Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States.
Front Immunol. 2019 Jan 31;10:101. doi: 10.3389/fimmu.2019.00101. eCollection 2019.
Monogenic autoinflammatory disorders are a group of conditions defined by systemic or localized inflammation without identifiable causes, such as infection. In contrast to classical primary immunodeficiencies that manifest with impaired immune responses, these disorders are due to defects in genes that regulate innate immunity leading to constitutive activation of pro-inflammatory signaling. Through studying patients with rare autoinflammatory conditions, novel mechanisms of inflammation have been identified that bare on our understanding not only of basic signaling in inflammatory cells, but also of the pathogenesis of more common inflammatory diseases and have guided treatment modalities. Autoinflammation has further been implicated as an important component of cardiovascular, neurodegenerative, and metabolic syndromes. In this review, we will focus on a subset of inherited enzymatic deficiencies that lead to constitutive inflammation, and how these rare diseases have provided insights into diverse areas of cell biology not restricted to immune cells. In this way, Mendelian disorders of the innate immune system, and in particular loss of catalytic activity of enzymes in distinct pathways, have expanded our understanding of the interplay between many seemingly disparate cellular processes. We also explore the overlap between autoinflammation, autoimmunity, and immunodeficiency, which has been increasingly recognized in patients with dysregulated immune responses.
单基因自身炎症性疾病是一组以全身性或局部性炎症为特征的疾病，没有明确的病因，如感染。与表现为免疫反应受损的经典原发性免疫缺陷不同，这些疾病是由于调节先天免疫的基因缺陷导致促炎信号的组成性激活。通过研究罕见的自身炎症性疾病患者，已经确定了新的炎症机制，不仅加深了我们对炎症细胞中基本信号转导的理解，也加深了我们对更常见炎症性疾病发病机制的理解，并指导了治疗方法。自身炎症也被认为是心血管、神经退行性和代谢综合征的一个重要组成部分。在这篇综述中，我们将重点介绍一组导致固有炎症的遗传性酶缺乏症，以及这些罕见疾病如何为细胞生物学的多个领域提供见解，而不仅仅局限于免疫细胞。通过这种方式，先天免疫系统的孟德尔疾病，特别是不同途径中酶的催化活性丧失，扩展了我们对许多看似不同的细胞过程之间相互作用的理解。我们还探讨了自身炎症、自身免疫和免疫缺陷之间的重叠，这在免疫反应失调的患者中越来越受到重视。
