Mechanisms of DiseaseAutoantibodies to inner ear and endothelial antigens in Cogan's syndrome
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.
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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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