TY - JOUR
T1 - Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome
AU - Huang, Janice J.
AU - Gaines, Samantha B.
AU - Amezcua, Mateo L.
AU - Lubell, Tamar R.
AU - Dayan, Peter S.
AU - Dale, Marissa
AU - Boneparth, Alexis D.
AU - Hicar, Mark D.
AU - Winchester, Robert
AU - Gorelik, Mark
N1 - Publisher Copyright:
© 2021 American Academy of Allergy, Asthma & Immunology
PY - 2022/3
Y1 - 2022/3
N2 - Background: Multisystem inflammatory syndrome in children (MIS-C) is an acute, febrile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated syndrome, often with cardiohemodynamic dysfunction. Insight into mechanism of disease is still incomplete. Objective: Our objective was to analyze immunologic features of MIS-C patients compared to febrile controls (FC). Methods: MIS-C patients were defined by narrow criteria, including having evidence of cardiohemodynamic involvement and no macrophage activation syndrome. Samples were collected from 8 completely treatment-naive patients with MIS-C (SARS-CoV-2 serology positive), 3 patients with unclassified MIS-C–like disease (serology negative), 14 FC, and 5 MIS-C recovery (RCV). Three healthy controls (HCs) were used for comparisons of normal range. Using spectral flow cytometry, we assessed 36 parameters in antigen-presenting cells (APCs) and 29 in T cells. We used biaxial analysis and uniform manifold approximation and projection (UMAP). Results: Significant elevations in cytokines including CXCL9, M-CSF, and IL-27 were found in MIS-C compared to FC. Classic monocytes and type 2 dendritic cells (DCs) were downregulated (decreased CD86, HLA-DR) versus HCs; however, type 1 DCs (CD11c+CD141+CLEC9A+) were highly activated in MIS-C patients versus FC, expressing higher levels of CD86, CD275, and atypical conventional DC markers such as CD64, CD115, and CX3CR1. CD169 and CD38 were upregulated in multiple monocyte subtypes. CD56dim/CD57−/KLRGhi/CD161+/CD38− natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome. Conclusion: Orchestrated by complex cytokine signaling, type 1 DC activation and NK dysregulation are key features in the pathophysiology of MIS-C. NK cell findings may suggest a relationship with macrophage activation syndrome, while type 1 DC upregulation implies a role for antigen cross-presentation.
AB - Background: Multisystem inflammatory syndrome in children (MIS-C) is an acute, febrile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated syndrome, often with cardiohemodynamic dysfunction. Insight into mechanism of disease is still incomplete. Objective: Our objective was to analyze immunologic features of MIS-C patients compared to febrile controls (FC). Methods: MIS-C patients were defined by narrow criteria, including having evidence of cardiohemodynamic involvement and no macrophage activation syndrome. Samples were collected from 8 completely treatment-naive patients with MIS-C (SARS-CoV-2 serology positive), 3 patients with unclassified MIS-C–like disease (serology negative), 14 FC, and 5 MIS-C recovery (RCV). Three healthy controls (HCs) were used for comparisons of normal range. Using spectral flow cytometry, we assessed 36 parameters in antigen-presenting cells (APCs) and 29 in T cells. We used biaxial analysis and uniform manifold approximation and projection (UMAP). Results: Significant elevations in cytokines including CXCL9, M-CSF, and IL-27 were found in MIS-C compared to FC. Classic monocytes and type 2 dendritic cells (DCs) were downregulated (decreased CD86, HLA-DR) versus HCs; however, type 1 DCs (CD11c+CD141+CLEC9A+) were highly activated in MIS-C patients versus FC, expressing higher levels of CD86, CD275, and atypical conventional DC markers such as CD64, CD115, and CX3CR1. CD169 and CD38 were upregulated in multiple monocyte subtypes. CD56dim/CD57−/KLRGhi/CD161+/CD38− natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome. Conclusion: Orchestrated by complex cytokine signaling, type 1 DC activation and NK dysregulation are key features in the pathophysiology of MIS-C. NK cell findings may suggest a relationship with macrophage activation syndrome, while type 1 DC upregulation implies a role for antigen cross-presentation.
KW - CLEC9A
KW - Kawasaki disease (KD)
KW - Multisystem inflammatory syndrome in children (MIS-C)
KW - NK cell cytotoxicity
KW - antigen cross-presentation
KW - dendritic cells
UR - http://www.scopus.com/inward/record.url?scp=85119442944&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2021.10.015
DO - 10.1016/j.jaci.2021.10.015
M3 - Article
C2 - 34688775
AN - SCOPUS:85119442944
SN - 0091-6749
VL - 149
SP - 912
EP - 922
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 3
ER -