Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States; Clinical Genomics Program, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, United States.
Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States; Clinical Genomics Program, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, United States.
Adv Immunol. 2018;138:99-193. doi: 10.1016/bs.ai.2018.02.003. Epub 2018 Mar 29.
Proper regulation of the immune system is required for protection against pathogens and preventing autoimmune disorders. Inborn errors of the immune system due to inherited or de novo germline mutations can lead to the loss of protective immunity, aberrant immune homeostasis, and the development of autoimmune disease, or combinations of these. Forward genetic screens involving clinical material from patients with primary immunodeficiencies (PIDs) can vary in severity from life-threatening disease affecting multiple cell types and organs to relatively mild disease with susceptibility to a limited range of pathogens or mild autoimmune conditions. As central mediators of innate and adaptive immune responses, T cells are critical orchestrators and effectors of the immune response. As such, several PIDs result from loss of or altered T cell function. PID-associated functional defects range from complete absence of T cell development to uncontrolled effector cell activation. Furthermore, the gene products of known PID causal genes are involved in diverse molecular pathways ranging from T cell receptor signaling to regulators of protein glycosylation. Identification of the molecular and biochemical cause of PIDs can not only guide the course of treatment for patients, but also inform our understanding of the basic biology behind T cell function. In this chapter, we review PIDs with known genetic causes that intrinsically affect T cell function with particular focus on perturbations of biochemical pathways.
免疫系统的正常调节对于抵御病原体和预防自身免疫性疾病至关重要。由于遗传或新生种系突变导致的免疫系统先天性缺陷可导致保护性免疫的丧失、免疫稳态异常以及自身免疫性疾病的发生，或这三者的组合。涉及原发性免疫缺陷（PID）患者临床标本的正向遗传筛选，其严重程度从影响多种细胞类型和器官的危及生命的疾病到对有限范围病原体易感性或轻度自身免疫状况的相对轻度疾病不等。作为先天和适应性免疫反应的核心介质，T 细胞是免疫反应的关键协调者和效应器。因此，几种 PID 是由于 T 细胞功能丧失或改变引起的。PID 相关的功能缺陷范围从 T 细胞发育完全缺失到效应细胞不受控制的激活。此外，已知 PID 因果基因的基因产物参与从 T 细胞受体信号传导到蛋白质糖基化调节剂的多种分子途径。鉴定 PID 的分子和生化原因不仅可以指导患者的治疗过程，还可以帮助我们了解 T 细胞功能背后的基本生物学。在本章中，我们回顾了具有已知遗传原因的 PID，这些 PID 会内在地影响 T 细胞功能，特别关注生化途径的干扰。
