Elsevier

The Lancet

Volume 360, Issue 9337, 21 September 2002, Pages 915-921
The Lancet

Mechanisms of Disease
Autoantibodies to inner ear and endothelial antigens in Cogan's syndrome

https://doi.org/10.1016/S0140-6736(02)11028-2Get rights and content

Summary

Background

Cogan's syndrome is a chronic inflammatory disease of unknown origin, characterised by sensorineural hearing loss, episcleritis, and vasculitis. An autoimmune origin has been suggested but not proven. Our aim was to establish whether or not an autoimmune process is the cause of the disease.

Methods

We used pooled IgG immunoglobulins derived from eight patients with Cogan's syndrome to screen a random peptide library to identify disease relevant autoantigen peptides. Among the identified peptides, one was recognised by all the patients’ sera. Antibodies against peptides were affinity purified from patients’ sera and used to characterise the autoantigen, to stain human cochlea, and to transfer the features of Cogan's disease into animals.

Findings

We identified an immunodominant peptide that shows similarity with autoantigens such as SSA/Ro and with the reovirus III major core protein lambda 1. The peptide sequence shows similarity also with the cell-density enhanced protein tyrosine phosphatase-1 (DEP-1/CD148), which is expressed on the sensory epithelia of the inner ear and on endothelial cells. IgG antibodies against the peptide, purified from the patients’ sera, recognised autoantigens and DEP-1/CD148 protein, bound human cochlea, and inhibited proliferation of cells expressing DEP-1/CD148. The same antibodies bound connexin 26, gene mutations of which lead to congenital inner-ear deafness. Furthermore, these antibodies were able to induce the features of Cogan's disease in mice.

Interpretation

Our results indicate that Cogan's syndrome is an autoimmune disease, characterised by the presence of autoantibodies able to induce tissue damage on binding of cell-surface molecules present on the sensory epithelia of the inner ear and on endothelial cells.

Introduction

Cogan's syndrome is a multisystem disease of unknown origin that arises mainly in children and young adults; its main clinical features are vestibuloauditory dysfunction and non-syphilitic interstitial keratitis,1 which causes eye pain, photophobia, and blurred vision. Vestibuloauditory dysfunction starts abruptly with Meniere-like attacks of vertigo, ataxia, tinnitus, nausea, vomiting, and sudden hearing loss. Inner ear manifestations and eye disease can develop at the same time or 1–2 years apart. Systemic disease arises in about half of cases.2 Constitutional features, such as fever and weight loss, are associated with active vasculitis, which can involve the aorta or medium and small vessels.3 Systemic necrotising vasculitis can lead to a myriad of organ system manifestations.1 Central and peripheral nervous system abnormalities, such as cerebellar involvement, meningeal syndrome, and peripheral neuropathy are also present in up to 50% of patients.4, 5 Permanent hearing loss and cardiovascular disease are the main causes of morbidity in Cogan's syndrome. Histological analysis of the inner ear shows degeneration of the sensory receptors and supporting structures of the cochlea and vestibular apparatus, and demyelinisation and atrophy of the vestibular and cochlear branches of the eighth cranial nerve.1

The cause of Cogan's syndrome is unknown; infections of the upper respiratory tract precede the onset of disease in 50% of cases, suggesting an infectious origin.6 Chlamydial infection in particular has received much attention for its ability to elude host defence mechanisms and cause chronic infection. However, a direct link between different Chlamydia species and Cogan's syndrome has not been proven.1 Immunological mechanisms play a part in disease pathogenesis, and the finding of serum antibodies to as yet undefined corneal antigens and to a mixture of inner ear extracts in patients with the disease7, 8 suggests that autoimmunity could initiate or perpetuate the immune response.9 The presence of rheumatoid factor10 and of cytoplasmic autoantibodies against neutrophils10, 11 in some patients with the disease, lends support to this notion. Our aim was to establish whether or not an autoimmune process is the cause of Cogan's syndrome.

Section snippets

Participants

We enrolled patients with Cogan's syndrome between December, 1995, and January, 1999. Diagnosis of the disease was based on the presence of inflammatory eye disease and vestibuloauditory dysfunction, leading to hearing loss. As controls, we used sera from individuals with rheumatoid arthritis or systemic lupus erythematosus (diagnosed with the American College for Rheumatology criteria), and from a group of age-matched and sex-matched healthy individuals. The local ethics committee approved the

Results

We obtained IgG from eight individuals (five men and three women, age at onset of disease 14–26 years) with Cogan's syndrome. Six patients had interstitial keratitis and two had uveitis. Vasculitis was present in three patients (aortitis in one and medium-vessel vasculitis in two). One patient had splenomegaly and another had abdominal pain and arthralgia. Five patients underwent cochlear implant.

We sequenced a peptide (the Cogan peptide; SGRDTSIQILWI) once after the second biopanning round and

Discussion

Our findings show that DEP-1/CD148 is a pathogenetically relevant autoantigen target in Cogan's syndrome. DEP-1/CD148 is thought to be involved in mechanisms of differentiation and contact inhibition of cell growth;26 it is a widespread cell-surface antigen and is present on endothelial cells and supporting cells within the sensorineural epithelia of the inner ear. The distribution of the DEP-1/CD148 antigen explains the wide clinical spectrum of Cogan's syndrome, including the neurological

GLOSSARY

auditory brainstem response (abr)
The response that originates from the auditory pathway, mostly from within the brainstem, after an acoustic stimulus, for example clicks, and which is recorded from the surface of the skull. This technique is routinely used in animals, since they represent important models for the study of genetic deafness.
connexin 26
A protein of the connexin family, whose members are important in intercellular communication. Connexin 26 is a gap junction protein selectively

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