Nguyen Cuong Q, Gao Jue-hua, Kim Hyuna, Saban Daniel R, Cornelius Janet G, Peck Ammon B
Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA.
J Immunol. 2007 Jul 1;179(1):382-90. doi: 10.4049/jimmunol.179.1.382.
NOD.B10-H2(b) and NOD/LtJ mice manifest, respectively, many features of primary and secondary Sjögren's syndrome (SjS), an autoimmune disease affecting primarily the salivary and lacrimal glands leading to xerostomia (dry mouth) and xerophthalmia (dry eyes). B lymphocytes play a central role in the onset of SjS with clinical manifestations dependent on the appearance of autoantibodies reactive to multiple components of acinar cells. Previous studies with NOD.IL4(-/-) and NOD.B10-H2(b).IL4(-/-) mice suggest that the Th2 cytokine, IL-4, plays a vital role in the development and onset of SjS-like disease in the NOD mouse model. To investigate the molecular mechanisms by which IL-4 controls SjS development, a Stat6 gene knockout mouse, NOD.B10-H2(b).C-Stat6(-/-), was constructed and its disease profile was defined and compared with that of NOD.B10-H2(b).C-Stat6(+/+) mice. As the NOD.B10-H2(b).C-Stat6(-/-) mice aged from 4 to 24 wk, they exhibited leukocyte infiltration of the exocrine glands, produced anti-nuclear autoantibodies, and showed loss and gain of saliva-associated proteolytic enzymes, similar to NOD.B10-H2(b).C-Stat6(+/+) mice. In contrast, NOD.B10-H2(b).C-Stat6(-/-) mice failed to develop glandular dysfunction, maintaining normal saliva flow rates. NOD.B10-H2(b).C-Stat6(-/-) mice were found to lack IgG1 isotype-specific anti-muscarinic acetylcholine type-3 receptor autoantibodies. Furthermore, the IgG fractions from NOD.B10-H2(b).C-Stat6(-/-) sera were unable to induce glandular dysfunction when injected into naive recipient C57BL/6 mice. NOD.B10-H2(b).C-Stat6(-/-) mice, like NOD.B10-H2(b).IL4(-/-) mice, are unable to synthesize IgG1 Abs, an observation that correlates with an inability to develop end-stage clinical SjS-like disease. These data imply a requirement for the IL-4/STAT6-pathway for onset of the clinical phase of SjS-like disease in the NOD mouse model.
NOD.B10-H2(b)小鼠和NOD/LtJ小鼠分别表现出原发性和继发性干燥综合征(SjS)的许多特征,干燥综合征是一种自身免疫性疾病,主要影响唾液腺和泪腺,导致口干症(口干)和干眼症(干眼)。B淋巴细胞在干燥综合征的发病中起核心作用,其临床表现取决于对腺泡细胞多种成分有反应的自身抗体的出现。先前对NOD.IL4(-/-)和NOD.B10-H2(b).IL4(-/-)小鼠的研究表明,Th2细胞因子IL-4在NOD小鼠模型中类干燥综合征疾病的发展和发病中起关键作用。为了研究IL-4控制干燥综合征发展的分子机制,构建了Stat6基因敲除小鼠NOD.B10-H2(b).C-Stat6(-/-),并定义了其疾病特征,并与NOD.B10-H2(b).C-Stat6(+/+)小鼠进行比较。随着NOD.B10-H2(b).C-Stat6(-/-)小鼠从4周龄到24周龄,它们表现出外分泌腺的白细胞浸润,产生抗核自身抗体,并显示唾液相关蛋白水解酶的丢失和增加,这与NOD.B10-H2(b).C-Stat6(+/+)小鼠相似。相比之下,NOD.B10-H2(b).C-Stat6(-/-)小鼠未能发展为腺体功能障碍,维持正常的唾液流速。发现NOD.B10-H2(b).C-Stat6(-/-)小鼠缺乏IgG1同种型特异性抗毒蕈碱型乙酰胆碱3型受体自身抗体。此外,当将NOD.B10-H2(b).C-Stat6(-/-)血清的IgG组分注射到未接触过的受体C57BL/6小鼠中时,它们无法诱导腺体功能障碍。NOD.B10-H2(b).C-Stat6(-/-)小鼠与NOD.B10-H2(b).IL4(-/-)小鼠一样,无法合成IgG1抗体,这一观察结果与无法发展为终末期临床类干燥综合征疾病相关。这些数据表明,在NOD小鼠模型中,类干燥综合征疾病临床阶段的发病需要IL-4/STAT6途径。