Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Emerging Infectious Diseases Graduate Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Clin Exp Immunol. 2023 Apr 25;212(2):117-128. doi: 10.1093/cei/uxad006.
Inborn errors of immunity (IEIs) continuously remind us that multiple checks and balances are built into the adaptive immune system to maintain homeostasis, ensuring effective pathogen defense without causing inadvertent immunopathology, autoimmunity, or lymphomagenesis. The nuclear factor of κB (NF-κB) family of transcription factors serve a vital role in the immune system, inducing scores of genes responsible for lymphocyte survival, proliferation, differentiation and effector function. In recent years, the discovery and characterization of IEIs that impact NF-κB activity have illuminated the importance of carefully tuning this pathway to ensure effective immune defense without hyperinflammation and immune dysregulation. Here we examine several illustrative cases of IEIs that arise from pathogenic mutations encoding NF-κB inducers, regulators, and NF-κB family components themselves, illuminating how these genes ensure normal adaptive immune system function by maintaining a "Goldilocks effect" state in NF-κB pathway activity.
先天性免疫缺陷(IEIs)不断提醒我们,适应性免疫系统中构建了多种制衡机制,以维持体内平衡,确保有效抵御病原体的同时,不会导致意外的免疫病理学、自身免疫或淋巴瘤发生。核因子 κB(NF-κB)转录因子家族在免疫系统中起着至关重要的作用,诱导大量负责淋巴细胞存活、增殖、分化和效应功能的基因。近年来,发现并描述了影响 NF-κB 活性的 IEIs,阐明了精细调节该途径的重要性,以确保有效免疫防御而不发生过度炎症和免疫失调。在这里,我们研究了几种由编码 NF-κB 诱导剂、调节剂和 NF-κB 家族成分的致病性突变引起的 IEIs 的实例,阐明了这些基因如何通过维持 NF-κB 通路活性的“金发姑娘效应”状态来确保正常的适应性免疫系统功能。