University of Wisconsin School of Pharmacy, Madison, Wisconsin, USA.
Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA; Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin, USA.
Mutat Res Rev Mutat Res. 2022 Jan-Jun;789:108414. doi: 10.1016/j.mrrev.2022.108414. Epub 2022 Mar 11.
Somatic cell gene mutations arise in vivo due to replication errors during DNA synthesis occurring spontaneously during normal DNA synthesis or as a result of replication on a DNA template damaged by endogenous or exogenous mutagens. In principle, changes in the frequencies of mutant cells in vivo in humans reflect changes in exposures to exogenous or endogenous DNA damaging insults, other factors being equal. It is becoming increasingly evident however, that somatic mutations in humans have a far greater range of interpretations. For example, mutations in lymphocytes provide invaluable probes for in vivo cellular and molecular processes, providing identification of clonal amplifications of these cells in autoimmune and infectious diseases, transplantation recipients, paroxysmal nocturnal hemoglobinuria (PNH), and cancer. The assay for mutations of the X-chromosomal hypoxanthine guanine phosphoribosyltransferase (HPRT) gene has gained popular acceptance for this purpose since viable mutant cells can be recovered for molecular and other analyses. Although the major application of the HPRT T cell assay remains human population monitoring, the enrichment of activated T cells in the mutant fraction in individuals with ongoing immunological processes has demonstrated the utility of surrogate selection, a method that uses somatic mutation as a surrogate marker for the in vivo T cell proliferation that underlies immunological processes to investigate clinical disorders with immunological features. Studies encompassing a wide range of clinical conditions are reviewed. Despite the historical importance of the HPRT mutation system in validating surrogate selection, there are now additional mutational and other methods for identifying immunologically active T cells. These methods are reviewed and provide insights for strategies to extend surrogate selection in future studies.
体细胞基因突变是由于 DNA 合成过程中的复制错误而在体内自发产生的，这些错误可能发生在正常的 DNA 合成过程中，也可能是由于内源性或外源性诱变剂对 DNA 模板的损伤导致的复制错误。原则上，人体内突变细胞频率的变化反映了对外源性或内源性 DNA 损伤因素暴露的变化，在其他因素相同的情况下。然而，越来越明显的是，人类体细胞突变具有更广泛的解释。例如，淋巴细胞中的突变提供了体内细胞和分子过程的宝贵探针，可用于识别自身免疫性疾病和感染性疾病、移植受者、阵发性夜间血红蛋白尿（PNH）和癌症中这些细胞的克隆扩增。由于可以回收有活力的突变细胞进行分子和其他分析，因此 X 染色体次黄嘌呤鸟嘌呤磷酸核糖转移酶（HPRT）基因突变检测已广泛用于该目的。尽管 HPRT T 细胞检测的主要应用仍然是人类群体监测，但在持续发生免疫过程的个体中，突变细胞在 T 细胞亚群中的富集证明了替代选择的有效性，这种方法利用体细胞突变作为体内 T 细胞增殖的替代标志物，该标志物是免疫过程的基础，用于研究具有免疫特征的临床疾病。涵盖广泛临床情况的研究进行了综述。尽管 HPRT 突变系统在验证替代选择方面具有重要的历史意义，但现在已经有其他用于识别免疫活性 T 细胞的突变和其他方法。这些方法进行了综述，并为未来研究中扩展替代选择提供了策略见解。
