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

Abstract

Treatment naive 14 Febrile Controls CXCL9/10 IL-27 M-CSF Spectral Flow Cytometry Upregulation of Conventional Dendritic Cells type 1 (cDC1) implicates antigen cross presentation in Multisystem Inflammatory Syndrome (MIS-C) cytokines MIS-C pa ents as compared to febrile controls 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 1 CD141 1 CLEC9A 1 ) 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 2 / KLRG hi /CD161 1 /CD38 2 natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome.

IL27 gene expression distinguishes multisystem inflammatory syndrome in children from febrile illness in a South African cohort

“…The role of IL-27 in MIS-C is less well understood. Recently IL-27 was reported as one of several cytokines to be significantly up-regulated in MIS-C compared to febrile controls ( 41 ), although IL-27 was one of the most markedly elevated markers in MIS-C. While this observation was limited to seven MIS-C patients, it does corroborate the findings of our RNA study at the cytokine level.…”

Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis

“…In severe MIS-C patients there is an enrichment of proteins involved in complement activation, neutrophil degranulation and dysregulated humoral responses ( 125 ). Immune profiling of MIS-C patients indicates activation of monocytes, neutrophils, and type 1 dendritic cells, decreased frequencies of circulating NK cells, and T cell lymphopenia affecting both CD4 + and CD8 + T cells, which are more proliferative and activated ( 95 , 124 , 126 , 127 ). A subset of CD8 + T cells expressing the fractalkine receptor CX3CR1, and able to interact with fractalkine expressing vascular endothelium, are more activated during MIS-C ( 95 ).…”

Myeloid CD169/Siglec1: An immunoregulatory biomarker in viral disease

“…The roles and functions in immunoregulatory processes seem to be manifold, including pathogen recognition (28), pathogen uptake (28,34,35) cross-presentation to CD8α + DCs (T cell priming) (25,33,36,37), as well as B-cell and invariant natural killer T-cell (iNKT) activation (33,38).…”