Daniella M Schwartz, MD (she/her/hers), University of Pittsburgh Medical Center, Pittsburgh, USA
The last several years have seen a virtual explosion of novel inborn errors of immunity (IEI), with 56 novel diseases discovered between 2020-2022 1. It should therefore come as no surprise that the spectrum of genetic immune dysregulation has continued to expand dramatically over the last year. While it is impossible to review all the major advances in the field, several recent publications will be of particular interest to cytokine biologists.
Down syndrome (DS), or trisomy 21, is the most common chromosomal condition worldwide, affecting about 1 in 1,000 births. Commonly recognized manifestations include dysmorphic features, cardiovascular abnormalities, and hematologic disorders. DS is also strongly associated with immune dysregulation, but the underlying mechanisms have been unclear. Malle et. al. demonstrate that DS affects Type I interferon (IFN-I) signaling due to increased expression of the IFN-I receptor subunits IFNAR1 and IFNAR2, which are on chromosome 212. Increased IFNAR1/2 expression initially causes hypersensitivity to IFN-I but then triggers a negative feedback loop that leads to IFN-I hyporesponsiveness. Ultimately, these oscillations protect subjects with DS from viral infection but also increase infection-driven morbidity. IFN-1 activation is also associated with systemic autoimmunity, and a second publication by the same group demonstrates that DS is characterized by global cytokine dysregulation, with increased levels of 22 distinct cytokines in one third of DS patients3. Chronic IL-6 signaling promotes T cell activation, which in turn activates B cells and plasmablasts, leading to autoantibody production. Importantly, IFN-I signaling and IL-6 signaling can be blocked individually with monoclonal antibodies or more broadly with JAK inhibitors, suggesting that the immune defects of DS can be targeted with FDA/EMA-approved therapies.
The JAK-STAT pathway is of broad interest to cytokine biologists due to its critical role in Type I/II cytokine signaling, which is illustrated by the efficacy of JAK inhibitors for immune-mediated diseases, and by the immunologic consequences of human JAK and STAT mutations4. Complete autosomal recessive TYK2 deficiency, first described in 2006, increases susceptibility to viral and mycobacterial disease, whereas a more common partial deficiency underlies primary tuberculosis susceptibility. A new study by Ogishi et. al. investigates 19 patients with rare (<1% frequency) or very rare (<0.01% frequency) TYK2 mutations 5. All variants cause impaired IL-23-dependent production of IFN-g, which increases susceptibility to mycobacterial disease. A subset of mutations also reduces responsiveness to IFN-I, IL-10, and IL-12, causing susceptibility to viral infection. In a related study, Philippot et. al. find that autosomal recessive loss-of-function IL23R mutations cause mycobacterial disease susceptibility due to impaired IL-23-driven IFN-g production6. IL-23 also induces IL-17A/IL-17F, and some affected subjects also suffer from chronic mucocutaneous candidiasis due to reduced IL-17A in mucosal-associated invariant T cells. However – as with TYK2-deficient patients – mycobacterial susceptibility is the more conserved phenotype in the IL23R-deficient cohort, because IFN-g production is impaired in multiple lymphocyte subsets whereas IL-17A/IL-17F production is only affected in one subset. Together, these studies identify IL-23/TYK2/IFN-g signaling as critical to host defense against mycobacterial diseases.
Downstream of interferon induction and JAK-STAT signaling, interferon regulatory factors (IRFs) are critical modulators of IFN signaling. Mutations in IRF3, IRF7, and IRF9 all increase susceptibility to viral disease. A 2022 study by Campbell et. al. has expanded the phenotypic characterization of IRF7 deficiency by investigating 7 patients with novel loss-of-function mutations 7. This reveals a spectrum of viral susceptibility that is quite narrow relative to other IFN-I defects, affecting only the respiratory tract. This may be because IFN-b signaling, while impaired, is not abolished in IRF7-deficiency. Deficiency of IRF1, is induced by both IFN-1 and IFN-g, causes susceptibility to both viral and mycobacterial infection in mice. Rosain et. al. demonstrate that human IRF1 hypomorphic mutations cause a severe form of mycobacterial disease susceptibility, with life-threatening infections due to weakly virulent pathogens 8. Unexpectedly, despite complete deficiency of IRF1, patients are not susceptible to viral infection, suggesting that IRF1 is largely redundant for IFN-I dependent antiviral immunity in humans. In contrast to these loss-of-function mutations, the IRF4 international consortium has reported a multimorphic IRF4 mutation causing autosomal dominant combined immunodeficiency 9. Patients present with agammaglobulinemia, opportunistic infections, reduced B cell maturation, and reduced Th17/Tfh differentiation. IRF4 is a transcription factor, and the mutant variant alters the protein’s DNA binding specificity. This causes a simultaneous loss of some functions, gain of other functions, and acquisition of some new transcriptional targets – a multimorphic combination that disrupts lymphocyte development and function. Together, these studies highlight the importance of IRFs to IFN-mediated host defense, as well as describing a novel potential mechanism of disease caused by a single gene mutation.
1 Tangye, S. G. et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 42, 1473-1507, doi:10.1007/s10875-022-01289-3 (2022).
2 Malle, L. et al. Excessive negative regulation of type I interferon disrupts viral control in individuals with Down syndrome. Immunity 55, 2074-2084 e2075, doi:10.1016/j.immuni.2022.09.007 (2022).
3 Malle, L. et al. Autoimmunity in Down’s syndrome via cytokines, CD4 T cells and CD11c(+) B cells. Nature 615, 305-314, doi:10.1038/s41586-023-05736-y (2023).
4 Luo, Y. et al. JAK-STAT signaling in human disease: From genetic syndromes to clinical inhibition. J Allergy Clin Immunol 148, 911-925, doi:10.1016/j.jaci.2021.08.004 (2021).
5 Ogishi, M. et al. Impaired IL-23-dependent induction of IFN-gamma underlies mycobacterial disease in patients with inherited TYK2 deficiency. J Exp Med 219, doi:10.1084/jem.20220094 (2022).
6 Philippot, Q. et al. Human IL-23 is essential for IFN-gamma-dependent immunity to mycobacteria. Sci Immunol 8, eabq5204, doi:10.1126/sciimmunol.abq5204 (2023).
7 Campbell, T. M. et al. Respiratory viral infections in otherwise healthy humans with inherited IRF7 deficiency. J Exp Med 219, doi:10.1084/jem.20220202 (2022).
8 Rosain, J. et al. Human IRF1 governs macrophagic IFN-gamma immunity to mycobacteria. Cell 186, 621-645 e633, doi:10.1016/j.cell.2022.12.038 (2023).
9 Consortium, I. R. F. I. et al. A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency. Sci Immunol 8, eade7953, doi:10.1126/sciimmunol.ade7953 (2023).