Kuwana M, Feghali C A, Medsger T A, Wright T M
University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Arthritis Rheum. 2001 Jul;44(7):1654-9. doi: 10.1002/1529-0131(200107)44:7<1654::AID-ART288>3.0.CO;2-O.
To examine T and B cell responses to topoisomerase I (topo I) in a monozygotic twin pair discordant for systemic sclerosis (SSc).
The peripheral blood T cell proliferative responses induced by topo I and in vitro anti-topo I antibody production in cultures of T and B cells were examined in an SSc patient with serum anti-topo I antibody and in her healthy monozygotic twin. Topo I-reactive T cell lines were generated from the twin pair and analyzed for antigenic specificity, major histocompatibility complex class II restriction, and T cell receptor (TCR) gene usage.
T cell proliferative responses to topo I were detected in both the SSc patient and her healthy twin, although the kinetics of the T cell response were accelerated in the patient compared with the healthy twin. The estimated frequency of circulating topo I-reactive T cells was 1/6,700 in the SSc patient and 1/39,000 in the healthy twin. Anti-topo I antibody production was observed in cultures of T and B cells from the SSc patient, but not in those from the healthy twin. When the cells from the twins were mixed in different combinations, T cells from the healthy twin did stimulate the SSc patient's B cells to produce anti-topo I antibody through a CD40-dependent mechanism. Topo I-reactive T cell lines generated from the twins had similar characteristics, including a CD4+ phenotype, restriction by HLA-DR, recognition of epitopes within amino acid residues 209-386 of topo I, and dominant usage of the TCR Vbeta20 gene segment.
These results indicate that topo I-reactive T cells were activated and clonally expanded in the SSc patient. However, there were no substantial differences in either phenotypic or functional properties of topo I-reactive T cells obtained from the SSc patient and those obtained from her healthy identical twin. It is likely, therefore, that the anti-topo I antibody response in the SSc patient is induced by in vivo activation of topo I-reactive T cells derived from the normal T cell repertoire.
研究一对单卵双胞胎中，患系统性硬化症（SSc）的一方与健康一方针对拓扑异构酶I（topo I）的T细胞和B细胞反应。
检测了一名血清抗拓扑异构酶I抗体阳性的SSc患者及其健康的单卵双胞胎外周血中topo I诱导的T细胞增殖反应以及T细胞和B细胞培养物中的体外抗topo I抗体产生情况。从这对双胞胎中产生了topo I反应性T细胞系，并分析了其抗原特异性、主要组织相容性复合体II类限制以及T细胞受体（TCR）基因使用情况。
在SSc患者及其健康双胞胎中均检测到了对topo I的T细胞增殖反应，不过与健康双胞胎相比，患者的T细胞反应动力学加快。SSc患者循环中topo I反应性T细胞的估计频率为1/6700，健康双胞胎中为1/39000。在SSc患者的T细胞和B细胞培养物中观察到了抗topo I抗体产生，而健康双胞胎的培养物中未观察到。当将双胞胎的细胞以不同组合混合时，健康双胞胎的T细胞确实通过CD40依赖性机制刺激SSc患者的B细胞产生抗topo I抗体。从双胞胎中产生的topo I反应性T细胞系具有相似的特征，包括CD4 +表型、受HLA - DR限制、识别topo I氨基酸残基209 - 386内的表位以及TCR Vbeta20基因片段的优势使用。
这些结果表明，topo I反应性T细胞在SSc患者中被激活并克隆性扩增。然而，从SSc患者获得的topo I反应性T细胞与从其健康同卵双胞胎获得的T细胞在表型或功能特性上均无实质性差异。因此，SSc患者中的抗topo I抗体反应很可能是由源自正常T细胞库的topo I反应性T细胞在体内激活所诱导的。
