Molecular Aspects of Medicine, Год журнала: 2023, Номер 94, С. 101213 - 101213
Опубликована: Сен. 11, 2023
Язык: Английский
Cell, Год журнала: 2022, Номер 185(17), С. 3086 - 3103
Опубликована: Авг. 1, 2022
The immense interindividual clinical variability during any infection is a long-standing enigma. Inborn errors of IFN-γ and IFN-α/β immunity underlying rare infections with weakly virulent mycobacteria seasonal influenza virus have inspired studies two common infections: tuberculosis COVID-19. A TYK2 genotype impairing production accounts for about 1% cases, autoantibodies neutralizing account 15% critical COVID-19 cases. discovery inborn mechanisms drove the identification monogenic or autoimmune determinants related infections. This “rare-to-common” genetic mechanistic approach to infectious diseases may be heuristic value.
Язык: Английский
Процитировано
106
The Journal of Experimental Medicine, Год журнала: 2022, Номер 219(11)
Опубликована: Сен. 16, 2022
Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies IFN-α2 alone (five patients) or with IFN-ω (eight from a cohort of 279 (4.7%) aged 6–73 yr influenza pneumonia. Nine four had antibodies high low concentrations, respectively, IFN-α2, six two IFN-ω. The patients’ increased A virus replication in both A549 cells reconstituted human airway epithelia. prevalence these was significantly higher than that the general population for <70 age (5.7 vs. 1.1%, P = 2.2 × 10−5), but not >70 (3.1 4.4%, 0.68). risk highest concentrations (OR 11.7, 1.3 especially those old 139.9, 3.1 10−10). also identified 10 additional patient cohorts. IFNs account ∼5% cases life-threatening old.
Язык: Английский
Процитировано
83
The Journal of Experimental Medicine, Год журнала: 2023, Номер 220(5)
Опубликована: Март 8, 2023
STAT6 (signal transducer and activator of transcription 6) is a factor that plays central role in the pathophysiology allergic inflammation. We have identified 16 patients from 10 families spanning three continents with profound phenotype early-life onset immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All carried monoallelic rare variants functional studies established their gain-of-function (GOF) sustained phosphorylation, increased target gene expression, TH2 skewing. Precision treatment anti–IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations immunological biomarkers. This study identifies heterozygous GOF as novel disorder. anticipate our discovery multiple kindreds germline will facilitate recognition more affected individuals full definition this new primary
Язык: Английский
Процитировано
66
The EMBO Journal, Год журнала: 2023, Номер 42(14)
Опубликована: Июнь 27, 2023
Язык: Английский
Процитировано
52
Frontiers in Immunology, Год журнала: 2023, Номер 14
Опубликована: Май 12, 2023
Interferon regulatory factor 7 (IRF7), a member of the interferon factors (IRFs) family, is located downstream pattern recognition receptors (PRRs)-mediated signaling pathway and essential for production type I (IFN-I). Activation IRF7 inhibits various viral bacterial infections suppresses growth metastasis some cancers, but it may also affect tumor microenvironment promote development other cancers. Here, we summarize recent advances in role as multifunctional transcription inflammation, cancer infection by regulating IFN-I or IFN-I-independent pathways.
Язык: Английский
Процитировано
49
Journal of Clinical Investigation, Год журнала: 2023, Номер 133(3)
Опубликована: Янв. 31, 2023
Since 2003, rare inborn errors of human type I IFN immunity have been discovered, each underlying a few severe viral illnesses. Autoantibodies neutralizing IFNs due to autoimmune regulator (AIRE)-driven T cell tolerance were discovered in 2006, but not initially linked any disease. These two lines clinical investigation converged 2020, with the discovery that inherited and/or deficiencies accounted for approximately 15%-20% cases critical COVID-19 pneumonia unvaccinated individuals. Thus, insufficient at onset SARS-CoV-2 infection may be general determinant life-threatening COVID-19. findings illustrate unpredictable, considerable, contribution study genetic diseases basic biology and public health.
Язык: Английский
Процитировано
46
The Journal of Experimental Medicine, Год журнала: 2024, Номер 221(2)
Опубликована: Янв. 4, 2024
We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only three, plus IFN-ω five, and IFN-α2, IFN-β two; nine patients). Seven (3.8%) Abs at least ng/ml one IFN, whereas the other 12 (6.6%) 100 pg/ml. The auto-Abs neutralized both unglycosylated glycosylated IFNs. also detected pg/ml 4 2,267 uninfected (0.2%) 45 (2%). odds ratios (ORs) life-threatening were, therefore, higher (OR [95% CI] = 67.6 [5.7-9,196.6]) than 2.6 [1.2-5.3]). ORs were high concentrations 12.9 [4.6-35.9]) those low 5.5 [3.1-9.6]) and/or IFN-α2.
Язык: Английский
Процитировано
24
Science Immunology, Год журнала: 2024, Номер 9(97)
Опубликована: Июль 5, 2024
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 delineate impact IFNs in natural conditions demonstrate that only a narrow window IFN activity is beneficial. Insufficient predisposes humans to life-threatening viral diseases (albeit unexpectedly few) with central role immunity respiratory cerebral infection. Excessive IFN, perhaps counterintuitively, appears underlie greater number autoinflammatory and/or known as interferonopathies, whose study has revealed multiple molecular programs involved induction signaling. observations suggest manipulation within physiological range may be clinically relevant for prevention treatment inflammatory diseases.
Язык: Английский
Процитировано
21
Frontiers in Immunology, Год журнала: 2023, Номер 14
Опубликована: Авг. 10, 2023
Interferon regulatory factor (IRF) 7 was originally identified as master transcriptional that produced IFN-I and regulated innate immune response, subsequent studies have revealed IRF7 performs a multifaceted versatile functions in multiple biological processes. In this review, we provide comprehensive overview on the current knowledge of role immunity autoimmunity. We focus latest mechanisms IFN-I, including signaling pathways, transcription, translation, post-translational levels, dimerization nuclear translocation, IFN-III COVID-19. addition to antiviral immunity, also discuss mechanism autoimmunity, further research will expand our understanding IRF7.
Язык: Английский
Процитировано
43
Annual Review of Immunology, Год журнала: 2023, Номер 41(1), С. 561 - 585
Опубликована: Апрель 26, 2023
Infection with SARS-CoV-2 results in clinical outcomes ranging from silent or benign infection most individuals to critical pneumonia and death a few. Genetic studies patients have established that cases can result inborn errors of TLR3- TLR7-dependent type I interferon immunity, preexisting autoantibodies neutralizing primarily IFN-α and/or IFN-ω. These findings are consistent virological showing multiple proteins interfere pathways induction of, response to, interferons. They also congruent cellular mouse models found interferons limit replication vitro vivo, while their absence diminution unleashes viral growth. Collectively, these point insufficient during the first days as general mechanism underlying COVID-19 pneumonia, implications for treatment directions future research.
Язык: Английский
Процитировано
35