Inborn errors of immunity: single mutations unravel mechanisms of immune disease.

Abstract

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 IFNγ 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 Feature8 highlights the constant evolution of PID diagnoses, using hyper IgE syndrome (HIES) as a prime example. What was once thought to be a characteristic well-defined clinical syndrome now needs to be revisited and broadened with the addition of new mutations included in the same disease spectrum. Initially defined by mutation in STAT3, this syndrome now encompasses many more mutations, covering multiple distinct molecular pathways. At the same time, mutations initially linked to HIES, such as mutations in TYK2, are now attributed to alternative PID (MSMD, in the TYK2 example). Multiple different PIDs share part of HIES clinical presentation, despite different molecular origins, challenging patient diagnosis. The study of PID is constantly providing unique insights into the healthy immune system. Worley and colleagues review how analysis of patients with STAT mutations can identify mechanisms of action of each gene, and indeed the role of particular domains and residues within each gene.9 The exploration of patients affected with STAT3 loss-of-function and STAT1 gain-of-function allele, and their impact on Th9 differentiation, demonstrate the value in understanding the phenotypic impact of point mutations. Finally, this Special Feature with a focus on PID concludes with a review by Tangye and colleagues on PID with cytoskeleton dysfunction.10 For a long time, Wiskott–Aldrich syndrome was the only cytoskeleton associated disorder, discovered in the mid-1950s. However, as attested in this featured review, there are now more than 10 molecules associated with this specific disorder, described within the last 10 years. The extensive and rapid growth of knowledge in the field of cytoskeleton dysfunction is a microcosm of the advancements within the broader PID field.