Autoimmune sensorineural hearing loss (ASNHL) is characterized typically by bilateral, rapidly progressive hearing loss that responds therapeutically to corticosteroid treatment. Despite its name, data implicating autoimmunity in the etiopathogenesis of ASNHL have been limited, and targeted self-antigens have not been identified. In the current study we show that the inner ear–specific proteins cochlin and β-tectorin are capable of targeting experimental autoimmune hearing loss (EAHL) in mice. Five weeks after immunization of SWXJ mice with either Coch 131–150 or β-tectorin 71–90, auditory brainstem responses (ABR) showed significant hearing loss at all frequencies tested. Flow cytometry analysis showed that each peptide selectively activated CD4+ T cells with a proinflammatory Th1-like phenotype. T cell mediation of EAHL was determined by showing significantly increased ABR thresholds 6 weeks after adoptive transfer of peptide-activated CD4+ T cells into naive SWXJ recipients. Immunocytochemical analysis showed that leukocytic infiltration of inner ear tissues coincided with onset of hearing loss. Our study provides a contemporary mouse model for clarifying our understanding of ASNHL and facilitating the development of novel effective treatments for this clinical entity. Moreover, our data provide experimental confirmation that ASNHL may be a T cell–mediated organ-specific autoimmune disorder of the inner ear
The middle ear consists of a tympanic membrane, ligaments, tendons, and three ossicles. An important function of the tympanic membrane is to deliver exterior sound stimulus to the ossicles and inner ear. In this study, the responses of the tympanic membrane in a human ear were measured and compared with those of a finite element model of the middle ear. A laser Doppler vibrometer (LDV) was used to measure the dynamic responses of the tympanic membrane, which had the measurement point on the cone of light of the tympanic membrane. The measured subjects were five Korean male adults and a cadaver. The tympanic membranes were stimulated using pure-tone sine waves at 18 center frequencies of one-third octave band over a frequency range of 200 Hz ~10 kHz with 60 and 80 dB sound pressure levels. The measured responses were converted into the umbo displacement transfer function (UDTF) with a linearity assumption. The measured UDTFs were compared with the calculated UDTFs using a finite element model for the Korean human middle ear. The finite element model of the middle ear consists of three ossicles, a tympanic membrane, ligaments, and tendons. In the finite element model, the umbo displacements were calculated under a unit sound pressure on the tympanic membrane. The UDTF of the finite element model exhibited good agreement with that of the experimental one in low frequency range, whereas in higher frequency band, the two response functions deviated from each other, which demonstrates that the finite element model should be updated with more accurate material properties and/or a frequency dependent material model.
Inflammatory response and calcification are strongly implicated in osteoarthritis (OA) progression. Key inflammatory biomarkers present throughout the process of OA have been established but an association with calcification has not been clarified. A faint line, tidemark, exists between the subchondral bone and the articular surface in knee joints that is presumed to be the line of demarcation between calcified and uncalcified cartilage. This study shows that the tidemark is where calcification is actively occurring. Mouse knees (n=8) were stained for both Alkaline Phosphatase (ALP) and Safranin-O/Fast Green. ALP, active during tissue calcification, was used to identify the true location of calcification. Images from both stains were overlaid for comparison of complementary tissues. The cartilage area above the tidemark was then compared to the area above the ALP line of calcification. Because the two areas proved to be nearly statistically identical, the conclusion is that the tidemark observed in the Safranin-O/Fast Green stain is indeed the line of calcification for articular cartilage. The role of calcification in OA was further examined by comparing NPP1, calcification marker, with HtrA1. We demonstrate a reciprocal correlation between HtrA1 and NPP1, suggesting a link between pathological calcification and inflammation in joints experiencing OA.
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