William Harvey Research Institute, Queen Mary University of London, London, UK.
Arthritis Rheumatol. 2014 Sep;66(9):2545-57. doi: 10.1002/art.38726.
To examine whether the B cell tropic γ-herpesvirus Epstein-Barr virus (EBV) is aberrantly expressed in its latent and lytic forms within ectopic lymphoid structures (ELS) in the salivary glands of patients with Sjögren's syndrome (SS), and to investigate the relationship between EBV dysregulation, B cell activation, in situ differentiation of autoreactive plasma cells, disease-specific autoantibody production, and cytotoxicity.
Latent and lytic EBV infection in the salivary glands of 28 patients with SS and 38 patients with nonspecific chronic sialadenitis (NSCS), characterized for the presence or absence of ELS, was investigated by reverse transcription-polymerase chain reaction, in situ hybridization, and immunohistochemical/immunofluorescence staining. Glandular versus synovial production of anti-Ro 52, anti-citrullinated protein antibodies (ACPAs), and anti-EBV peptide antibodies was analyzed in situ or in vivo in human SS/SCID and human rheumatoid arthritis/SCID mouse chimeras.
EBV dysregulation within inflammatory infiltrates was observed exclusively in ELS+ SS salivary gland tissue, as revealed by latent EBV infection and lytic EBV infection in B cells and plasma cells, respectively. Conversely, epithelial latent membrane protein 2A expression was observed in both patients with SS and patients with NSCS. Importantly, perifollicular plasma cells displaying Ro 52 immunoreactivity were frequently infected by EBV. Furthermore, ELS-containing SS salivary gland tissue that was transplanted into SCID mice supported the production of anti-Ro 52/anti-La 48 and anti-EBV antibodies but not ACPAs. Analysis of CD4+ and CD8+ T cell localization and granzyme B expression demonstrated that the persistence of EBV in ELS-containing SS salivary glands was associated with follicular exclusion of CD8+ T cells and impaired CD8-mediated cytotoxicity.
Active EBV infection is selectively associated with ELS in the salivary glands of patients with SS and appears to contribute to local growth and differentiation of disease-specific autoreactive B cells.
研究在干燥综合征（SS）患者唾液腺异位淋巴样结构（ELS）中，B 细胞亲嗜性γ疱疹病毒 EBV 是否以潜伏和裂解形式异常表达，并探讨 EBV 失调、B 细胞活化、自身反应性浆细胞原位分化、疾病特异性自身抗体产生和细胞毒性之间的关系。
采用逆转录-聚合酶链反应、原位杂交和免疫组化/免疫荧光染色，检测 28 例 SS 患者和 38 例非特异性慢性涎腺炎（NSCS）患者唾液腺中 EBV 的潜伏和裂解感染，这些患者的 ELS 存在或不存在。在人 SS/SCID 和人类风湿关节炎/SCID 嵌合小鼠中，通过体内或体外分析，检测抗 Ro 52、抗瓜氨酸化蛋白抗体（ACPAs）和抗 EBV 肽抗体在腺体和滑膜中的产生情况。
仅在 ELS+SS 唾液腺组织的炎症浸润中观察到 EBV 失调，表现为 B 细胞和浆细胞中的潜伏 EBV 感染和裂解 EBV 感染。相反，SS 患者和 NSCS 患者的上皮细胞潜伏膜蛋白 2A 表达均可见。重要的是，具有 Ro 52 免疫反应性的滤泡周围浆细胞经常被 EBV 感染。此外，移植到 SCID 小鼠中的含有 ELS 的 SS 唾液腺组织支持抗 Ro 52/抗 La 48 和抗 EBV 抗体的产生，但不支持 ACPA 的产生。分析 CD4+和 CD8+T 细胞定位和颗粒酶 B 表达表明，在含有 ELS 的 SS 唾液腺中 EBV 的持续存在与滤泡中 CD8+T 细胞的排除和 CD8 介导的细胞毒性受损有关。
活跃的 EBV 感染与 SS 患者唾液腺中的 ELS 选择性相关，似乎有助于疾病特异性自身反应性 B 细胞的局部生长和分化。
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