Le interferonopatie di tipo I

2021 ◽  
Vol 40 (8) ◽  
pp. 509-514
Author(s):  
Alberto Tommasini ◽  
Irene Bruno ◽  
Maria Elisa Morelli ◽  
Loredana Lepore
Keyword(s):  
Genetic Analysis ◽  
Type I ◽  
Definite Diagnosis ◽  
Jak Inhibitors ◽  
Monogenic Disorders ◽  
Neurologic Involvement ◽  
Multifactorial Disorders ◽  
Type I Interferonopathies

Type I interferonopathies are autoinflammatory monogenic disorders arising from excessive production of interferons. Some manifestations like chilblains, neurologic involvement, arthritis and lipodystrophy may be shared by several diseases. Measure of interferon score and genetic analysis can assist a definite diagnosis. Among immunomodulant drugs, glucocorticoids, micofenolate and antimalarials can be of some benefit, however other drugs like JAK inhibitors seem more effective in controlling interferon-related complaints. Apart from allowing better diagnosis and care to affected patients, the study of interferonopathies may also reflect on a better knowledge on multifactorial disorders associated with interferon-related inflammation.

scholarly journals Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

2019 ◽  
Author(s):  
Conor Gruber ◽  
Marta Martin-Fernandez ◽  
Fatima Ailal ◽  
Xueer Qiu ◽  
Justin Taft ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Transcriptional Activity ◽  
Type I Interferon ◽  
Early Response ◽  
Type I ◽  
Homozygous State ◽  
Gain Of Function ◽  
Monogenic Disorders ◽  
Sterically Hinder ◽  
Type I Interferonopathies

AbstractType I interferonopathies are monogenic disorders characterized by enhanced Type I interferon (IFN-I) activity. Inherited ISG15 and USP18 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, ISG15/USP18 are induced by IFN-I and sterically hinder JAK1 from binding to the IFNAR2 subunit of IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is gain-of-function (GOF) for ISGF3-dependent induction of late but not early response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic transcriptional activity of ISGF3. Rather, the STAT2 R148Q variant is GOF because it fails to appropriately interact with and traffic USP18 to IFNAR2, preventing USP18 from negatively regulating responses to IFN-I. Overall, a STAT2 missense mutation that fails to facilitate USP18-mediated signal termination in the homozygous state underlies a novel genetic etiology of type I interferonopathy.

scholarly journals Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

2020 ◽  
Vol 217 (5) ◽  
Author(s):  
Conor Gruber ◽  
Marta Martin-Fernandez ◽  
Fatima Ailal ◽  
Xueer Qiu ◽  
Justin Taft ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Type I Interferon ◽  
Cellular Responses ◽  
Early Response ◽  
Intrinsic Activity ◽  
Type I ◽  
Gain Of Function ◽  
Monogenic Disorders ◽  
Transcriptional Complex ◽  
Type I Interferonopathies

Type I interferonopathies are monogenic disorders characterized by enhanced type I interferon (IFN-I) cytokine activity. Inherited USP18 and ISG15 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, USP18, being stabilized by ISG15, sterically hinders JAK1 from binding to the IFNAR2 subunit of the IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is a gain of function (GOF) for induction of the late, but not early, response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic activity of the STAT2-containing transcriptional complex responsible for IFN-I–stimulated gene induction. Rather, the STAT2 R148Q variant is a GOF because it fails to appropriately traffic USP18 to IFNAR2, thereby preventing USP18 from negatively regulating responses to IFN-I. Homozygosity for STAT2 R148Q represents a novel molecular and clinical phenocopy of inherited USP18 deficiency, which, together with inherited ISG15 deficiency, defines a group of type I interferonopathies characterized by an impaired regulation of late cellular responses to IFN-I.

scholarly journals Vasculitis, Autoimmunity, and Cytokines: How the Immune System Can Harm the Brain

2021 ◽  
Vol 18 (11) ◽  
pp. 5585
Author(s):  
Alessandra Tesser ◽  
Alessia Pin ◽  
Elisabetta Mencaroni ◽  
Virginia Gulino ◽  
Alberto Tommasini
Keyword(s):  
Clinical Trials ◽  
Neurological Disorders ◽  
Brain Inflammation ◽  
Jak Inhibitors ◽  
Simplified Models ◽  
Monogenic Disorders ◽  
Targeted Treatments ◽  
Multifactorial Disorders ◽  
Immune Pathology ◽  
The Brain

