SPECIAL FEATURE EDITORIAL Inborn errors of immunity: single mutations unravel mechanisms of immune disease Adrian Liston 1 & Stephanie Humblet-Baron 2,3 1 The Babraham Institute, Cambridge, UK 2 VIB Center for Brain and Disease Research, Leuven, Belgium 3 Department of Microbiology and Immunology, KU Leuven - University of Leuven, Leuven, Belgium Correspondence Stephanie Humblet-Baron, VIB Center for Brain and Disease Research, 3000 Leuven, Belgium. E-mail: stephanie.humbletbaron@kuleuven.vib.be doi: 10.1111/imcb.12247 Immunology & Cell Biology 2019; 1–2 Inborn errors of immunity, or primary immunodeficiency disorders (PID), are monogenic diseases of the immune system. These affections give rise to complex diseases with a wide range of susceptibility to infections. At one end of the spectrum, severe combined immunodeficiency (SCID) patients, with broad deficiencies in the adaptive immune system, present with a high risk of multiple opportunistic microorganisms, invariably fatal without transplantation. At the other end of the spectrum, PID can be present with very narrow cellular defects and pathogen-specific susceptibility, as seen with predisposition to develop herpes encephalitis in TLR3-deficient patients. 1 In addition to the intrinsic value of studying (and curing) such severe diseases, PID patients are proving to be the key to unlocking our knowledge of human immunology. Just as knockout mice have been the tool of choice to understand the basic components of the murine immune system, PID patients provide the chance to study the essential nonredundant functions of each immune gene. From the innate to adaptive immune system, from cellular differentiation pathways to effector molecules, every aspect of the immune response can be affected in PID. In the early 1990s, fewer than five genes were identified as causing PID. The advent of next-generation sequencing, has, however, ushered in the Golden Age of PID research. The number of genes identified as responsible for PID has been rapidly rising, with a new PID gene identified on average every week for the past 10 years. 2,3 Despite the recent explosion of knowledge, a wealth of untapped cases remain to be studied: 90% of the estimated 3000 PID genes have yet to be studied. 4 Importantly, each of these unique mutations can advance our understanding of the complexity of the immune system. In this Special Feature, four selected reviews will highlight recent advances in understanding the mechanisms that underlie PID genetics. The in-depth investigations reviewed here explain the susceptibility of different PID patients to specific pathogens, describe the role of precise cellular subsets in human immunity and identify novel regulatory mechanisms of immunological pathways. Fortunately, this understanding of the mechanistic basis of PID often unlocks treatment: unlike common immune diseases, where multiple pathways contribute to pathology, PID often require correction of only a single pathway to reverse disease. We start with the Mendelian susceptibility of mycobacterial disease (MSMD). MSMD has allowed the comprehensive exploration of the IFNc signaling pathway in humans. While IFNGR1 was the first gene to be identified as responsible for MSMD in the mid-1990s, 5,6 there are now up to 11 different genes involved as a direct cause of MSMD. Importantly, the molecules implicated in this pathway reveal the importance of the cross-talk between innate and adaptive cells for complete elimination of mycobacteria infections. In their article, Rosain et al. review the clinical characteristics of the disease, with a special focus on the new genes recently described to play a mechanistic role. 7 The article by Ochs et al. in the Special Feature 8 highlights the constant evolution of PID diagnoses, using 1 Immunology & Cell Biology 2019; 1–2 www.wileyonlinelibrary.com/journal/icb