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      Human life within a narrow range: The lethal ups and downs of type I interferons

      Author(s): 1 , 2 , 3 , 3 , 4 , 5 , 6 , 7
      Publication date Created:
      Publication date (Print):
      Journal: Science Immunology
      Publisher: American Association for the Advancement of Science (AAAS)

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          Abstract

          The past 20 years have seen the definition of human monogenic disorders and their autoimmune phenocopies underlying either defective or enhanced type I interferon (IFN) activity. These disorders delineate the impact of type I IFNs in natural conditions and demonstrate that only a narrow window of type I IFN activity is beneficial. Insufficient type I IFN predisposes humans to life-threatening viral diseases (albeit unexpectedly few) with a central role in immunity to respiratory and cerebral viral infection. Excessive type I IFN, perhaps counterintuitively, appears to underlie a greater number of autoinflammatory and/or autoimmune conditions known as type I interferonopathies, whose study has revealed multiple molecular programs involved in the induction of type I IFN signaling. These observations suggest that the manipulation of type I IFN activity to within a physiological range may be clinically relevant for the prevention and treatment of viral and inflammatory diseases.

          Abstract

          Genetic studies of type I interferon signaling reveal the narrow physiological range that is compatible with and essential for life.

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          Autoantibodies against type I IFNs in patients with life-threatening COVID-19

          Paul Bastard, Lindsey B. Rosen, Qian Zhang … (2021)
          The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science, this issue p. eabd4570, p. eabd4585; see also p. 404
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            Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

            Qian Zhang, Paul Bastard, Zhiyong Liu … (2021)
            The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science, this issue p. eabd4570, p. eabd4585; see also p. 404
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              Shared and Distinct Functions of Type I and Type III Interferons

              Helen M. Lazear, John W Schoggins, Michael S. Diamond (2019)
              Type I interferons (IFNs) (IFN-α, IFN-β) and type III IFNs (IFN-λ) share many properties, including induction by viral infection, activation of shared signaling pathways, and transcriptional programs. However, recent discoveries have revealed context-specific functional differences. Here, we provide a comprehensive review of type I and type III IFN activities, highlighting shared and distinct features from molecular mechanisms through physiological responses. Beyond discussing canonical antiviral functions, we consider the adaptive immune priming, anti-tumor, and autoimmune functions of IFNs. We discuss a model wherein type III IFNs serve as a front-line defense that controls infection at epithelial barriers while minimizing damaging inflammatory responses, reserving the more potent type I IFN response for when local responses are insufficient. In this context, we discuss current therapeutic applications targeting these cytokine pathways and highlight gaps in understanding of the biology of type I and type III IFNs in health and disease.
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                Author and article information

                Contributors
                Yanick J. Crow: (View ORCID Profile)
                Jean-Laurent Casanova: (View ORCID Profile)
                Journal
                Title: Science Immunology
                Abbreviated Title: Sci. Immunol.
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Electronic): 2470-9468
                Publication date Created: July 05 2024
                Publication date (Print): July 05 2024
                Volume: 9
                Issue: 97
                Affiliations
                [1 ]MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
                [2 ]Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, INSERM UMR 1163, Paris, France.
                [3 ]University Paris Cité, Paris, France.
                [4 ]St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.
                [5 ]Howard Hughes Medical Institute, New York, NY, USA.
                [6 ]Department of Pediatrics, Necker Hospital for Sick Children, Paris, France.
                [7 ]Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Imagine Institute, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France.
                Article
                DOI: 10.1126/sciimmunol.adm8185
                SO-VID: ab7fb120-3d34-4419-b2d2-6de5f000a9b3
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