Department of Rheumatology and Immunology, Medical University of Graz, Graz, Austria.
Department of Neurology, Harvard Medical School, Brigham and Women's Hospital, Harvard, MA, USA.
Rheumatology (Oxford). 2021 Feb 1;60(2):588-597. doi: 10.1093/rheumatology/keaa105.
To investigate peripheral lymphopenia, a frequent finding in primary Sjögren's syndrome (pSS) associated with higher disease activity and increased mortality.
Prospective, cross-sectional study of consecutive patients with pSS (n = 66) and healthy controls (n = 181). Lymphocyte subsets were analysed by flow cytometry, naïve (CD45RA+) and memory (CD45RO+) CD4+ T cells were purified by MACS technology. In vitro proliferation and senescence-associated β-galactosidase (SABG) were assessed by flow cytometry. Telomere length and TCR excision circles (TREC) were measured by real-time PCR. Telomerase activity was analysed according to the telomeric repeat amplification protocols (TRAP).
In pSS, lymphopenia mainly affected naïve CD4+ T cells. We noted a lower frequency of proliferating naïve CD4+ T cells ex vivo and decreased homeostatic proliferation in response to IL-7 stimulation in vitro. Furthermore, naïve CD4+ T cells exhibited signs of immune cell aging including shortened telomeres, a reduction in IL-7R expression and accumulation of SABG. The senescent phenotype could be explained by telomerase insufficiency and drastically reduced levels of T-cell receptor excision circles (TRECs), indicating a history of extensive post-thymic cell division. TRECs correlated with the number of naïve CD4+ T cells linking the extend of earlier proliferation to the inability to sustain normal cell numbers.
In pSS, evidence for increased proliferation of naïve CD4+ T cells earlier in life is associated with a senescent phenotype unable to sustain homeostasis. The lack of naïve CD4+ T cells forms the basis of lymphopenia frequently observed in pSS.
研究外周血淋巴细胞减少症，这是原发性干燥综合征（pSS）的常见表现，与更高的疾病活动度和更高的死亡率相关。
对连续的 pSS 患者（n=66）和健康对照者（n=181）进行前瞻性、横断面研究。采用流式细胞术分析淋巴细胞亚群，通过 MACS 技术纯化幼稚（CD45RA+）和记忆（CD45RO+）CD4+T 细胞。通过流式细胞术评估体外增殖和衰老相关β-半乳糖苷酶（SABG）。通过实时 PCR 测量端粒长度和 T 细胞受体切除环（TREC）。根据端粒重复扩增协议（TRAP）分析端粒酶活性。
在 pSS 中，淋巴细胞减少主要影响幼稚 CD4+T 细胞。我们发现，体外幼稚 CD4+T 细胞的增殖频率较低，对 IL-7 刺激的稳态增殖减少。此外，幼稚 CD4+T 细胞表现出免疫细胞衰老的迹象，包括端粒缩短、IL-7R 表达减少和 SABG 积累。衰老表型可通过端粒酶不足和 T 细胞受体切除环（TREC）水平显著降低来解释，这表明广泛的胸腺后细胞分裂史。TRECs 与幼稚 CD4+T 细胞数量相关，将早期增殖的程度与维持正常细胞数量的能力联系起来。
在 pSS 中，生命早期幼稚 CD4+T 细胞增殖增加的证据与无法维持体内平衡的衰老表型相关。幼稚 CD4+T 细胞数量减少是 pSS 中经常观察到的淋巴细胞减少症的基础。
