Koetz K, Bryl E, Spickschen K, O'Fallon W M, Goronzy J J, Weyand C M
Departments of Medicine and Immunology, and Section of Biostatistics, Mayo Clinic, Rochester, MN 55905, USA.
Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9203-8. doi: 10.1073/pnas.97.16.9203.
The immune system is equipped with an extremely large spectrum of structurally diverse receptors to recognize all potential antigens. This fundamental principle of receptor diversity is no longer upheld in patients with rheumatoid arthritis (RA), who have a marked contraction of the T cell receptor repertoire. In this study, the ability of RA patients to produce T cells and to maintain T cell homeostasis was examined. CD4 T cells containing T cell receptor rearrangement excision circles (TREC) were substantially reduced in RA patients; TREC levels in young adult patients matched those of controls 20 years older. Increased self-replication of T cells in RA was indicated by age-inappropriate erosion of telomeres in circulating T cells with almost complete attrition of telomeric reserves in patients 20-30 yr of age. The degree of telomere loss was not related to disease duration or the use of disease-modifying medication and was most pronounced in CD4(+)CD45RO(null) (naive) T cells. The loss of TREC-positive T cells could be a consequence of a primary defect in peripheral T cell homeostasis. Alternatively, RA patients may have impaired thymic function with the increased turnover of peripheral T cells being a secondary compensatory event.
免疫系统配备了种类极其繁多、结构各异的受体，以识别所有潜在抗原。类风湿关节炎（RA）患者不再遵循这一受体多样性的基本原理，这类患者的T细胞受体库明显收缩。在本研究中，对RA患者产生T细胞及维持T细胞稳态的能力进行了检测。含T细胞受体重排切除环（TREC）的CD4 T细胞在RA患者中显著减少；年轻成年患者的TREC水平与年长20岁的对照组相当。RA中T细胞自我复制增加的表现为，循环T细胞中端粒出现与年龄不符的缩短，在20至30岁的患者中，端粒储备几乎完全耗竭。端粒丢失程度与疾病持续时间或使用改善病情的药物无关，在CD4(+)CD45RO(null)（初始）T细胞中最为明显。TREC阳性T细胞的丢失可能是外周T细胞稳态原发性缺陷的结果。或者，RA患者可能存在胸腺功能受损，外周T细胞更新增加是继发的代偿事件。
