Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Ann Rheum Dis. 2021 Jul;80(7):912-919. doi: 10.1136/annrheumdis-2020-218918. Epub 2021 Jan 25.
Systemic sclerosis (SSc) is an autoimmune fibrotic disease affecting multiple tissues including the lung. A subset of patients with SSc with lung disease exhibit short telomeres in circulating lymphocytes, but the mechanisms underlying this observation are unclear.
Sera from the Johns Hopkins and University of California, San Francisco (UCSF) Scleroderma Centers were screened for autoantibodies targeting telomerase and the shelterin proteins using immunoprecipitation and ELISA. We determined the relationship between autoantibodies targeting the shelterin protein TERF1 and telomere length in peripheral leucocytes measured by qPCR and flow cytometry and fluorescent in situ hybridisation (Flow-FISH). We also explored clinical associations of these autoantibodies.
In a subset of patients with SSc, we identified autoantibodies targeting telomerase and the shelterin proteins that were rarely present in rheumatoid arthritis, myositis and healthy controls. TERF1 autoantibodies were present in 40/442 (9.0%) patients with SSc and were associated with severe lung disease (OR 2.4, p=0.04, Fisher's exact test) and short lymphocyte telomere length. 6/6 (100%) patients with TERF1 autoantibodies in the Hopkins cohort and 14/18 (78%) patients in the UCSF cohort had a shorter telomere length in lymphocytes or leukocytes, respectively, relative to the expected age-adjusted telomere length. TERF1 autoantibodies were present in 11/152 (7.2%) patients with idiopathic pulmonary fibrosis (IPF), a fibrotic lung disease believed to be mediated by telomere dysfunction.
Autoantibodies targeting telomere-associated proteins in a subset of patients with SSc are associated with short lymphocyte telomere length and lung disease. The specificity of these autoantibodies for SSc and IPF suggests that telomere dysfunction may have a distinct role in the pathogenesis of SSc and pulmonary fibrosis.
系统性硬化症（SSc）是一种影响包括肺部在内的多种组织的自身免疫性纤维化疾病。一小部分患有肺部疾病的 SSc 患者的循环淋巴细胞中存在短端粒，但这一观察结果的机制尚不清楚。
使用免疫沉淀和 ELISA 从约翰霍普金斯大学和加利福尼亚大学旧金山分校（UCSF）硬皮病中心的血清中筛选针对端粒酶和庇护蛋白的自身抗体。我们通过 qPCR 和流式细胞术和荧光原位杂交（Flow-FISH）确定针对外周白细胞中端粒长度的庇护蛋白 TERF1 的自身抗体与端粒长度之间的关系。我们还探讨了这些自身抗体的临床相关性。
在一小部分 SSc 患者中，我们鉴定出了针对端粒酶和庇护蛋白的自身抗体，这些抗体在类风湿关节炎、肌炎和健康对照中很少出现。TERF1 自身抗体存在于 442 例 SSc 患者中的 40 例（9.0%）中，与严重的肺部疾病（OR 2.4，p=0.04，Fisher 确切检验）和短淋巴细胞端粒长度相关。在 Hopkins 队列中，6/6（100%）具有 TERF1 自身抗体的患者和在 UCSF 队列中，14/18（78%）具有 TERF1 自身抗体的患者的淋巴细胞或白细胞中的端粒长度分别短于预期的年龄调整端粒长度。TERF1 自身抗体存在于 152 例特发性肺纤维化（IPF）患者中的 11 例（7.2%）中，这是一种纤维化肺部疾病，据信是由端粒功能障碍介导的。
在一小部分 SSc 患者中针对端粒相关蛋白的自身抗体与短端粒淋巴细胞长度和肺部疾病相关。这些自身抗体对 SSc 和 IPF 的特异性表明，端粒功能障碍可能在 SSc 和肺纤维化的发病机制中具有独特的作用。