More and more findings suggest that neurological disorders could have an immunopathological cause. Thus, immune-targeted therapies are increasingly proposed in neurology (even if often controversial), as anakinra, inhibiting IL-1 for febrile inflammatory illnesses, and JAK inhibitors for anti-interferons treatment. Precision medicine in neurology could be fostered by a better understanding of the disease machinery, to develop a rational use of immuno-modulators in clinical trials. In this review, we focus on monogenic disorders with neurological hyper-inflammation/autoimmunity as simplified “models” to correlate immune pathology and targeted treatments. The study of monogenic models yields great advantages for the elucidation of the pathogenic mechanisms that can be reproduced in cellular/animal models, overcoming the limitations of biological samples to study. Moreover, monogenic disorders provide a unique tool to study the mechanisms of neuroinflammatory and autoimmune brain damage, in all their manifestations. The insight of clinical, pathological, and therapeutic aspects of the considered monogenic models can impact knowledge about brain inflammation and can provide useful hints to better understand and cure some neurologic multifactorial disorders.

scholarly journals Nucleic acid-mediated autoinflammation and autoimmunity—type I interferonopathies

2016 ◽  
Vol 94 (10) ◽  
pp. 1081-1084 ◽  
Author(s):  
Min Ae Lee-Kirsch ◽  
Claudia Günther ◽  
Axel Roers
Keyword(s):  
Nucleic Acid ◽  
Type I ◽  
Type I Interferonopathies

scholarly journals RIG-I-Like Receptors and Type I Interferonopathies

2017 ◽  
Vol 37 (5) ◽  
pp. 207-213 ◽  
Author(s):  
Hiroki Kato ◽  
Seong-Wook Oh ◽  
Takashi Fujita
Keyword(s):  
Type I ◽  
Type I Interferonopathies

Genetic Analysis and Molecular Phylogeny of Simian T-Cell Lymphotropic Virus Type I: Evidence for Independent Virus Evolution in Asia and Africa

Virology ◽  
1994 ◽  
Vol 199 (1) ◽  
pp. 56-66 ◽  
Author(s):  
Ki-Joon Song ◽  
Vivek R. Nerurkar ◽  
Naruya Saitou ◽  
Aristides Lazo ◽  
James R. Blakeslee ◽  
...  
Keyword(s):  
T Cell ◽  
Molecular Phylogeny ◽  
Genetic Analysis ◽  
Virus Type ◽  
Virus Evolution ◽  
Type I

First Genetic Analysis of Lattice Corneal Dystrophy Type I in a Family from Bulgaria

2005 ◽  
Vol 15 (6) ◽  
pp. 804-808 ◽  
Author(s):  
E. Capoluongo ◽  
G. De benedetti ◽  
P. Concolino ◽  
M. Sepe ◽  
R. Ambu ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Corneal Dystrophy ◽  
Type I ◽  
Lattice Corneal Dystrophy

Therapeutic Approaches to Type I Interferonopathies

2018 ◽  
Vol 20 (6) ◽  
Author(s):  
Marc Bienias ◽  
Normi Brück ◽  
Constanze Griep ◽  
Christine Wolf ◽  
Stefanie Kretschmer ◽  
...  
Keyword(s):  
Type I ◽  
Therapeutic Approaches ◽  
Type I Interferonopathies

Clinical case of type I interferonopathy: homozygous STAT2 gain-of-function mutation

2021 ◽  
Vol 20 (3) ◽  
pp. 132-139
Author(s):  
А. L. Kozlova ◽  
М. Е. Leonteva ◽  
V. I. Burlakov ◽  
Z. А. Nesterenko ◽  
О. М. Laba ◽  
...  
Keyword(s):  
Side Effects ◽  
Clinical Case ◽  
Kinase Inhibitor ◽  
Genetic Defect ◽  
Type I ◽  
Gain Of Function ◽  
The World ◽  
Key Aspects ◽  
Methods Of Treatment ◽  
Type I Interferonopathies

The article is devoted to an extremely rare variant of type I interferonopathies associated with a homozygous gain of function (GOF) mutation in the STAT2 gene in a 5-year-old child. This genetic defect was first described in 2019, and so far only 3 cases are known in the world with a similar pathology. Here we present the fourth clinical case and our experience in managing a patient with STAT2 GOF. The article presents the key aspects of the pathogenesis, clinical picture based on the analysis of all known cases of the disease. The absence of established criteria and methods of treatment for this disease is due to the rarity and relative novelty of the described nosology. We present the experience of treatment using a JAK kinase inhibitor, followed by an assessment of the effectiveness of the therapy and side effects. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.

Is Hyperprolinemia Type I Actually a Benign Trait? Report of a Case With Severe Neurologic Involvement and Vigabatrin Intolerance

2001 ◽  
Vol 16 (8) ◽  
pp. 622-623 ◽  
Author(s):  
Véronique Humbertclaude ◽  
François Rivier ◽  
Agathe Roubertie ◽  
Bernard Echenne ◽  
Helène Bellet ◽  
...  
Keyword(s):  
Type I ◽  
Neurologic Involvement
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