Additionally, patients with autoantibodies against type I interferon exhibited the most severe immune dysregulation. This age-associated signaling shift was also replicated in COVID-19-infected hamsters, affirming its broader relevance to aging-related immune changes.

Our in vitro experiments revealed diminished responsiveness to type I interferons in cells from uninfected adults, reducing their capacity to suppress inflammatory cytokines like IFNg and IL-6. Elevated IL-1b levels in older individuals further exacerbated this inflammatory feedback loop.

Moreover, adult immune responses showed prolonged activity, evidenced by sustained activation of CD4+ T cells beyond two weeks post-infection, and heightened production of complement-activating antibodies.

Adults uniquely displayed extrafollicular B cell activation following infection, a phenomenon not detected in pediatric cases.

These signaling modifications correlated with inflammatory profiles in monocytes and T cells, aligning with our previous findings (Schulte-Schrepping et al. 2020 Cell, Georg et al. 2022 Cell). Notably, these inflammatory signatures were consistent even within individual family units.

Immune profiling showed distinct patterns: infection-associated clusters in pediatric patients had strong interferon-stimulated gene expression, whereas adult clusters lacked this, despite similar type I interferon concentrations. Instead, adult clusters prominently expressed S100A family genes.

We observed a notable shift in type I interferon signaling pathways, transitioning from a STAT1-dominant response to a STAT3-driven mechanism, potentially amplified by elevated IL-1b levels.

Employing multi-omics analyses on samples from 254 individuals aged between 1 and 86, we extensively characterized immune responses, identified key signaling mechanisms, and validated findings through targeted in vitro experiments.

Excited to see my magnum opus published! Here, we explore how age correlates with changes in STAT signaling and modulates the immune response towards inflammation. See for youself!
Also, it's been a long time since pre-print, so here's the reworked explainer thread!
www.cell.com/cell-reports...

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