骨形态发生蛋白6与干燥综合征患者及小鼠外分泌腺功能障碍的关联
Association of bone morphogenetic protein 6 with exocrine gland dysfunction in patients with Sjögren's syndrome and in mice.
作者信息
Yin Hongen, Cabrera-Perez Javier, Lai Zhenan, Michael Drew, Weller Melodie, Swaim William D, Liu Xibao, Catalán Marcelo A, Rocha Eduardo M, Ismail Nevien, Afione Sandra, Rana Noreen A, Di Pasquale Giovanni, Alevizos Ilias, Ambudkar Indu, Illei Gabor G, Chiorini John A
机构信息
National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland.
出版信息
Arthritis Rheum. 2013 Dec;65(12):3228-38. doi: 10.1002/art.38123.
OBJECTIVE
Primary Sjögren's syndrome (SS) is characterized by autoimmune activation and loss of function in secretory epithelia. The present study was undertaken to investigate and characterize changes in the epithelia associated with the loss of gland function in primary SS.
METHODS
To identify changes in epithelial gene expression, custom microarrays were probed with complementary RNA (cRNA) isolated from minor salivary glands (MSGs) of female patients with primary SS who had low focus scores and low salivary flow rates, and the results were compared with those obtained using cRNA from the MSGs of sex-matched healthy volunteers. The effect of bone morphogenetic protein 6 (BMP-6) on salivary gland function was tested using adeno-associated virus-mediated gene transfer to the salivary glands of C57BL/6 mice.
RESULTS
A significant increase in expression of BMP-6 was observed in RNA isolated from SS patients compared with healthy volunteers. Overexpression of BMP-6 locally in the salivary or lacrimal glands of mice resulted in the loss of fluid secretion as well as changes in the connective tissue of the salivary gland. Assessment of the fluid movement in either isolated acinar cells from mice overexpressing BMP-6 or a human salivary gland cell line cultured with BMP-6 revealed a loss in volume regulation in these cells. Lymphocytic infiltration in the submandibular gland of BMP-6 vector-treated mice was increased. No significant changes in the production of proinflammatory cytokines or autoantibodies associated with SS (anti-Ro/SSA and anti-La/SSB) were found after BMP-6 overexpression.
CONCLUSION
In addition to identifying BMP-6 expression in association with xerostomia and xerophthalmia in primary SS, the present results suggest that BMP-6-induced salivary and lacrimal gland dysfunction in primary SS is independent of the autoantibodies and immune activation associated with the disease.
目的
原发性干燥综合征（SS）的特征是自身免疫激活和分泌上皮功能丧失。本研究旨在调查和描述原发性SS中与腺体功能丧失相关的上皮细胞变化。
方法
为了鉴定上皮基因表达的变化，用从原发性SS女性患者小唾液腺（MSG）中分离的互补RNA（cRNA）对定制微阵列进行检测，这些患者聚焦评分低且唾液流速低，并将结果与使用性别匹配的健康志愿者MSG的cRNA获得的结果进行比较。使用腺相关病毒介导的基因转移至C57BL/6小鼠的唾液腺来测试骨形态发生蛋白6（BMP-6）对唾液腺功能的影响。
结果
与健康志愿者相比，在从SS患者分离的RNA中观察到BMP-6表达显著增加。在小鼠唾液腺或泪腺中局部过表达BMP-6导致液体分泌丧失以及唾液腺结缔组织变化。对过表达BMP-6的小鼠分离的腺泡细胞或用BMP-6培养的人唾液腺细胞系中的液体运动进行评估，发现这些细胞的体积调节丧失。BMP-6载体处理的小鼠下颌下腺中的淋巴细胞浸润增加。BMP-6过表达后，未发现与SS相关的促炎细胞因子或自身抗体（抗Ro/SSA和抗La/SSB）产生有显著变化。
结论
除了鉴定原发性SS中与口干和眼干相关的BMP-6表达外，本研究结果表明原发性SS中BMP-6诱导的唾液腺和泪腺功能障碍独立于与该疾病相关的自身抗体和免疫激活。
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