Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Nat Rev Rheumatol. 2021 Jul;17(7):405-425. doi: 10.1038/s41584-021-00614-1. Epub 2021 May 25.
Monogenic autoinflammatory diseases are a group of rheumatologic disorders caused by dysregulation in the innate immune system. The molecular mechanisms of these disorders are linked to defects in inflammasome-mediated, NF-κB-mediated or interferon-mediated inflammatory signalling pathways, cytokine receptors, the actin cytoskeleton, proteasome complexes and various enzymes. As with other human disorders, disease-causing variants in a single gene can present with variable expressivity and incomplete penetrance. In some cases, pathogenic variants in the same gene can be inherited either in a recessive or dominant manner and can cause distinct and seemingly unrelated phenotypes, although they have a unifying biochemical mechanism. With an enhanced understanding of protein structure and functionality of protein domains, genotype-phenotype correlations are beginning to be unravelled. Many of the mutated proteins are primarily expressed in haematopoietic cells, and their malfunction leads to systemic inflammation. Disease presentation is also defined by a specific effect of the mutant protein in a particular cell type and, therefore, the resulting phenotype might be more deleterious in one tissue than in another. Many patients present with the expanded immunological disease continuum that includes autoinflammation, immunodeficiency, autoimmunity and atopy, which necessitate genetic testing.
单基因自身炎症性疾病是一组由固有免疫系统失调引起的风湿性疾病。这些疾病的分子机制与炎症小体介导、NF-κB 介导或干扰素介导的炎症信号通路、细胞因子受体、肌动蛋白细胞骨架、蛋白酶体复合物和各种酶的缺陷有关。与其他人类疾病一样，单个基因中的致病变异可表现出不同的表现度和不完全外显率。在某些情况下，同一基因中的致病性变异可以以隐性或显性方式遗传，并可导致不同且看似无关的表型，尽管它们具有统一的生化机制。随着对蛋白质结构和蛋白质结构域功能的深入了解，基因型-表型相关性开始被揭示。许多突变蛋白主要在造血细胞中表达，其功能障碍导致全身炎症。疾病表现也由特定细胞类型中突变蛋白的特定作用来定义，因此，在一种组织中比在另一种组织中产生的表型可能更具危害性。许多患者表现出扩大的免疫疾病谱，包括自身炎症、免疫缺陷、自身免疫和过敏，这需要进行基因检测。
