Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies

The Journal of Experimental Medicine, Год журнала: 2024, Номер 221(9)

Опубликована: Июль 17, 2024

Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.9% acquired anti-IFN-I as they aged (median onset ∼63 years). Once detected, persisted lifelong, and titers increased decades. Individuals developed distinct non-neutralizing autoantibody repertoires discrete times that selectively targeted combinations IFNα, IFNβ, IFNω. Emergence anti-IFNα correlated reduced baseline IFN-stimulated gene levels was associated subsequent susceptibility severe COVID-19 several years later. Retrospective measurements revealed enrichment pre-existing autoreactivity against other autoantigens in who later autoantibodies, there evidence for prior viral infections or IFN time triggering. These analyses suggest age-related loss self-tolerance IFN-I immune-triggering poses risk developing lifelong functional deficiency.

Язык: Английский

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Autoantibodies neutralizing type I IFNs underlie severe tick-borne encephalitis in ∼10% of patients

The Journal of Experimental Medicine, Год журнала: 2024, Номер 221(10)

Опубликована: Сен. 24, 2024

Tick-borne encephalitis (TBE) virus (TBEV) is transmitted to humans via tick bites. Infection benign in >90% of the cases but can cause mild (<5%), moderate (<4%), or severe (<1%) encephalitis. We show here that ∼10% patients hospitalized for TBE cohorts from Austria, Czech Republic, and France carry auto-Abs neutralizing IFN-α2, -β, and/or -ω at onset disease, contrasting with only ∼1% TBE. These were found two eight who died none 13 silent infection. The odds ratios (OR) individuals these relative those without them general population 4.9 (95% CI: 1.5–15.9, P < 0.0001) neutralization 100 pg/ml IFN-α2 -ω, 20.8 4.5–97.4, 10 ng/ml -ω. Auto-Abs type I IFNs accounted three European cohorts.

Язык: Английский

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IgG4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant

Journal of Allergy and Clinical Immunology, Год журнала: 2024, Номер 154(3), С. 819 - 826

Опубликована: Апрель 4, 2024

Язык: Английский

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Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases

The Journal of Experimental Medicine, Год журнала: 2024, Номер 221(11)

Опубликована: Окт. 1, 2024

Human inborn errors of thymic T cell tolerance underlie the production autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven these (36%) have auto-Abs IFN-α and/or IFN-ω, a proportion 23 times higher than that age-matched controls. This remains stable age 6 years onward. On imaging, IP small, abnormally structured thymus. Auto-Abs against IFNs confer predisposition life-threatening By contrast, lacking are at no particular risk disease. These results suggest accelerates involution, thereby underlying least third IP, predisposing them

Язык: Английский

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Non-neutralizing anti-type I interferon autoantibodies could increase thrombotic risk in critical COVID-19 patients

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Март 17, 2025

During the COVID-19 pandemic, approximately 15% of patients with severe pneumonia were reported to have neutralizing anti-type I interferon (IFN) autoantibodies, which impaired antiviral response and led a poorer prognosis. However, physiological impact non-neutralizing autoantibodies remains unclear. In our cohort admitted intensive care, presence IFN increased risk thrombotic complications, likely via cytokine carrier mechanism, prolonging half-life cytokines dysregulating vascular endothelial function. Previous studies associated an cardiovascular complications in autoimmune diseases like systemic lupus erythematosus, but their relevance infectious uncertain. Stratifying based on capacity may clinical significance not only terms susceptibility also predicting events.

Язык: Английский

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Type I interferon autoantibody footprints reveal neutralizing mechanisms and allow inhibitory decoy design

The Journal of Experimental Medicine, Год журнала: 2025, Номер 222(6)

Опубликована: Март 20, 2025

Autoantibodies neutralizing type I interferons (IFN-Is; IFNα or IFNω) exacerbate severe viral disease, but specific treatments are unavailable. With footprint profiling, we delineate two dominant IFN-I faces commonly recognized by autoantibody–containing plasmas from aged individuals with HIV-1 and COVID-19. These overlap regions independently essential for engaging the IFNAR1/IFNAR2 heterodimer, efficiently block interaction of both receptor subunits in vitro. In contrast, non-neutralizing limit only one subunit display relatively low IFN-I–binding avidities, thus likely hindering function. Iterative engineering signaling-inert mutant IFN-Is (simIFN-Is) retaining autoantibody targets created potent decoys that prevent neutralization autoantibody-containing restore IFN-I–mediated antiviral activity. Additionally, microparticle-coupled simIFN-Is were effective at depleting autoantibodies plasmas, leaving antibodies unaffected. Our study reveals mechanisms action demonstrates a proof-of-concept strategy to alleviate pathogenic effects.

