Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome

Janice J. Huang; Samantha B. Gaines; Mateo L. Amezcua; Tamar R. Lubell; Peter S. Dayan; Marissa Dale; Alexis D. Boneparth; Mark D. Hicar; Robert Winchester; Mark Gorelik

doi:10.1016/j.jaci.2021.10.015

Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome

Janice J. Huang
, Samantha B. Gaines
, Mateo L. Amezcua
, Tamar R. Lubell
, Peter S. Dayan
, Marissa Dale
, Alexis D. Boneparth
, Mark D. Hicar
, Robert Winchester
, Mark Gorelik

Pediatrics

Columbia University

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

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. CD56^dim/CD57⁻/KLRG^hi/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.

Original language	English
Pages (from-to)	912-922
Number of pages	11
Journal	Journal of Allergy and Clinical Immunology
Volume	149
Issue number	3
DOIs	https://doi.org/10.1016/j.jaci.2021.10.015
State	Published - Mar 2022

Keywords

CLEC9A
Kawasaki disease (KD)
Multisystem inflammatory syndrome in children (MIS-C)
NK cell cytotoxicity
antigen cross-presentation
dendritic cells

Access to Document

10.1016/j.jaci.2021.10.015

Cite this

Huang, J. J., Gaines, S. B., Amezcua, M. L., Lubell, T. R., Dayan, P. S., Dale, M., Boneparth, A. D., Hicar, M. D., Winchester, R., & Gorelik, M. (2022). Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome. Journal of Allergy and Clinical Immunology, 149(3), 912-922. https://doi.org/10.1016/j.jaci.2021.10.015

@article{61f098a9f0374cf5a7f812f13c4ddbd1,

title = "Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome",

abstract = "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.",

keywords = "CLEC9A, Kawasaki disease (KD), Multisystem inflammatory syndrome in children (MIS-C), NK cell cytotoxicity, antigen cross-presentation, dendritic cells",

author = "Huang, \{Janice J.\} and Gaines, \{Samantha B.\} and Amezcua, \{Mateo L.\} and Lubell, \{Tamar R.\} and Dayan, \{Peter S.\} and Marissa Dale and Boneparth, \{Alexis D.\} and Hicar, \{Mark D.\} and Robert Winchester and Mark Gorelik",

note = "Publisher Copyright: {\textcopyright} 2021 American Academy of Allergy, Asthma \& Immunology",

year = "2022",

month = mar,

doi = "10.1016/j.jaci.2021.10.015",

language = "English",

volume = "149",

pages = "912--922",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "3",

}

Huang, JJ, Gaines, SB, Amezcua, ML, Lubell, TR, Dayan, PS, Dale, M, Boneparth, AD, Hicar, MD, Winchester, R & Gorelik, M 2022, 'Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome', Journal of Allergy and Clinical Immunology, vol. 149, no. 3, pp. 912-922. https://doi.org/10.1016/j.jaci.2021.10.015

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

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 - https://www.scopus.com/pages/publications/85119442944

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 -

Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this