1/ 📢 📰 In @JExpMed, we report that about 10% of children with life-threatening #COVID19 harbor auto-antibodies to type I IFNs. ()rupress.org/jem/article/22… 2/ Since first being discovered in a patient with severe VZV infection by Ion Gresser in 1984, these auto-Abs have been thought to be silent 🔇()jstor.org/stable/30134062

1/ We are excited to report in @Nature the discovery that human inborn errors of the alternative NF-κB pathway-dependent immunity underlie the development of auto-Abs neutralizing type I IFNs ().rdcu.be/dqBBU 2/ Auto-Abs neutralizing type I IFNs are present in the general population, with a prevalence that sharply increases over 70 years old, reaching 4-8% ().science.org/doi/10.1126/sc…

1/ We are happy to share our report of inherited RIPK3 deficiency in a child with HSV-1 encephalitis (HSE) in @SciImmunology (doi.org/10.1126/sciimm…­­­­­). HUGE thanks to all collaborators (list below)! 2/ HSV-1 is a ubiquitous virus that infects over 80% of the global population. HSE is perhaps the most common sporadic life-threatening encephalitis in the world.

1/ We are excited to share exciting news about human IL-23 in #ScienceImmunology (science.org/doi/10.1126/sc…). 2/ The early 2000s discovery of IL-23 and IL-23R was associated with the characterization of TH17 cells as distinct T-cell lineage, different from TH1 / TH2 cells (nature.com/articles/natur…).

1/ We are excited to share some news about human IRF1, which surprisingly turns out to be the key transcription factor downstream from IFN-gamma and STAT1 in macrophages (sciencedirect.com/science/articl…). 2/ IRF1 was discovered in 1988 by Tada Taniguchi (tinyurl.com/mr48xn5e). In 1993, his team also reported IRF1-deficient mice (tinyurl.com/387mwvup). Both studies were published in @CellCellPress.

1/ Together with the COVID Human Genetics Effort, we are happy to report our finding of inborn errors of the OAS-RNase L pathway in children with MIS-C #Misc #Pims in @ScienceMagazine (science.org/doi/10.1126/sc…) 2/ Multisystem inflammatory syndrome of children (MIS-C) is characterized by a massive inflammation about 4 weeks post benign #COVID19 upon infection by #SARSCoV2, with life-threatening cardio-vascular manifestations (nejm.org/doi/10.1056/NE…; link.springer.com/article/10.100…)

1/ We are happy to share with you our paper in @JExpMed reporting auto-Abs to type I IFNs in 5% of patients with critical influenza pneumonia (rupress.org/jem/article/21…; ). 2/ The risk of critical influenza was highest in patients with auto-Abs neutralizing high concentrations of both IFN-alpha2 and IFN-omega (OR=11.7, P=1.3x10-5), especially those <70 yr old (OR=139.9, P=3.1x10-10).

1/ Happy to share a perspective of our 30-year-long journey searching for human genetic and immunological determinants of infectious diseases (sciencedirect.com/science/articl…). 2/ The key question in the field of infectious diseases is paradoxically that of their root cause, as only a small proportion of infected people are severely ill – this is “the infection enigma” (annualreviews.org/doi/abs/10.114…).

1/ Today in @ScienceMagazine, @aspaan1 & colleagues show that human #OTULIN #haploinsufficiency impairs non-leukocytic cell-intrinsic immunity to the #staphylococcal alpha-toxin (science.org/doi/10.1126/sc…). 2/ They discovered OTULIN haploinsufficiency via a genome-wide approach in a cohort of patients with unexplained, life-threatening staphylococcal disease – the findings are relevant in vivo.

1/ In @JExpMed, we report a null IFNAR1 allele that is surprisingly common in western Polynesia, with a MAF>1%. 2/ This work was a fantastic collaboration with @QuintanaMurci, @pittjryan, @morestrada, @LaurentAbel4, @ShenYingZhang1, @JouanguyE, @stutangye, @BeziatV, @JeremyChoin,
@BigioBenedetta, @StatGenDan, @RMaguelonne, @jiechen1982, @tutu_ZQ, and others not on Twitter.

1/ Here is a review in @Nature by the CovidHGE.com of the human #genetic and immunological determinants of life-threatening #COVID-19 (nature.com/articles/s4158…). 2/ We review what has been learned over the last two years about a simple question: why do about 3% of (#unvaccinated) infected people end up in an ICU with critical C-19 pneumonia when 97% of people control the virus well?

1/ In #JoCI/#Springer, @xsolanich & team report #autoAbs neutralizing high concentrations of #type1IFN in 10% of patients with critical #COVID19 pneumonia in their hospital (link.springer.com/article/10.100…). 2/ After Amsterdam (link.springer.com/article/10.100…), Lyon (onlinelibrary.wiley.com/doi/10.1002/ct…), New Haven (nature.com/articles/s4158… ), San Francisco (science.org/doi/10.1126/sc…; link.springer.com/article/10.100…), Boston(sciencedirect.com/science/articl…)…

1/ In this 2nd @SciImmunology paper (immunology.sciencemag.org/content/6/62/e…), we show pre-existing auto-Abs neutralizing low physiological concentrations of type I IFNs account for 15% of critical COVID-19 cases, including 20% of critical cases in patients >80 yrs and 20% of deaths across ages. 2/ We tested 100-fold lower concentrations of type I IFN than in our previous report (science.sciencemag.org/content/370/65…). We also found that, in most patients, these auto-Abs neutralize IFN-alphas and/or -omega, while other patients carry auto-Abs that neutralize IFN-beta only.

1/ In this first @SciImmunology paper (immunology.sciencemag.org/content/6/62/e…), we show that at least 1% of men younger than 60 years with life-threatening COVID-19 are sick because of X-linked recessive (XR) TLR7 deficiency. 2/ In an unbiased burden test, we found TLR7 as the most significant hit on the X chromosome; with very rare (MAF<10e-4) nonsynonymous variants found in patients with critical COVID-19, but not in patients with asymptomatic/mild infection.

We report @JExpMed an international survey of SARS-CoV-2-infected APS-1 patients and show that they are at very high risk of life-threatening, critical C-19 pneumonia due to preexisting auto-Abs neutralizing type I IFNs (urldefense.proofpoint.com/v2/url?u=https…) APS-1 patients typically carry bi-allelic mutations in 𝘈𝘐𝘙𝘌, which controls thymic expression of peripheral antigens, thereby governing central T cell tolerance (science.sciencemag.org/content/298/55…).

We show that neutralizing autoantibodies to type I IFNs underlie a third of the life-threatening adverse reactions to yellow fever virus live-attenuated virus (YFV 17D): rupress.org/jem/article/21… We also report a patient with YFV 17D disease due to inherited IFNAR2 deficiency, consistent with our previous description of a patient with inherited IFNAR1 deficiency: rupress.org/jem/article/21…

We have been silent for a while because our lab and the CHGE were entirely focused on finishing 'twin papers' in @ScienceMagazine about inborn errors of type I IFN or auto-antibodies to type I IFN in nearly 15% of patients with life-threatening #COVID19 😀 science.sciencemag.org/content/369/65… Here is the first paper, which shows that variants in only 13 influenza susceptibility candidate genes that govern TLR3- and IRF7-dependent production of type I IFNs account for at least 3.5% of critical cases of #COVID19 science.sciencemag.org/content/early/… @ScienceMagazine