Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
Front Immunol. 2019 Mar 13;10:416. doi: 10.3389/fimmu.2019.00416. eCollection 2019.
Inherited defects in adenosine deaminase (ADA) cause severe immune deficiency, which can be corrected by ADA enzyme replacement therapy (ERT). Additionally, ADA-deficient patients suffer from hearing impairment. We hypothesized that ADA-deficient (-/-) mice also exhibit hearing abnormalities and that ERT from an early age will improve the hearing and immune defects in these mice. Auditory brainstem evoked responses, organ weights, thymocytes numbers, and subpopulations, lymphocytes in peripheral blood as well as T lymphocytes in spleen were analyzed in ADA-/- and ADA-proficient littermate post-partum (pp). The cochlea was visualized by scanning electron microscopy (SEM). The effects of polyethylene glycol conjugated ADA (PEG-ADA) ERT or 40% oxygen initiated at 7 days pp on the hearing and immune abnormalities were assessed. Markedly abnormal hearing thresholds responses were found in ADA-/- mice at low and medium tone frequencies. SEM demonstrated extensive damage to the cochlear hair cells of ADA-/- mice, which were splayed, short or missing, correlating with the hearing deficits. The hearing defects were not reversed when hypoxia in ADA-/- mice was corrected. Progressive immune abnormalities were detected in ADA-/- mice from 4 days pp, initially affecting the thymus followed by peripheral lymphocytes and T cells in the spleen. ERT initiated at 7 days pp significantly improved the hearing of ADA-/- mice as well as the number of thymocytes and T lymphocytes, although not all normalized. ADA deficiency is associated with hearing deficits and damage to cochlear hair cells. Early initiation of ERT improves the hearing and immune abnormalities.
腺苷脱氨酶（ADA）遗传缺陷导致严重免疫缺陷，可以通过 ADA 酶替代疗法（ERT）纠正。此外，ADA 缺陷患者还会遭受听力损伤。我们假设 ADA 缺陷（-/-）小鼠也表现出听力异常，并且早期的 ERT 将改善这些小鼠的听力和免疫缺陷。在产后（pp）时，分析 ADA-/-和 ADA 功能正常的同窝仔鼠的听觉脑干诱发反应、器官重量、胸腺细胞数量和亚群、外周血中的淋巴细胞以及脾中的 T 淋巴细胞。通过扫描电子显微镜（SEM）观察耳蜗。评估聚乙二醇缀合 ADA（PEG-ADA）ERT 或 7 天时开始的 40%氧气对听力和免疫异常的影响。ADA-/- 小鼠在低频和中频时发现明显异常的听力阈值反应。SEM 显示 ADA-/- 小鼠的耳蜗毛细胞广泛受损，毛细胞张开、缩短或缺失，与听力缺陷相关。当 ADA-/- 小鼠的缺氧得到纠正时，听力缺陷并未逆转。ADA-/- 小鼠从第 4 天开始出现进行性免疫异常，最初影响胸腺，随后影响外周淋巴细胞和脾中的 T 细胞。ERT 从第 7 天开始显著改善 ADA-/- 小鼠的听力以及胸腺细胞和 T 淋巴细胞的数量，尽管并非所有都正常化。ADA 缺乏与听力缺陷和耳蜗毛细胞损伤有关。早期开始 ERT 可改善听力和免疫异常。
