自体炎症和自身免疫疾病中的体细胞突变
Somatic mutations in autoinflammatory and autoimmune disease
DOI 原文链接
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影响因子:32.7
分区:医学1区 Top / 风湿病学1区
发表日期:2024 Nov
作者:
Sofia Torreggiani, Flore S Castellan, Ivona Aksentijevich, David B Beck
DOI:
10.1038/s41584-024-01168-8
摘要
体细胞突变（亦称获得性突变）正逐渐被认识为一种常见的、与年龄相关的过程，发生于全身所有细胞。虽然体细胞突变传统上与恶性过程相关联，但在过去十年中，其与良性疾病（包括风湿性疾病）的因果联系日益明确。本文概述了体细胞突变在复杂和单基因免疫疾病中的作用，并详细回顾了与这些原因相关的独特特征。体细胞突变可以引起早发或晚发的风湿性单基因疾病，也参与复杂炎症性和免疫介导疾病的发病机制，影响疾病的进展，并定义新的临床亚型。即使变异等位基因频率较低的变异也可能具有致病性，克隆动态可能导致突变细胞比例随时间变化，可能对个体表现出表型影响。因此，体细胞诱变和克隆扩增在基因检测和咨询中具有重要意义。随着临床实践中对体细胞疾病的认识不断提高，以及技术和生物信息学流程的改进，我们假设，未来在多种基因中导致炎症状态的体细胞突变清单将不断扩大，尤其在晚发性疾病中尤为显著。
Abstract
Somatic mutations (also known as acquired mutations) are emerging as common, age-related processes that occur in all cells throughout the body. Somatic mutations are canonically linked to malignant processes but over the past decade have been increasingly causally connected to benign diseases including rheumatic conditions. Here we outline the contribution of somatic mutations to complex and monogenic immunological diseases with a detailed review of unique aspects associated with such causes. Somatic mutations can cause early- or late-onset rheumatic monogenic diseases but also contribute to the pathogenesis of complex inflammatory and immune-mediated diseases, affect disease progression and define new clinical subtypes. Although even variants with a low variant allele fraction can be pathogenic, clonal dynamics could lead to changes over time in the proportion of mutant cells, with possible phenotypic consequences for the individual. Thus, somatic mutagenesis and clonal expansion have relevant implications in genetic testing and counselling. On the basis of both increased recognition of somatic diseases in clinical practice and improved technical and bioinformatic processes, we hypothesize that there will be an ever-expanding list of somatic mutations in various genes leading to inflammatory conditions, particularly in late-onset disease.