The cause of CS is unknown, but it has long been suspected to be triggered by infection. In approximately 40% of cases, the onset of CS is preceded by an infectious illness; however, numerous studies addressing this question have failed to uncover evidence of an inciting microbial agent. The clinical and pathological features of CS are compatible with a disease pathogenesis based on immune-mediated mechanisms. The ocular and vestibuloauditory manifestations of CS typically follow a relapsing-remitting course, which supports the concept of an immune-mediated process. In addition, CS has been associated with other immune-mediated systemic inflammatory diseases such as vasculitis. Moreover, patients with CS may improve using corticosteroid or other immunosuppressive therapies.
The histopathology of the IK lesions in CS reveals an infiltration of lymphocytes and plasma cells in the deeper layers of the cornea. The cornea and anterior chamber of the eye are usually considered immunologically privileged sites, as described previously. The insult in CS presumably revokes this immunological privilege by promoting corneal neovascularization, which, in turn, allows inflammatory cells to access these sites. In response to antigenic challenge or other "danger signals," corneal tissue has been shown to upregulate expression of proinflammatory cytokines such as tumor necrosis factor (TNF)-a and IL-1, which promotes trafficking of antigen-presenting cells from the intravascular space to the corneal tissue, as well as from the cornea to the regional lymph nodes (21). These mechanisms, together with upregulation of critical costimulatory molecules, prime naïve T-cells and elicit an adaptive immune response.
Although the blood-labyrinthine barrier was initially believed to protect the inner ear from an immune stimulus, subsequent work has shown that the inner ear is capable of eliciting a robust inflammatory response (22). Indeed, the inner ear has multiple routes of communication with the immune system, including a separate lymphatic drainage to the cervical lymph nodes (23). Experimentally, antigenic challenge in the inner ear can result in rapid accumulation of leukocytes (including activated T- and B-cells) that enter from the systemic circulation through the spiral modiolar veins. In animal studies, chronic inflammation of the inner ear, regardless of the nature of the insult, leads to accumulation of extracellular matrix and endolymphatic hydrops, and ultimately ossification. Further work in animals indicates that systemic activation of innate immunity (e.g., injection of lipopolysaccharide) can enhance the adaptive immune response to antigen challenge in the inner ear (24). The pathologic descriptions of the vestibuloauditory apparatus are limited to a few autopsy reports. Temporal bone specimens from these cases imply that the earliest lesions consist of lymphocytic and plasma cell infiltration of the spiral ligament, endolymphatic hydrops, degeneration of the Organ of Corti, and demyelination of the vestibular and cochlear branches of cranial nerve VIII (25). The specimens from patients with late disease showed extensive new bone formation, severe hydrops, and degeneration of the sensory receptors and supporting structures (26,27). Importantly, histopathological signs of vasculitis were absent in these specimens.
The eye and inner ear disease in CS has been postulated to result from organ-system-specific autoimmunity. While a few studies have described antibodies to corneal antigens, the most compelling evidence for organ-system autoimmunity in CS comes from recent work characterizing a putative autoantigen from the inner ear. In this study, antibodies in sera from eight patients with CS were shown to bind a peptide antigen sharing sequence homology with CD148 (cell-density enhanced protein tyrosine phosphatase-1) and connexin 26 (28), which are two proteins expressed in the inner ear. Interestingly, connexin 26 has been implicated in congenital deafness. These antibodies also cross-react with Ro/Sjogren's Syndrome A (Ro/SSA), a known autoantigen and the major core protein lambda 1 of Rheovirus III. They were not present in sera from 25 patients with rheumatoid arthritis, 25 patients with systemic lupus erythematosus, or 40 healthy controls. Moreover, affinity-purified antibodies to this peptide were also shown to react with human cochlear tissue, and to cause corneal pathology, hearing loss, and vasculitis when passively transferred to Balb/c mice (28).
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