Experimental Hyperactivity of the Endolymphatic Sac

Abstract

Injury to the endolymphatic sac may play an important role in the pathogenesis of Ménière’s disease, an inner ear disorder characterized by hearing loss, tinnitus and attacks of vertigo. Isoimmunization of 16 inbred Lewis rats with a crude endolymphatic sac extract and complete Freund’s adjuvant induced hyperactivity of the endolymphatic sac. One group of rats was immunized by a single dose whereas a second group was immunized twice. Control animals were injected with Freund’s adjuvant in saline only. Serum was collected from all rats by the end of the study and harvested autoantibodies were tested by immunohistochemistry. The endolymphatic sacs were investigated by transmission electron microscopy. Endolymphatic sac stimulation was observed in all immunized rats. Based on detailed ultrastructural observations, the degree of reactivity seemed proportional to the number of injections and the extent of immunization. Moreover, the ribosome-rich cells seemed hyperactive with an extravagant content of intracellular components: numerous rough endoplasmic reticulum and free ribosomes, morphological signs of extensive endo- and exocytosis, vesicles of material with a density similar to the homogeneous substance of which many were observed to fuse with primary lysozymes. Basolateral foldings were numerous and in the subepithelial capillaries formation of multiple and apposing fenestrations were observed. No endolymphatic sac stimulation was observed in the control animals. Specific ribosome-rich cell alterations identical to those present in the endolymphatic sac of Ménière’s disease were observed 21 days after the first immunization. The observations suggest that either an autoantigen or a trophic factor, capable of inducing a hyperactivity of the ribosome-rich cells and an imbalance of the homogeneous substance metabolism, exists in the endolymphatic sac of the rat.

Auto-inflammatory challenge of the endolymphatic sac – Cochlear damage measured by distortion product oto-acoustic emissions

“…The protocol for use of ES extract for auto-immunization has previously been documented. In an immunization experiment similar to this study, the ES epithelial cell changes such as hyperactivity of the ribosome-rich cells and displacement of the mitochondria-rich cells were observed [6]. The changes were suggested to be the result of a chronic auto-inflammatory response in the epithelium of the ES.…”

“…An explanation for the hearing loss in MD could be a compromised function of the ES and its capacity to participate in the endolymph homeostasis due to attacks of the ES, as suggested in the autoimmune saccitis model [6]. The autoimmune saccitis model suggested that attacks by auto-antigens, an inflammatory response, and recurrent focal inflammation of the ES epithelium could cause MD.…”

“…Also, a significant association between MD and autoantibodies increments has been demonstrated [3,4] and some cases of MD may be attributed to an autoimmune mechanism dependent on a humoral and/or a cellular response [5]. Additionally, an autoimmune injury of the endolymphatic sac (ES) is suggested to play an important role in the pathogenesis of MD [6,7].…”

“Reversed polarization” of Na/K-ATPase—a sign of inverted transport in the human endolymphatic sac: a super-resolution structured illumination microscopy (SR-SIM) study

“…In a recent case-control study (Kolla and Litwack 2000), the authors found a gene locus associated with bilateral MD suggesting that carriers may develop a NF-κB-mediated inflammatory response in MD. Friis et al (2013) found that the ES of rats that were isoimmunized with an ES extract developed specific tissue alterations identical to those present in the ES of active MD. Those findings support the theory that an immune injury may be important in the pathogenesis in MD.…”

Gene expression demonstrates an immunological capacity of the human endolymphatic sac

“…The localization of immunofluorescent labeling of the TLRs in the ES epithelium suggests that the receptors are located on the nonspecific (or immature) epithelial cells and/or the ribosome rich cells. Interestingly, the latter are implicated in the hyperreactivity seen in an experimental animal study of ES isoimmunization and the induction of autoimmune disease. In this perspective, it is also intriguing that the above‐mentioned cytokines, including variants of IL17, previously have been suggested to play a role in autoimmune diseases …”