Multisystem inflammatory syndrome in children (MIS-C) has puzzled researchers since its emergence during the COVID-19 pandemic. Occurring weeks after SARS-CoV-2 infection, MIS-C presents a severe hyperinflammatory condition affecting multiple organ systems. Recent findings shed light on its complex pathogenesis, revealing how immune dysfunction and viral reactivation contribute to this rare but serious pediatric condition.
A multi-center study published in Nature identifies elevated cytokine transforming growth factor beta (TGFβ) levels as a central driver of MIS-C. Researchers found that TGFβ impairs the reactivation of virus-fighting memory T cells, compromising their ability to target viral antigens. This dysfunction triggers a cascade of immune irregularities, including a heightened reactivation of latent Epstein-Barr virus (EBV), a common virus linked to several inflammatory diseases. In MIS-C patients, TGFβ disrupts immune cell signaling, reduces antigen presentation, and fuels systemic inflammation, distinguishing it from other pediatric inflammatory conditions.
The study revealed striking differences in immune profiles between MIS-C patients and children who experienced mild COVID-19 or other viral infections. Using single-cell RNA sequencing, researchers observed that TGFβ-induced gene signatures were prevalent in T cells, B cells, and monocytes from MIS-C patients. These signatures were absent in healthy controls and children recovering from SARS-CoV-2 without MIS-C, emphasizing the unique role of TGFβ in this condition. Importantly, TGFβ not only suppressed T-cell activity but also facilitated EBV reactivation by inducing the virus’s lytic cycle, further exacerbating inflammation.
Epstein-Barr virus emerged as a key player in MIS-C’s pathogenesis. The study found that 80.7% of MIS-C patients tested seropositive for EBV, compared to 56% of age-matched healthy children. Elevated EBV antibody levels, particularly IgA1 antibodies, suggested active viral reactivation in MIS-C patients. EBV mRNA was detected in B cells and plasmablasts of these patients but not in controls, highlighting the interplay between immune suppression and viral activity. Further, T cells expressing the TCRVβ21.3 receptor, a subset expanded in MIS-C, were found to target EBV peptides. However, these cells struggled to effectively eliminate EBV-infected targets, indicating a breakdown in their cytotoxic function due to TGFβ dysregulation.
Neutralizing TGFβ offers a potential therapeutic avenue. In vitro experiments demonstrated that blocking TGFβ restored T cell functionality and reduced EBV activity, suggesting that targeting TGFβ signaling could alleviate MIS-C’s severe inflammation. The findings also highlight TGFβ as a potential diagnostic biomarker for distinguishing MIS-C from other post-COVID-19 complications in children.
The implications extend beyond MIS-C. Elevated TGFβ levels and similar immune dysfunctions were observed in severe adult COVID-19 cases, indicating shared mechanisms of immune suppression and viral reactivation across age groups. By unraveling the complex interplay between SARS-CoV-2, TGFβ, and EBV, this research offers critical insights into the delicate balance of immune responses in post-COVID-19 conditions.
These discoveries pave the way for new diagnostic and therapeutic strategies to address MIS-C. While the condition remains rare, its potential for severe outcomes underscores the importance of continued research. By targeting the immune pathways disrupted by SARS-CoV-2 and latent viruses like EBV, scientists aim to mitigate the devastating effects of MIS-C and protect children from its long-term consequences.
