Recent developments in the detection and characterization of novel immunodeficiency diseases associated with gain-of-function (GOF) mutations in immunological signaling molecules will be presented. Extensive cellular and molecular research over the last two years have shed light on the underlying reasons of pathogenesis for many novel monogenic primary immunodeficiency diseases (PIDs) connected to GOF mutations in signaling pathways. In this section, we will look at two diseases that have a similar clinical appearance. These findings highlight an emerging theme: both loss-of-function and gain-of-function mutations in critical molecules can alter finely regulated immunoreceptor signaling modes, resulting in lymphocyte differentiation dysregulation and reduced adaptive immunity.

Continued study into the molecular etiology of PIDs characterized by overactive signaling molecules will help differentiate these and similar diseases, as well as identify specific treatment approaches for ‘retuning’ the immune response in these individuals.