Mechanisms of inflammation in Meniere's disease

Abstract

Meniere's disease [MD; MIM 156000] is a chronic disorder with a prevalence of ~ 0.5-1 / 1000 which is characterized by attacks of vertigo associated with sensorineural hearing loss involving low to medium frequencies. Although its etiology remains unknown, MD is often found in families with incomplete phenotypic forms, leading to a high clinical heterogeneity. Furthermore, several evidences have associated MD with autoimmunity where allelic variation in the innate immune response and inflammation genes seem to contribute the hearing outcome of the disease. Otherwise, multiple studies have demonstrated an epidemiologic association between allergy status and MD. With this in mind, the goals of this PhD thesis were: first, to define a clinical group of patients with autoimmune MD within a large cohort of MD patients using two-step cluster analysis. Second, to identify allelic variants associated with autoimmune MD that could be used as genetic markers and, to investigate their role in MD inflammatory response performing gene expression analysis in the SNV carriers and using proliferation and confocal assays. Finally, to define the effect of allergenic extracts from Penicillium and Aspergillus in proinflammatory cytokines and gene expression profile in MD patients PBMCs. Our findings support that: 1) There are 5 clinical subgroups in uni- and bilateral MD; a subgroup of patients was associated with another autoimmune disease (MD type 5, 11%). 2) A locus at 6p21.33, suggests an association with bilateral MD, which could regulate pathways involving TNF family members and through NFκB-mediated inflammation. 3) There are two different subgroups of MD patients according to their basal levels of cytokines and, mold extracts are able to trigger a significant release of IL-6 and TNF-α in MD patients when compared to healthy controls. We have found evidences that support several mechanisms of inflammation involving proinflammatory cytokines, regulation of TWEAK/Fn14 pathway and an aberrant response to mold extracts in MD patients.