Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome

Abstract

BackgroundSARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD).ObjectiveWith this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations.MethodsWe investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission.ResultsPatients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19.ConclusionsOur results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C.

Case Report: Changes in Cytokine Kinetics During the Course of Disease in a Japanese Patient With Multisystem Inflammatory Syndrome in Children

“…IL-6 is a major pro-inflammatory cytokine that was reportedly elevated in patients with MIS-C in previous studies (15)(16)(17)(18)(19)(20)22). In our patient, IL-6 titer also rapidly increased (21.1-fold) with the onset of symptoms.…”

“…The clinical significance of cytokines with titers that did not immediately decline to baseline after the fifth day of illness (but showed a gradual decline; Figure 3C ) is difficult to determine on the basis of data from our single patient; however, Caldarale et al showed that IL-6, CXCL8, CCL2, CXCL9, and CXCL10 were higher in MIS-C patients than in pediatric COVID-19 patients, and that treatment with IVIG and methylprednisolone resulted in a rapid decrease in IL-6, but the decrease of CCL 2, CXCL9, and CXCL10 were delayed ( 22 ). The same changes in these cytokines/chemokines were observed in our study.…”

“…We observed kinetics of various cytokines that are reportedly increased in patients with MIS-C, including IL-1Ra ( 14 , 21 ), IL-1β ( 19 ), IL-6 ( 15 – 20 , 22 ), IL-8 ( 18 , 19 ), IL-10 ( 16 , 20 ), IL-17 ( 17 ), IL-18 ( 20 ), CXCL10 ( 15 , 17 , 21 , 22 ), tumor necrosis factor-α ( 18 , 19 ), interferon-γ ( 20 , 21 ), CCL3 ( 17 ), CCL20 ( 17 ), CCL19 ( 17 ), CCL2 ( 21 , 22 ), CXCL1 ( 17 ), and CXCL11 ( 17 ). We found five patterns in the cytokine kinetics in contrast with patient's symptoms.…”

“…The cytokines with titers that peaked on the 5th day of illness and rapidly decreased after treatment as symptoms improved on the next day of treatment are shown in Figure 3B ; those cytokines sensitively reflected the patient's clinical course, and thus, may be directly related to MIS-C disease activity. IL-6 is a major pro-inflammatory cytokine that was reportedly elevated in patients with MIS-C in previous studies ( 15 – 20 , 22 ). In our patient, IL-6 titer also rapidly increased (21.1-fold) with the onset of symptoms.…”

“…In our case, IL-6 decreased on the day after treatment; in contrast, CXCL9, CXCL10, MCP-1 and some others took about 5 days. Caldarale et al discussed that these interferon-γ induced chemokines (CXCL9 and CXCL10) showed significant changes in MIS-C patients and are markers of Th1 type immune response ( 22 ). In our study, in addition to CXCL9 and CXCL10, interferon-γ also showed the same pattern.…”