Thread by @casanova_lab

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…)

3/ A specific feature of MIS-C is the massive expansion of Vbeta21.3 CD4 and CD8 T cells in most patients (science.org/doi/10.1126/sc…, doi.org/10.1016/j.immu…, nature.com/articles/s4159…, jci.org/articles/view/…, doi.org/10.1084/jem.20…)

4/ We previously proposed that MIS-C is a type of Kawasaki Disease triggered by a single virus and might be caused by monogenic inborn errors of immunity that can be detected by searching for genetic homogeneity in a sufficiently large cohort of patients (doi.org/10.1084/jem.20…)

5/ We first searched for autosomal recessive defects. We found that about 1% of the children with MIS-C studied are deficient for OAS1, OAS2, or RNase L

6/ We teamed up with Robert H. Silverman at the @ClevelandClinic, who has been studying this pathway since it was discovered in the 1970s (doi.org/10.1089/jir.20…)

7/ The OAS1 and OAS2 (like OAS3) are type I IFN-inducible proteins that can sense (viral or host) dsRNA in the cytosol, releasing 2-5A, which activates RNase L that will degrade (viral or host) ssRNA

8/ Since the late Ion Gresser showed that this pathway is particularly active in mononuclear phagocytes in 1985 (journals.asm.org/doi/10.1128/jv…), we tested the impact of these defects in these cells

9/ We found that monocytic cell lines, like monocytes and dendritic cells lacking OAS1, OAS2, or RNase L, produce massive amounts of inflammatory cytokines when stimulated with dsRNA or SARS-CoV-2

10/ Given that the OAS-RNase L "cellular brake" was evidently impaired in these cells, we sought to identify the "cellular accelerator" responsible for inducing the cytokines and determined it to be the MDA5-RIG-I-MAVS pathway

11/ Overall, MIS-C can be caused by autosomal recessive defects of the OAS-RNase L pathway, which unleash the activation of mononuclear phagocytes by SARS-CoV-2-triggered dsRNA, thereby possibly facilitating the expansion of Vbeta21.3 T cells

12/ Interestingly, while inborn errors or auto-Abs that impair type I IFN activity underlie critical COVID-19 pneumonia (science.org/doi/10.1126/sc…, science.org/doi/10.1126/sc…), the deficiency of this single type I IFN-inducible pathway does not – on the contrary, it underlies MIS-C

13/ This mechanism of disease may operate generally, facilitating the search for other genetic lesions in children with MIS-C

14/ This observation also suggests that other forms of Kawasaki Disease may be deciphered by searching for monogenic lesions in cohorts of patients whose Kawasaki was triggered by one virus or a group of related viruses

15/ Huge thanks to the many teams of the COVID Human Genetic Effort (covidhge.com) including particularly @IsabelleMeyts, Filomeen Haerynck, @PujolLab, @SanchoShimizu, Rebeca Perez de Diego, Carlos Rodriguez-Gallego, @ldnotar, Helen C. Su, and @LaurentAbel4

16/ Special thanks to Robert H. Silverman, @RiceLaboratory, @QuintanaMurci, @AlexandreBelot and their research teams

17/ Special thanks to @ElieHaddad55, @laiaalsina, Iolanda Jordan, Sevgi Keles and their clinical teams

18/ Thanks to all co-authors @DanyelLee123, @Jeremie_LP, @AhmadYatim_, @aquino_yann, @MasatoOgishi, @zhangpeng1202, @ZhiyongLiu7, @JordanIolanda, @weitelei, @jiechen1982, @FabriceJaffre, @michailidis_hbv, @Yseeleuthner, @LabCflores, @AriasAAS, @BigioBenedetta, @Marce_MoncadaV...

19/ @LevyRomain, @ALNeehus, @JRosain, @yihaoo, @RosaMar64577668, @joancmarch, @SelketDelafont1, @ChenShuibing, @weisssr, @panhammarstrom, @BustamanteJaci1, @anne_puel, @BoissonDupuis, @Boisson_Bebo, @tutu_ZQ, @ldnotar, @BeziatV, @JouanguyE, @AurelieCobat, @ShenYingZhang1...

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