Drug Discovery Department, Halozyme Therapeutics, Inc., San Diego, CA, USA.
F1 Oncology, West Palm Beach, FL, USA.
Glycobiology. 2018 Dec 1;28(12):958-967. doi: 10.1093/glycob/cwy064.
Modification of hyaluronan (HA) accumulation has been shown to play a key role in regulating inflammatory processes linked to the progression of multiple sclerosis (MS). The aim of this study was to characterize the enzymatic activity involved in HA degradation observed within focal demyelinating lesions in the experimental autoimmune encephalomyelitis (EAE) animal model. EAE was induced in 3-month-old female C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein 33-35 (MOG33-35) peptide. The mice were monitored for 21 days. Formalin-fixed paraffin-embedded tissue from control and EAE mice were labeled with an immunoadhesin against HA, antibodies against KIAA1199 and glial fibrillary acidic protein, a marker for astrocytes. In situ hybridization was conducted using a KIAA1199 nucleic acid probe. In histologic sections of spinal cord from EAE mice, abnormal HA accumulation was observed in the close vicinity of the affected areas, whereas HA was totally degraded within the focal loci of damaged tissue. KIAA1199 immunoreactivity was exclusively associated with focal loci in damaged white columns of the spinal cord. KIAA1199 was mainly expressed by activated astrocytes that invaded damaged tissue. Similar findings were observed in tissue from an MS patient. Here, we show that KIAA1199, a protein that plays a role in a HA degradation pathway independent of the canonical hyaluronidases such as PH20, is specifically expressed in tissue lesions in which HA is degraded. KIAA1199 expression by activated astrocytes may explain the focal HA degradation observed during progression of MS and could represent a possible new therapeutic target.
透明质酸（HA）积累的修饰已被证明在调节与多发性硬化症（MS）进展相关的炎症过程中起着关键作用。本研究的目的是表征在实验性自身免疫性脑脊髓炎（EAE）动物模型中的局灶性脱髓鞘病变中观察到的参与 HA 降解的酶活性。通过用髓鞘少突胶质细胞糖蛋白 33-35（MOG33-35）肽免疫接种 3 个月大的雌性 C57BL/6J 小鼠来诱导 EAE。监测小鼠 21 天。用针对 HA 的免疫黏附素、针对 KIAA1199 和神经胶质纤维酸性蛋白（星形胶质细胞的标志物）的抗体对对照和 EAE 小鼠的福尔马林固定石蜡包埋组织进行标记。使用 KIAA1199 核酸探针进行原位杂交。在 EAE 小鼠的脊髓组织的组织学切片中，在受影响区域的附近观察到异常的 HA 积累，而在受损组织的局灶部位 HA 完全降解。KIAA1199 免疫反应性仅与脊髓受损白柱的局灶部位相关。在 MS 患者的组织中也观察到了类似的发现。在这里，我们表明，KIAA1199 是一种在与 PH20 等经典透明质酸酶无关的 HA 降解途径中发挥作用的蛋白质，在 HA 降解的组织病变中特异性表达。激活的星形胶质细胞中 KIAA1199 的表达可能解释了 MS 进展过程中观察到的局灶性 HA 降解，并且可能代表了一个潜在的新的治疗靶点。
