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

3
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 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 inflam- matory 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. 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 glycosy- lated in its mature form. In the inner ear three glycosylated Auris Nasus Larynx 41 (2014) 499–501 A R T I C L E I N F O Article history: Received 9 June 2014 Accepted 18 August 2014 Available online 8 September 2014 Keywords: Autoimmune inner ear disease Cochlin A B S T R A C T 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. * Tel.: +44 07540729971. E-mail address: [email protected] Contents lists available at ScienceDirect Auris Nasus Larynx jo u rn al h om epag e: ww w.els evier.c o m/lo cat e/anl http://dx.doi.org/10.1016/j.anl.2014.08.014 0385-8146/ß 2014 Elsevier Ireland Ltd. All rights reserved.

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Page 1: Cochlin in autoimmune inner ear disease: Is the search for an inner ear autoantigen over?

Auris Nasus Larynx 41 (2014) 499–501

Cochlin in autoimmune inner ear disease: Is the search for an inner earautoantigen 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

Article history:

Received 9 June 2014

Accepted 18 August 2014

Available online 8 September 2014

Keywords:

Autoimmune inner ear disease

Cochlin

A B S T R A C T

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.

� 2014 Elsevier Ireland Ltd. All rights reserved.

Contents lists available at ScienceDirect

Auris Nasus Larynx

jo u rn al h om epag e: ww w.els evier .c o m/lo cat e/anl

1. Introduction

Autoimmune inner ear disease (AIED) is rare and accounts forless than 1% of hearing loss or vestibular pathology and was firstdescribed in 1979 by McCabe [1]. Clinically it is characterised by arapidly progressive, fluctuating, commonly bilateral sensorineuralhearing loss. The progression of the disease may be slower than theclassic sudden onset sensorineural hearing loss but is faster thanage-related hearing deterioration. Vestibular symptoms may bethe presenting feature in up to 50% of AIED [2].

Autoimmune pathology of the inner ear is difficult to confirmdue to an absence of specific test that could identify the inner earantigen(s) at fault. As with other organ specific autoimmunity,inner ear antigens could become the target for the body’s immuneresponse following events such as infections, trauma or vascularevents. Current therapy includes steroids to dampen the inflam-matory response and this is reported to improve hearing in up to60% of patients. Other treatments include immunomodulationwith cyclophosphamide and methotrexate or plasmaphereis toremove 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/� 2014 Elsevier Ireland Ltd. All rights reserved.

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

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 boththe cochlea and the vestibule of the inner ear. Cochlin is encoded bythe COCH (Coagulation factor C homology) gene. Cochlin is highlyconserved among species with 94% aminoacid homology betweenhuman and mouse and 79% amino acid identity between humanand chicken, suggesting that this protein has important functionsin cellular processes.

Cochlin is secreted via the endoplasmic reticulum/Golgiapparatus network, and is proteolytically processed and glycosy-lated in its mature form. In the inner ear three glycosylated

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P. Baruah / Auris Nasus Larynx 41 (2014) 499–501500

isoforms of cochlin have been described with molecular weights of40 kDa, 46 kDa and 60 kDa [3,5,6]. In addition, a smaller 16 kDaisoform called cochlin-tomoprotein has been identified in theperilymph.

High levels of cochlin have been detected in the stromata of themaculae of otolithic organs and cristae of semicircular canals in thechannels in the bony labyrinth that transmit the dendriticinnervation to the cristae and maculae. In contrast, sensory cells,dark cells and acellular structures such as otolithic membrane andcupula do not express cochlin [7].

Although cochlin is the second most abundant protein in theextracellular matrix of the inner ear, its precise function remainspoorly understood. It has been suggested that cochlin may have arole in the structural homeostasis of the vestibule by acting inconcert with the bundles of fibrillar Collagen II. Indeed, immuno-electromicroscopy analysis revealed cochlin co-localised withCollagen II in the fibrillar substance underlying the supportingepithelium of the sensory cells and beneath the epithelial cellsfacing the endolymph in the semicircular canals in rat labyrinths[8].

3. Cochlin and inner ear disease

Defects in cochlin have been identified in the autosomaldominant non-syndromic auditory and vestibular disorder DFNA9,Meniere’s disease and in presbyacusis [3,9–11]. The DFNAsyndrome is characterised by neurodegeneration of inner ear thatresults in hearing loss and vestibular symptoms. PathologicallyDFNA is characterised by loss of cellularity and aggregation ofabundant homogenous acellular eosiniphilic deposits in thecochlear and vestibular labyrinth similar to the aggregation ofproteins that characterises neurodegenerative disorders. Of note,these acellular deposits were found to contain cochlin aggregates.

Cochlin expression has been found to be increased in thevestibule of patients with Meniere’s disease compared to controlsubjects [12]. This was associated with a decrease in collagen IVand laminin b2 which are basement membrane proteins. Over-expression of cochlin was thus suggested to contribute to inner eardysfunction.

4. Cochlin and the immune system

The expression of Cochlin is highly selective – it is abundant inthe inner ear [13], as described earlier, but is also present in thespleen. Cochlin has recently been shown to be expressed byfollicular dendritic cells and localises in the fine extracellularnetworks of spleen and lymph nodes [14]. Follicular dendritic cellspresent antigens to B cells and have important roles in theproduction of antibodies and regulation of humoral immuneresponses.