Язык: Английский

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Powassan and other emerging neuroinvasive arboviruses in North America

Current Opinion in Infectious Diseases, Год журнала: 2025, Номер unknown

Опубликована: Март 30, 2025

Purpose of review Arthropod-borne viruses (arboviruses) represent a group pathogens with increasing global relevance, some which cause neuroinvasive disease. Transmitted by arthropod vectors and maintained variety primary amplifying hosts, epidemics are dependent on numerous environmental anthropogenic factors. This serves to highlight several important arboviruses relevant North America discuss the neurologic presentations, diagnosis, outcomes, future trends. Recent findings shifts in epidemiology ecology include divergence such as dengue chikungunya from dependence enzootic cycles, geographical expansion Oropouche virus, incidence established American Powassan virus. Accurate identification factors contributing arboviral outbreaks is critical improve preventive public health measures. Similarly, further elucidating pathogen host that determine neuroinvasiveness, neurotropism, neurovirulence will be key development successful vaccines targeted therapeutics. Summary Arboviruses an human Familiarity diagnostic workup, treatment strategies, expected course for clinicians caring these patients.

Язык: Английский

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Sterile production of interferons in the thymus

The Journal of Immunology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 4, 2025

Abstract T-cell central tolerance is controlled by thymocyte TCR recognition of self-peptides presented thymic APCs. While epithelial cells are essential for tolerance, a variety other traditional APCs also play critical roles in selection. Similar to how peripheral require activation become effective, tolerogenic. Recent studies have identified IFNs as an factor the and generation optimally tolerogenic environment. In this review, we focus on interferon (IFN) production within thymus its effects developing thymocytes. We examine importance IFN itself well interferon-stimulated proteins generated during immune responses.

Язык: Английский

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Anti-cytokine autoantibodies in human susceptibility to infectious diseases: insights from Inborn errors of immunity

Immunological Medicine, Год журнала: 2025, Номер unknown, С. 1 - 17

Опубликована: Апрель 8, 2025

The study of Inborn Errors Immunity (IEIs) is critical for understanding the complex mechanisms human immune response to infectious diseases. Specific IEIs, characterized by selective susceptibility certain pathogens, have enhanced our key molecular pathways and cellular subsets involved in host defense against pathogens. These insights revealed that patients with anti-cytokine autoantibodies exhibit phenotypes similar those pathogenic mutations genes encoding signaling molecules. This new disease concept currently categorized as 'Phenocopies IEI'. category includes targeting IL-17/IL-22, IFN-γ, IL-6, GM-CSF, type I IFNs. Abundant deplete corresponding cytokines, impair pathways, increase specific We herein demonstrate clinical etiological significance immunity Insights from studies rare IEIs underscore pathological importance cytokine-targeting autoantibodies. Simultaneously, diverse phenotype these suggests influences cytokine dysfunction are broader than previously recognized. Furthermore, comprehensive prompted COVID-19 pandemic highlighted substantial impact their potential role shaping outcomes disease.

Язык: Английский

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Rapid Detection of Anti‐IFN‐α2 Autoantibodies Using a New Automated VIDAS Assay Prototype

European Journal of Immunology, Год журнала: 2025, Номер 55(4)

Опубликована: Апрель 1, 2025

Autoantibodies neutralizing Type I interferons increase the risk of severe viral diseases and are linked to autoimmune conditions. The automated VIDAS assay is suitable for anti-IFN-α2 IgGs quantification, offering a swift, reliable, user-friendly, single test clinical management.

Язык: Английский

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