The influence of genetics, environment, and disease state on the human T-cell receptor repertoire.
The influence of genetics, environment, and disease state on the human T-cell receptor repertoire.
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遗传、环境和疾病状态对人类 T 细胞受体库的影响。
DOI：
10.1111/j.1749-6632.1995.tb44480.x
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发表时间：
1995
影响因子：
5.2
通讯作者：
Akolkar,PN
中科院分区：
文献类型：
--
作者：
Silver,J;Gulwani-Akolkar,B;Akolkar,PN
在过去的十年中，识别与各种自身免疫性疾病（如类风湿关节炎、多发性硬化症和I型糖尿病）有关的t细胞一直是免疫学研究的主要焦点。这些研究的灵感部分来自于以下观察：在几个自身免疫实验模型中，对抗原诱导疾病的反应在t细胞受体（TCR）方面表现出令人惊讶的高度限制性异质性。因此，在人类中进行类似研究的基本原理是，如果人们能够类似地识别出人类自身免疫性疾病中t细胞反应的有限异质性，那么就有可能设计出专门针对这种t细胞的治疗方法。这将允许在不实质性影响免疫反应的其余部分的情况下，在人的疾病过程的衰减。当然，由于在大多数自身免疫性疾病中，负责病理过程的抗原的性质尚不清楚，因此在人体中识别此类t细胞是复杂的。此外，尚不清楚最初诱发疾病的抗原是否与使疾病持续存在的抗原相同。最后，即使人们能够识别这样的t细胞并描述它们的TCR特征，人们也可能会发现，由于人类在基因上是异质的，因此在使用的TCR中存在大量的个体差异，而在实验模型中用于定义受限TCR反应的动物通常在基因上是同质的。因此，许多遗传位点（如HLA和TCR）的个体差异可能会深刻影响人类的TCR库，并导致TCR介导自身免疫性疾病过程的大量个体差异。下面描述的研究代表了我们试图定义人类正常的功能性TCR库，并描述影响它并导致个体差异的遗传和环境因素。此外，几项研究旨在定义自身免疫性疾病过程本身引起的TCR库的变化，这些变化叠加在正常的TCR库上。
The identification of T-cells involved in a variety of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and type I diabetes mellitus has been a prime focus of immunological research for the last decade. These studies have been inspired partly by the observations that in several experimental models of autoimmunity, the responses to the antigens inducing disease show a surprisingly high degree of restricted heterogeneity with respect to the T-cell receptor (TCR). The rationale for pursuing comparable studies in man, therefore, has been that if one can similarly identify restricted heterogeneity in the T-cell responses in human autoimmune diseases, it might be possible to devise therapies that are specifically focused on such T-cells. This would allow attenuation of the disease process in man without substantially affecting the remainder of the immune response. Of course, the identification of such T-cells in man is complicatcd by the fact that in most autoimmune diseases, the nature of the antigens responsible for thc pathological process is unknown. Furthermore, it is not clear whether the antigens that initially induce the disease are the same as thc ones that perpetuate it. Finally, even if one could identify such T-cells and characterize their TCR, one might find a great deal of individual variations in thc TCR that arc used because man is genetically heterogeneous, whereas the animals used to define restricted TCR responses in experimental models are, in general, genetically homogeneous. Thus, individual variation in a number of genetic loci such as HLA and TCR might profoundly influence the TCR repertoire in man and lead to a great deal of individual variation with respect to the TCR mediating the autoimmune diseasc process.The studies described below represent our attempts to definc the normal, functional TCR repertoire in man and to delineate thc genetic and environmental factors that influence it and lead to individual variation. In addition, several studies aimed at defining changes in the TCR repertoire induced by the autoimmune disease process itself, which is superimposed on the normal TCR repertoire, are described.