Primary immunodeficiency diseases, inflammation and mitochondrial dysfunction

Primary immunodeficiency diseases (PIDs) are a heterogeneous group of inherited disorders characterized by impaired immune function, leading to increased susceptibility to infections, autoimmunity, and malignancies. While traditionally defined by immune cell defects, emerging evidence highlights the critical role of inflammation in PID pathogenesis. This review explores the intricate relationship between mitochondrial dysfunction and inflammation in PIDs. We examine how genetic defects in PIDs disrupt immune homeostasis, promoting pro-inflammatory states through cytokine dysregulation. Additionally, we discuss the vicious cycle involving oxidative stress, mitochondrial dysfunction, and inflammation, emphasizing the contribution of mitochondrial ROS production, mtDNA damage, and inflammasome activation in sustaining chronic inflammation. Furthermore, we propose that impaired mitochondrial function —potentially through mechanisms involving calcium signalling, ATP synthase regulation, and mitochondrial permeability transition pore formation — may serve as a central link between immune deficiency and hyperinflammation in PIDs. Understanding these complex interactions may provide new insights into the pathogenesis of PIDs and open avenues for targeted therapeutic strategies to improve patient outcomes.