MIS-C: A COVID-19-as sociated condition between hypoimmunity and hyperimmunity

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-β, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM, NCF1, MCM4, FCN3, and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1, NOD2, and MEF. Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management.

Keywords: MIS-C; autoimmune diseases; autoinflammatory diseases; cytokines; flow cytometry.

Figure 1

Comparison of serum values of IFN-α, IFN-β, IFN-γ and TNF in 37 patients with MIS-C and in 24 HC. The black line represents the median value. The red box represents the interquartile range. The blank circles correspond to the outliers and the black circles side by side to these correspond to duplicates *p < 0.01; ***p < 0.0001; n.s.: not significant (p > 0.05).

Figure 2

Comparison of serum levels of IL-6, IL-10, IL-17A and IL-12p70 in 37 patients with MIS-C and in 24 HC. The black line represents the median value. The red box represents the interquartile range. The blank circles correspond to the outliers and the black circles side by side to these correspond to duplicates *p < 0.01; ***p < 0.0001; n.s.: not significant (p > 0.05).

Figure 3

Comparison of the complete blood count (CBC) in 37 patients with MIS-C and in 24 HC. The black line represents the median value. The red box represents the interquartile range. The blank circles correspond to the outliers and the black circles side by side to these correspond to duplicates *p < 0.01; ***p < 0.0001; n.s.: not significant (p > 0.05).

Figure 4

Comparison of total T lymphocytes and T lymphocyte populations in 37 patients with MIS-C and in 24 HC. The black line represents the median value. The red box represents the interquartile range. The blank circles correspond to the outliers and the black circles side by side to these correspond to duplicates *p < 0.01; **p < 0.001; ***p < 0.0001; n.s.: not significant (p > 0.05).

Figure 5

Comparison of B and NK lymphocytes in 37 patients with MIS-C and in 24 HC. The black line represents the median value. The red box represents the interquartile range. The blank circles correspond to the outliers and the black circles side by side to these correspond to duplicates **p < 0.001; n.s.: not significant (p > 0.05).

Figure 6

Comparison of T activated, activated Th1 and Th17 lymphocytes in 37 patients with MIS-C and in 24 HC. The black line represents the median value. The red box represents the interquartile range. The blank circles correspond to the outliers and the black circles side by side to these correspond to duplicates *p < 0.01; **p < 0.001; n.s.: not significant (p > 0.05).