Genetic disorders of the NF-κB pathways: The role of NFKB1 haploinsuf-ficiency and CD40LG triplication in patients

The advances in genetics and the growing interest towards personalized medicine have increased interest in the study of inborn errors of immunity. In these conditions, single-gene defects can impair the body’s immune defense, but they also provide a unique opportunity to study how the immune system functions. NF-κB signaling pathways play a central role in immune defense, as they regulate inflammation and the survival of immune cells. Two genes involved in these pathways are NFKB1 and CD40LG, and mutations in these genes are known to cause different forms of primary immunodeficiency.

In this doctoral thesis, the effects of mutations in the NFKB1 and CD40LG genes on immune cell function were studied in patients with primary immunodeficiency carrying these variants. The study included families in which immune deficiencies associated with abnormalities in the NFKB1 and CD40LG genes had been identified.

The aim of the study was to compare the effects of different NFKB1 and CD40LG mutations on the patients’ ability to produce inflammatory mediators regulated by the NF-κB signaling pathway, as well as on other immune cell functions. One objective of the study was to identify cellular-level differences between patients carrying NFKB1 mutations and to better understand the mechanisms underlying the development of their clinical symptoms. The study also aimed to understand the biological differences between symptomatic and asymptomatic carriers of these harmful variants.

The study revealed new mechanisms through which alterations in the NFKB1 and CD40LG genes affect immune cell function. The results expand our understanding of the relationship between mutations in immune-regulating genes, the resulting biological abnormalities, and the clinical manifestations that arise from them. These findings may contribute to the development of improved diagnostic approaches and more personalized treatment strategies for patients with primary immunodeficiencies.