The ouroboros of autoimmunity

Nature Immunology, Journal Year: 2024, Volume and Issue: 25(5), P. 743 - 754

Published: May 1, 2024

Language: Английский

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Vaccine adjuvants: Tailoring innate recognition to send the right message

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 772 - 789

Published: April 1, 2024

Language: Английский

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

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(9)

Published: July 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.

Language: Английский

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

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(10)

Published: Sept. 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.

Language: Английский

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Human determinants of age-dependent patterns of death from infection

Immunity, Journal Year: 2024, Volume and Issue: 57(7), P. 1457 - 1465

Published: July 1, 2024

Regardless of microbial virulence (i.e., the global infection-fatality ratio), age generally drives prevalence death from infection in unvaccinated humans. Four mortality patterns are recognized: common U- and L-shaped curves endemic infections unique W- J-shaped pandemic infections. We suggest that these result different sets human genetic immunological determinants. In this model, it is interplay between (1) monogenic genotypes affecting immunity to primary preferentially manifest early life related or their phenocopies, including auto-antibodies, which later (2) occurrence persistence adaptive, acquired cross-reactive infections, shapes age-dependent pattern deaths infection.

Language: Английский

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

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(11)

Published: Oct. 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

Language: Английский

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Life-threatening infections in human newborns: Reconciling age-specific vulnerability and interindividual variability

Cellular Immunology, Journal Year: 2024, Volume and Issue: 397-398, P. 104807 - 104807

Published: Jan. 13, 2024

Language: Английский

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Auto-Abs neutralizing type I IFNs in patients with severe Powassan, Usutu, or Ross River virus disease

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(12)

Published: Nov. 1, 2024

Arboviral diseases are a growing global health concern. Pre-existing autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) can underlie encephalitis due to West Nile virus (WNV) (∼40% of patients) and tick-borne (TBE, TBE [TBEV]) (∼10%). We report here that these auto-Abs also severe forms rarer arboviral infections. Auto-Abs high concentrations IFN-α2, IFN-β, and/or IFN-ω present in the single case Powassan (POWV) studied, two three cases Usutu (USUV) infection most 24 Ross River (RRV) disease studied. These not found any 137 individuals with silent or mild infections viruses. Thus, IFNs an increasing list Flaviviridae (WNV, TBEV, POWV, USUV) Togaviridae viruses transmitted humans by mosquitos USUV, RRV) ticks (TBEV, POWV).

Language: Английский

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Deciphering the IgG Idiotype Network Through Proteomic Analysis of Potential Targets in SARS‐CoV‐2‐Induced Immune Responses

Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

ABSTRACT The association between COVID‐19 and autoimmune diseases has gained increasing recognition, yet the specific targets of SARS‐CoV‐2‐induced IgG are currently in focus for several studies. This study aims to explore proteomic these antibodies their potential role autoimmunity. We utilised a human proteome microarray encompassing 23 736 unique proteins, including isoform variants fragments, as catalogued by Human Protein Atlas. Serum samples were analysed from four groups: healthy controls (N‐exp HC), individuals vaccinated with protein‐based vaccines (N‐Cov Vac) patients moderate or severe (COVID‐Mod COVID‐Sev). evaluation revealed recognise multiple proteins. Key included interferon alpha (IFN‐α), tumour growth factor beta (TGF‐β), interleukin 1 (IL‐1), CXCL16, TGF‐β receptors, CD34, CD47 BCL2. also targeted proteins genes overexpressed various immune cells, such CD4+ CD8+ T γδ B dendritic cells NK cells. Reactivity was observed specifically expressed organs, brain, liver, lungs heart. Targeting patterns differed controls, some showing differential recognition versus cases. Furthermore, we evaluated protein–protein interaction network (PPIN) all minimal structural homology co‐expression among almost no relation SARS‐CoV‐2 system reactome. results suggest that profile autoantibodies is associated disease severity. In contrast, protein‐vaccinated exhibited similar non‐exposed suggesting autoreactive linked active infection. These findings reveal complex idiotypes capable targeting not merely through simple cross‐recognition homologous highlights need further investigations determine whether they may influence pathophysiology its clinical outcomes.

Language: Английский

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

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(6)

Published: March 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.

Language: Английский

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