Type I interferon is a potent substance. As such, the induction, transmission, and resolution of the type I interferon-mediated immune response are tightly regulated. As defined, the type I ...interferonopathies represent discrete examples of a disturbance of the homeostatic control of this system caused by Mendelian mutations. Considering the complexity of the interferon response, the identification of further monogenic diseases belonging to this disease grouping seems likely, with the recognition of type I interferonopathies becoming of increasing clinical importance as treatment options are developed based on an understanding of disease pathology and innate immune signaling. Definition of the type I interferonopathies indicates that autoinflammation can be both interferon and noninterferon related, and that a primary disturbance of the innate immune system can "spill over" into autoimmunity in some cases. Indeed, that several non-Mendelian disorders, most particularly systemic lupus erythematosus and dermatomyositis, are also characterized by an up-regulation of type I interferon signaling suggests the possibility that insights derived from this work will have relevance to a broader field of clinical medicine.
The concept of grouping Mendelian disorders associated with an upregulation of type I interferon is not currently recognized in the medical literature. Here, we argue that such a concept has ...scientific validity and clinical utility. Specifically, we discuss a group of conditions, including Aicardi–Goutières syndrome, spondyloenchondrodysplasia, and cases of systemic lupus erythematosus with complement deficiency, in which an upregulation of type I interferons is apparently central to their pathogenesis. We believe that these diseases can usefully be considered to represent a novel set of inborn errors of immunity, and that the recognition of such diseases as type I interferonopathies will have significance in the development and use of targeted therapies.
Dissection of the genetic basis of Aicardi-Goutières syndrome has highlighted a fundamental link between nucleic acid metabolism, innate immune sensors and type I interferon induction. This had led ...to the concept of the human interferonopathies as a broader set of Mendelian disorders in which a constitutive upregulation of type I interferon activity directly relates to disease pathology. Here, we discuss the molecular and cellular basis of the interferonopathies, their categorization, future treatment strategies and the insights they provide into normal physiology.
Highlights • Uncontrolled up-regulation of type I interferon signaling can cause human disease. • Human monogenic type I interferonopathies are being increasingly recognized. • Therapies will likely ...become available to control type I interferon up-regulation.
As brutally demonstrated by the COVID-19 pandemic, an effective immune system is essential for survival. Developed over evolutionary time, viral nucleic acid detection is a central pillar in the ...defensive armamentarium used to combat foreign microbial invasion. To ensure cellular homeostasis, such a strategy necessitates the efficient discrimination of pathogen-derived DNA and RNA from that of the host. In 2011, it was suggested that an upregulation of type I interferon signalling might serve as a defining feature of a novel set of Mendelian inborn errors of immunity, where antiviral sensors are triggered by host nucleic acids due to a failure of self versus non-self discrimination. These rare disorders have played a surprisingly significant role in informing our understanding of innate immunity and the relevance of type I interferon signalling for human health and disease. Here we consider what we have learned in this time, and how the field may develop in the future.
Recognition of foreign nucleic acids is the primary mechanism by which a type I interferon-mediated antiviral response is triggered. Given that human cells are replete with DNA and RNA, this ...evolutionary strategy poses an inherent biological challenge, i.e., the fundamental requirement to reliably differentiate self-nucleic acids from nonself nucleic acids. We suggest that the group of Mendelian inborn errors of immunity referred to as the type I interferonopathies relate to a breakdown of self nonself discrimination, with the associated mutant genotypes involving molecules playing direct or indirect roles in nucleic acid signaling. This perspective begs the question as to the sources of self-derived nucleic acids that drive an inappropriate immune response. Resolving this question will provide fundamental insights into immune tolerance, antiviral signaling, and complex autoinflammatory disease states. Here we develop these ideas, discussing type I interferonopathies within the broader framework of nucleic acid-driven inflammation.
Dans cette brève revue, nous montrons les liens entre les différentes recherches qui ont conduit à la mise en évidence d’un rôle délétère d’un excès d’interféron de type 1, depuis la découverte de ...son activité antivirale en 1957 par A. Isaacs et J. Lindemann jusqu’au concept d’interféronopathie introduit par Y. Crow en 2011.
In this brief review, the authors present a history of the different aspects of the scientific puzzle leading from pioneer animal studies and astute clinical experimental observations to a mature appreciation of the deleterious role of excess of a type I interferon in human pathology.
Treatments in Aicardi–Goutières syndrome Crow, Yanick J; Shetty, Jayakara; Livingston, John H
Developmental medicine and child neurology,
January 2020, Volume:
62, Issue:
1
Journal Article
Peer reviewed
Open access
Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi–Goutières syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, ...already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy.
What this paper adds
Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment.
Further rational therapies are expected to become available in the short‐ to medium‐term.
What this paper adds
Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment.
Further rational therapies are expected to become available in the short‐ to medium‐term.
Mitochondria have emerged as critical players in immune homeostasis and disease. Recently in Cell, while characterizing the removal of mitochondria from red blood cells during human erythropoiesis, ...Caielli et al. highlight the interferon-inducing potential of erythrocyte-derived mitochondria in lupus.
Mitochondria have emerged as critical players in immune homeostasis and disease. Recently in Cell, while characterizing the removal of mitochondria from red blood cells during human erythropoiesis, Caielli et al. highlight the interferon-inducing potential of erythrocyte-derived mitochondria in lupus.
The Aicardi-Goutières syndrome (AGS) was first described in 1984, and over the following years was defined by the clinical and radiological features of an early onset, severe, neurologic disorder ...with intracranial calcification, leukoencephalopathy, and cerebral atrophy, usually associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF interferon α activity. It is now recognized that mutations in any of the following seven genes may result in the classical AGS phenotype:
(AGS1),
(AGS2),
(AGS3),
(AGS4),
(AGS5),
(AGS6), and
(AGS7). All of these genes encode proteins involved in nucleotide metabolism and/or sensing. Mutations in these genes result in the induction of type 1 interferon production and an upregulation of interferon stimulated genes. As more patients harboring mutations in these genes have been described, in particular facilitated by the advent of whole exome sequencing, a remarkably broad spectrum of associated neurologic phenotypes has been revealed, which we summarize here. We propose that the term AGS has continued clinical utility in the designation of a characteristic phenotype, which suggests relevant diagnostic investigations and can inform outcome predictions. However, we also suggest that the use of the term "type 1 interferonopathy" is appropriate for the wider spectrum of disease consequent upon dysfunction of these genes and proteins since it implies the possibility of a common "anti-interferon" approach to therapy as such treatments become available.
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