Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Science Immunology, Journal Year: 2021, Volume and Issue: 6(62)

Published: Aug. 10, 2021

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found about 10% patients with critical COVID-19 pneumonia, but not subjects asymptomatic infections. We detect auto-Abs 100-fold lower, more physiological, (100 pg/mL, 1/10 dilutions plasma) 13.6% 3,595 COVID-19, including 21% 374 > 80 years, and 6.5% 522 severe COVID-19. These antibodies also detected 18% the 1,124 deceased (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% 0.9% have IFN-β. show, a sample 34,159 uninfected from general population, that present 0.18% individuals between 18 69 1.1% 79 3.4% >80 years. proportion carrying lower is greater subsample 10,778 individuals: 1% <70 2.3% 6.3% By contrast, IFN-β do become frequent age. Auto-Abs type I IFNs predate SARS-CoV-2 infection sharply increase prevalence after age They account for 20% both cases over-80s, total fatal cases.

Language: Английский

---

Innate immunity: the first line of defense against SARS-CoV-2

Nature Immunology, Journal Year: 2022, Volume and Issue: 23(2), P. 165 - 176

Published: Feb. 1, 2022

Language: Английский

---

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Science Immunology, Journal Year: 2021, Volume and Issue: 6(62)

Published: Aug. 10, 2021

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort 1,202 patients 0.5 99 52.9 with unexplained pneumonia. None the 331 asymptomatically or mildly infected 1.3 102 38.7 tested carry such (p = 3.5 × 10-5). The phenotypes five hemizygous relatives index cases SARS-CoV-2 include asymptomatic mild infection (n=2, 5 38 years), moderate (n=1, severe 27 29 Two boys (aged 12 262 51.0 are for variant. cumulative allele frequency general population is < 6.5x10-4 also show that blood B cell lines myeloid subsets do not respond stimulation, phenotype rescued by wild-type patients' plasmacytoid dendritic cells (pDCs) produce low levels IFNs response SARS-CoV-2. Overall, recessive deficiency highly penetrant genetic etiology pneumonia, about 1.8% below age 60 years. Human pDCs essential protective respiratory tract.

Language: Английский

---

Human genetic and immunological determinants of critical COVID-19 pneumonia

Nature, Journal Year: 2022, Volume and Issue: 603(7902), P. 587 - 598

Published: Jan. 28, 2022

Language: Английский

---

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19

Cell, Journal Year: 2021, Volume and Issue: 184(18), P. 4713 - 4733.e22

Published: July 23, 2021

SARS-CoV-2 infection can cause severe respiratory COVID-19. However, many individuals present with isolated upper symptoms, suggesting potential to constrain viral pathology the nasopharynx. Which cells primarily targets and how influences epithelium remains incompletely understood. We performed scRNA-seq on nasopharyngeal swabs from 58 healthy COVID-19 participants. During COVID-19, we observe expansion of secretory, loss ciliated, epithelial cell repopulation via deuterosomal expansion. In mild moderate express anti-viral/interferon-responsive genes, while in have muted anti-viral responses despite equivalent loads. RNA

Language: Английский

---

Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19

Science Translational Medicine, Journal Year: 2021, Volume and Issue: 13(612)

Published: Aug. 24, 2021

Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the caused by severe acute respiratory syndrome 2 (SARS-CoV-2). However, prevalence of these antibodies, their longitudinal dynamics across severity scale, and functional effects on circulating leukocytes remain unknown. Here, 284 COVID-19, we IFN–specific peripheral blood samples from 19% 6% disease. We no IFN individuals moderate Longitudinal profiling over 600,000 mononuclear cells using multiplexed single-cell epitope transcriptome sequencing 54 COVID-19 26 non–COVID-19 controls revealed a lack IFN–stimulated gene (ISG-I) responses myeloid This was especially evident dendritic cell populations isolated producing autoantibodies. Moreover, elevated expression inhibitory receptor leukocyte-associated immunoglobulin-like 1 (LAIR1) surface monocytes early course. LAIR1 is inversely correlated ISG-I response but not expressed healthy controls. The deficient observed without supports unifying model for pathogenesis involving suppression through convergent mechanisms.

Language: Английский

---

SARS‐CoV‐2 Alpha, Beta, and Delta variants display enhanced Spike‐mediated syncytia formation

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(24)

Published: Oct. 4, 2021

Language: Английский

---

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(21)

Published: May 16, 2022

Significance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It important to estimate their quantitative impact on mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence these risk death increase with higher in men. Using an unvaccinated sample 1,261 deceased patients 34,159 individuals from general population, we found against IFNs strongly increased infection fatality rate at all ages, men women. Autoantibodies common predictors COVID-19. Testing for should be considered population.

Language: Английский

---

Immunology of SARS-CoV-2 infection in children

Nature Immunology, Journal Year: 2022, Volume and Issue: 23(2), P. 177 - 185

Published: Feb. 1, 2022

Language: Английский

---

Sex Differences in Immunity

Annual Review of Immunology, Journal Year: 2022, Volume and Issue: 40(1), P. 75 - 94

Published: Jan. 5, 2022

Strong epidemiological evidence now exists that sex is an important biologic variable in immunity. Recent studies, for example, have revealed differences are associated with the severity of symptoms and mortality due to coronavirus disease 2019 (COVID-19). Despite this evidence, much remains be learned about mechanisms underlying associations between immune-mediated conditions. A growing body experimental data has made significant inroads into understanding sex-influenced immune responses. As physicians seek provide more targeted patient care, it critical understand how sex-defining factors (e.g., chromosomes, gonadal hormones) alter responses health disease. In review, we highlight recent insights autoimmunity; virus infection, specifically severe acute respiratory syndrome 2 (SARS-CoV-2) infection; cancer immunotherapy. deeper will allow development a sex-based approach screening treatment.

Language: Английский

---