One of the mysteries of the #COVID pandemic is how MIS-C (multi-inflammatory syndrome-children), a rare life-threatening condition in children, is connected to the SARS-CoV-2 virus. A new preprint finds some surprising links. 🧵1/13

At first it seemed kids were spared from severe COVID, but in some kids doctors started to see a mix of serious symptoms a month after they had seemingly recovered. The disease often required ICU interventions, and was dubbed MIS-C. 2/13 cdc.gov/mis/mis-c.html

Now, in the largest #MISC immune profiling study ever, a team led by #CZBiohubSF & UC San Francisco has found new evidence in kids with MIS-C of an unusual cross-reaction of the immune system between the virus and normal cells, raising tantalizing questions. 3/13

“It makes you wonder how many other autoimmune diseases might be triggered by common viruses," says Aaron Bodansky, a pediatric ICU doc at UCSF, preprint lead author & fellow in the lab of Joe DeRisi, president of #CZBiohubSF & a senior author. 4/13

The scientists obtained 199 blood samples from children who had MIS-C, most of whom were critically ill in the ICU with myocarditis, or inflammation of the heart. The study size was far larger than in previous comparable studies. 5/13

Also notable was their use of an ideal control group: 45 kids who had severe COVID in the previous 5+ weeks but not MIS-C, allowing comparison of the immune response in kids with MIS-C vs a normal immune response to the virus. Read: medrxiv.org/content/10.110… 6/13

Thanks to #PhiPSeq, a powerful tool which DeRisi has pioneered for immune profiling of a variety of diseases, they compared autoantibodies in the 2 groups, then used machine learning to analyze the data, and found novel autoantibodies that distinguished MIS-C from controls. 7/13

They were also fascinated to see very different immune responses to SARS-CoV-2. While both had antibody responses against the virus’s nucleocapsid protein, they targeted different parts of the protein, “which is something we never could’ve found w/o PhiP-Seq,” Bodansky says. 8/13

They further found that the part of the virus being preferentially targeted in the MIS-C group looked extremely similar to an immune-system protein involved in fighting viruses–the immune system was exhibiting cross-reactivity and mistakenly attacking itself. 9/13

Although MIS-C is now rare, this study could have implications for unraveling other autoimmune diseases, including #kawasakidisease, a very similar condition in kids that is poorly understood but suspected to be preceded by a viral infection. 10/13

“This study is a significant step forward toward understanding this rare and often devastating complication post-COVID infection. Of course, it surfaces even more questions, but that is always the case with new discoveries,” says DeRisi, who is also a UC San Francisco professor. 11/13

It’s still unknown why MIS-C is most prevalent in children, but Bodansky notes that “MIS-A” does occur in adults and suggests that it might be underdiagnosed due to conflation with other severe COVID symptoms. 12/13

The study took 2 years and involved many collaborators, including Adrienne Randolph of Boston Children's, Mark Anderson of UC San Francisco, the CDC COVID-19 Response Team, and the OvercomingCOVID19 Network. /end

新型コロナ感染小児に稀に起こるMIS-Cで注目結果(preprint) MIS-Cの子を調べ次の可能性浮上 感染→コロナのN(ヌクレオカプシド)領域に対し異常な免疫反応→同免疫が自己の蛋白と反応→発症 接種の反応はS(スパイク)対象で無関係な上MIS-Cが減ったのも接種等で免疫が抗S等にシフトしたからの可能性

感染が前駆するとNへ免疫反応が起き稀に通常と異なる反応から自己の蛋白とも反応MIS-Cに進展 一方接種での免疫はSへのものでこれは起きずむしろ感染時も上述の反応回避される可能性 感染すればOK等の発信がこの様な事がわかる前から継続的に為されてきたが改めて感染と接種は異なると認識させる結果

Thank you for this summary of our work. Very interesting link to these previously discussed anti-N antibodies.

Excited to share our findings on novel autoantibodies in autoimmune hepatitis (AIH); thankful to this team of collaborators for moving us closer to understanding AIH pathogenesis and to UCSF Gastroenterology Fellowship and Women Physician-Scientists at UCSF for support! medrxiv.org/content/10.110…

Excited to share our new paper exploring the "autoreactome", our autoantibody fingerprints, and how it can better assess emerging autoimmune therapies. jci.org/articles/view/… Thank you to all of my mentors and collaborators Chan Zuckerberg Biohub Network Fred Hutch Cancer Center UCSF Pediatrics Seattle Children's