineural hearing loss [15]. Interestingly, cochlin has been shown to have a stronger link to autoimmune hearing loss. 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. Pathak et al. reported that patients with AIED had higher levels of antifungal and anti-cochlin IgG antibodies in plasma compared to healthy controls. 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]. T cell responses to cochlin have also been reported earlier. AIED patients were shown to have higher frequencies of circulating T cells producing interferon-g (IFN-g) or IL-5 in response to cochlin. Both CD4+ and CD8+ T cell responses were noted. This was actually the first study to demonstrate T cell responses to cochlin in patients with AIED and implicated cochlin as a prominent autoantigen driving autoimmune inner ear disease [16]. Animal studies also support a role of cochlin in AIED. Targeting cochlin can result in experimental autoimmune hearing loss in mice. A strain of mice (SWXJ) immunised with a cochlin peptide exhibited a reduction in auditory brain stem responses. This hearing loss was noted to be T cell mediated as activated CD4+ T cells isolated from immunised mice and transferred to naı¨ve mice induced hearing loss in the recipient mice as well. This study indicates that AIED is a T cell mediated autoimmune disorder of the inner ear with cochlin as a target antigen [18]. 6. Discussion Immunology of the inner ear is difficult to investigate due to inaccessibility of the tissue in the human disease. Several antigens have been postulated to be targeted by the immune system in patients with AIED. These include proteins such as HSP70, P0 myelin protein, Collagen II and S-100 beta [19–22]. None of the above is specific to the inner ear and therefore presence of antibodies to these antigens is not pathognomic of inner ear pathology. Cochlin is a promising candidate as its expression is predominantly confined to the inner ear, where it is present abundantly and has been suggested to have important roles in the homeostasis of the vestibule together with collagen II. Several lines of evidence support a role for cochlin in AIED. Anti-cochlin antibodies and T cells specific for cochlin [16] have been detected in patients with AIED, suggesting an active immune response to this protein. Murine models provide further support to cochlin mediated AIED. Immunisation with cochlin induced hearing loss in a SYKKK mouse strain and this was mediated by CD4+ T cells [18]. It remains to be determined how the immune response to cochlin is triggered. 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. Indeed, the perilymph contains a short isoform of cochlin called cochlin-tomoprotein which is detected following stapes surgery and can also be used as a marker to diagnose perilymphatic leaks [23]. Interestingly, immune cells involved in regulation of antibody production by B cells (i.e. follicular dendritic cells) have been shown to produce cochlin to aid defence against microorganisms [14]. This dual role of cochlin as a major structural protein in the inner ear and a modulator of immune responses to microbes may be relevant to the role of this protein in AIED. The other question that remains to be answered is how cochlinspecific antibodies and T cells gain access to the inner ear to

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mediate damage. The presence of the blood–labyrinth barrier, which is similar to the blood–brain barrier, should prevent antibodies and T cells from entering the inner ear, although this function may be compromised in the presence of inflammation of the inner ear, which may be secondary to trauma or viral infections. In conclusion, a substantial body of evidence implicates cochlin in the pathogenesis of AIED. It would be reasonable therefore to routinely test for antibodies to cochlin in patients presenting with unexplained sensorineural hearing loss as a diagnostic tool. This could allow a judicious use of plasmapheresis and cytotoxic immunosuppressive drugs in patients with sensorineural hearing loss not responding to steroids. Another interesting facet to consider is the possibility of de-sensitisation protocols to cochlin in the treatment of AIED. It would be simplistic however to assume that cochlin is the only autoantigen in the pathogenesis of AIED which often associates with the presence of multiple autoantibodies in patient sera. If these antibodies are a cause or a consequence of inner ear damage by the immune system is a question still to be addressed. Conflict of interest The author does not have any conflict of interest to declare in relation to this work. References [1] McCabe BF. Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol 1979;88:585–9. [2] Rauch SD. Clinical management of immune-mediated inner-ear disease. Ann N Y Acad Sci 1997;830:203–10. [3] Robertson NG, Hamaker SA, Patriub V, Aster JC, Morton CC. Subcellular localisation, secretion, and post-translational processing of normal cochlin, and of mutants causing the sensorineural deafness and vestibular disorder, DFNA9. J Med Genet 2003;40:479–86. [4] Robertson NG, Khetarpal U, Gutierrez-Espeleta GA, Bieber FR, Morton CC. Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening. Genomics 1994;23: 42–50. [5] Ikezono T, Shindo S, Li L, Omori A, Ichinose S, Watanabe A, et al. Identification of a novel Cochlin isoform in the perilymph: insights to Cochlin function and the pathogenesis of DFNA9. Biochem Biophys Res Commun 2004;314:440–6.

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

Autoimmune inner ear disease (AIED) is characterised by a rapidly progressive, often fluctuating, bilateral sensorineural hearing loss over a period o...
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