TY - JOUR
T1 - Host Genetics and Antiviral Immune Responses in Adult Patients With Multisystem Inflammatory Syndrome
AU - Ronit, Andreas
AU - Jørgensen, Sofie E
AU - Roed, Casper
AU - Eriksson, Robert
AU - Iepsen, Ulrik W
AU - Plovsing, Ronni R
AU - Storgaard, Merete
AU - Gustafsson, Finn
AU - Hansen, Ann-Brit E
AU - Mogensen, Trine H
N1 - Copyright © 2021 Ronit, Jørgensen, Roed, Eriksson, Iepsen, Plovsing, Storgaard, Gustafsson, Hansen and Mogensen.
PY - 2021/8/31
Y1 - 2021/8/31
N2 - COVID-19 associated multisystem inflammatory syndrome (MIS) is a rare condition mostly affecting children but also adults (MIS-A). Although severe systemic inflammation and multiorgan dysfunction are hallmarks of the syndrome, the underlying pathogenesis is unclear. We aimed to provide novel immunological and genetic descriptions of MIS-A patients. Cytokine responses (IL-6, IL-1β, TNFα, CXCL10, type I, II and III interferons) following SARS-CoV-2 infection of peripheral blood mononuclear cells in vitro were analyzed as well as antibodies against IFNα and IFNω (by ELISA) in patients and healthy controls. We also performed whole exome sequencing (WES) of patient DNA. A total of five patients (ages 19, 23, 33, 38, 50 years) were included. The patients shared characteristic features, although organ involvement and the time course of disease varied slightly. SARS-CoV-2 in vitro infection of patient PBMCs revealed impaired type I and III interferon responses and reduced CXCL10 expression, whereas production of proinflammatory cytokines were less affected, compared to healthy controls. Presence of interferon autoantibodies was not detected. Whole exome sequencing analysis of patient DNA revealed 12 rare potentially disease-causing variants in genes related to autophagy, classical Kawasaki disease, restriction factors and immune responses. In conclusion, we observed an impaired production of type I and III interferons in response to SARS-CoV-2 infection and detected several rare potentially disease-causing gene variants potentially contributing to MIS-A.
AB - COVID-19 associated multisystem inflammatory syndrome (MIS) is a rare condition mostly affecting children but also adults (MIS-A). Although severe systemic inflammation and multiorgan dysfunction are hallmarks of the syndrome, the underlying pathogenesis is unclear. We aimed to provide novel immunological and genetic descriptions of MIS-A patients. Cytokine responses (IL-6, IL-1β, TNFα, CXCL10, type I, II and III interferons) following SARS-CoV-2 infection of peripheral blood mononuclear cells in vitro were analyzed as well as antibodies against IFNα and IFNω (by ELISA) in patients and healthy controls. We also performed whole exome sequencing (WES) of patient DNA. A total of five patients (ages 19, 23, 33, 38, 50 years) were included. The patients shared characteristic features, although organ involvement and the time course of disease varied slightly. SARS-CoV-2 in vitro infection of patient PBMCs revealed impaired type I and III interferon responses and reduced CXCL10 expression, whereas production of proinflammatory cytokines were less affected, compared to healthy controls. Presence of interferon autoantibodies was not detected. Whole exome sequencing analysis of patient DNA revealed 12 rare potentially disease-causing variants in genes related to autophagy, classical Kawasaki disease, restriction factors and immune responses. In conclusion, we observed an impaired production of type I and III interferons in response to SARS-CoV-2 infection and detected several rare potentially disease-causing gene variants potentially contributing to MIS-A.
KW - Adult
KW - Autoantibodies/blood
KW - COVID-19/pathology
KW - Chemokine CXCL10/biosynthesis
KW - Comorbidity
KW - Cytokines/blood
KW - Exome/genetics
KW - Female
KW - Humans
KW - Interferon-alpha/biosynthesis
KW - Interferons/biosynthesis
KW - Leukocytes, Mononuclear/immunology
KW - Male
KW - Middle Aged
KW - SARS-CoV-2/immunology
KW - Systemic Inflammatory Response Syndrome/pathology
KW - Whole Exome Sequencing
KW - Young Adult
KW - interferon
KW - whole exome sequencing
KW - SARS-CoV-2
KW - coronavirus disease 2019
KW - multisystem inflammatory syndrome
UR - http://www.scopus.com/inward/record.url?scp=85115034401&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.718744
DO - 10.3389/fimmu.2021.718744
M3 - Journal article
C2 - 34531865
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 718744
ER -