Cochlin shares homology with Factor C, a serine protease foundin horseshoe crabs and that has been shown to have a role inantibacterial immune responses. Thus cochlin may have importantroles in the immune defence against microbes. This has indeedbeen shown to be the case. Animal models with cochlin deficiencysuch as the cochlin knock-out (Coch�/�) mice have decreasedsurvival to infections with Pseudomonas aeruginosa and Staphylo-

coccus aureus [14]. Thus, cochlin may very well be involved in innerear immune responses to pathogens.

5. Cochlin and autoimmune inner ear disease

Detection of cochlin specific antibodies has been reported in14% of patients with idiopathic sensorineural hearing loss [15].Interestingly, cochlin has been shown to have a stronger link toautoimmune hearing loss. AIED patients were found to have

significantly higher serum levels of anti-cochlin antibodiescompared to healthy controls and patients with noise and/orage-related hearing loss by Baek et al. [16]. Further evidence for ahumoral immune response to cochlin in AIED has been presentedrecently by Pathak et al. [17]. Cochlin has been shown to sharehomology with several Aspergillus and Penicillium species. Pathaket al. reported that patients with AIED had higher levels of anti-fungal and anti-cochlin IgG antibodies in plasma compared tohealthy controls. Moreover, peripheral mononuclear cells fromAIED patients also produced high levels of inflammatory cytokinesinterleukin-6 (IL-6) and IL-1b upon stimulation with fungalantigens. The authors suggested that autoimmune responses tofungal antigens can contribute to the pathogenesis of AIED [17].

T cell responses to cochlin have also been reported earlier. AIEDpatients were shown to have higher frequencies of circulatingT cells producing interferon-g (IFN-g) or IL-5 in response tocochlin. Both CD4+ and CD8+ T cell responses were noted. This wasactually the first study to demonstrate T cell responses to cochlin inpatients with AIED and implicated cochlin as a prominentautoantigen driving autoimmune inner ear disease [16].

Animal studies also support a role of cochlin in AIED. Targetingcochlin can result in experimental autoimmune hearing loss inmice. A strain of mice (SWXJ) immunised with a cochlin peptideexhibited a reduction in auditory brain stem responses. Thishearing loss was noted to be T cell mediated as activated CD4+ Tcells isolated from immunised mice and transferred to naı̈ve miceinduced hearing loss in the recipient mice as well. This studyindicates that AIED is a T cell mediated autoimmune disorder of theinner ear with cochlin as a target antigen [18].

6. Discussion

Immunology of the inner ear is difficult to investigate due toinaccessibility of the tissue in the human disease. Several antigenshave been postulated to be targeted by the immune system inpatients with AIED. These include proteins such as HSP70, P0myelin protein, Collagen II and S-100 beta [19–22]. None of theabove is specific to the inner ear and therefore presence ofantibodies to these antigens is not pathognomic of inner earpathology.

Cochlin is a promising candidate as its expression is predomi-nantly confined to the inner ear, where it is present abundantly andhas been suggested to have important roles in the homeostasis ofthe vestibule together with collagen II. Several lines of evidencesupport a role for cochlin in AIED. Anti-cochlin antibodies and Tcells specific for cochlin [16] have been detected in patients withAIED, 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 mousestrain and this was mediated by CD4+ T cells [18].

It remains to be determined how the immune response tocochlin is triggered. Cross-reactivity between cochlin and fungaland bacterial antigens is an attractive hypothesis [17]. Antibodiesto cochlin may also be generated following exposure of inner earcochlin to the immune system as may occur with inner ear trauma/surgery, infections. Indeed, the perilymph contains a short isoformof cochlin called cochlin-tomoprotein which is detected followingstapes surgery and can also be used as a marker to diagnoseperilymphatic leaks [23]. Interestingly, immune cells involved inregulation of antibody production by B cells (i.e. follicular dendriticcells) have been shown to produce cochlin to aid defence againstmicroorganisms [14]. This dual role of cochlin as a major structuralprotein in the inner ear and a modulator of immune responses tomicrobes may be relevant to the role of this protein in AIED.

The other question that remains to be answered is how cochlin-specific antibodies and T cells gain access to the inner ear to

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P. Baruah / Auris Nasus Larynx 41 (2014) 499–501 501

mediate damage. The presence of the blood–labyrinth barrier,which is similar to the blood–brain barrier, should preventantibodies and T cells from entering the inner ear, although thisfunction may be compromised in the presence of inflammation ofthe inner ear, which may be secondary to trauma or viralinfections.

In conclusion, a substantial body of evidence implicates cochlinin the pathogenesis of AIED. It would be reasonable therefore toroutinely test for antibodies to cochlin in patients presenting withunexplained sensorineural hearing loss as a diagnostic tool. Thiscould allow a judicious use of plasmapheresis and cytotoxicimmunosuppressive drugs in patients with sensorineural hearingloss not responding to steroids. Another interesting facet toconsider is the possibility of de-sensitisation protocols to cochlin inthe treatment of AIED. It would be simplistic however to assumethat cochlin is the only autoantigen in the pathogenesis of AIEDwhich often associates with the presence of multiple autoanti-bodies in patient sera. If these antibodies are a cause or aconsequence of inner ear damage by the immune system is aquestion still to be addressed.

Conflict of interest

The author does not have any conflict of interest to declare inrelation to this work.

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