Primary atopic disorders: Monogenic insights into immunity

Primary atopic disorders (PADs), a subset of inborn errors of immunity, are a growing group of more than 50 monogenic diseases characterized by severe, early-onset allergic inflammation, often coexisting with immune deficiency or dysregulation. Once considered clinical curiosities, PADs have emerged as powerful human models for understanding immune homeostasis. Advances in next-generation sequencing have accelerated gene discovery, revealing that allergic disease can arise from disruption of interconnected regulatory systems rather than immune hyperactivity alone. Here, we synthesize insights from genetically defined PADs to illustrate how defects across epithelial barrier function, immune signaling, cytoskeletal organization, antigen receptor pathways, lymphocyte repertoire, and regulatory networks converge on impaired tolerance and persistent type 2 inflammation. Beyond mechanistic insights, PADs provide a framework for precision therapy enabling targeted use of cytokine inhibitors, JAK inhibitors, biologics, hematopoietic stem cell transplantation, and emerging gene therapies. These insights bridge rare and common disease, informing the pathophysiology and treatment of polygenic atopy.