Schuetz, C. | Search bioRxiv

bioRxiv2025

Truncating RELA variants drive autoinflammation and autoimmunity by impairing the negative feedback control of NF-kB

The NF-{kappa}B signaling pathway coordinates inflammation, cell survival, and proliferation, while restraining excessive cell death to maintain immune homeostasis. Truncating mutations in RELA, encoding the NF-{kappa}B subunit p65, have been linked to autoinflammation and autoimmunity, but the underlying mechanisms remain incompletely defined. We investigated six patients from five unrelated families carrying novel heterozygous truncating RELA variants. Despite reduced p65 expression, patients exhibited a broad spectrum of inflammatory manifestations alongside elevated baseline and stimulus-induced pro-inflammatory cytokines. Functional analyses in patient-derived cells and mutant RELA knock-in models showed that upstream NF-{kappa}B signaling was intact, but induction of inhibitory regulators such as I{kappa}B and A20 was impaired. This defective feedback control shifted immune homeostasis toward amplified inflammatory responses that depended on the residual activity of the remaining functional RELA allele. Single-cell transcriptomics revealed distinct cell type-specific consequences: monocytes displayed constitutive type I interferon and NF-{kappa}B activation, B cells retained partial compensatory signaling, whereas T and NK cells exhibited transcriptional signatures of cell death pathways. Patient fibroblasts and mutant RELA knock-in cells further confirmed enhanced TNF-induced inflammatory gene expression and hypersensitivity to apoptosis and necroptosis. These findings establish RELA haploinsufficiency as a cause of systemic immune dysregulation, and link defective NF-{kappa}B feedback control to unchecked inflammation and inflammatory cell death. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/687461v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1f0bfe6org.highwire.dtl.DTLVardef@c6cb60org.highwire.dtl.DTLVardef@1522accorg.highwire.dtl.DTLVardef@177c724_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

Perceptions and Prospects in Life Sciences in a Heterogenous Latin American Population

Particular challenges exist for science education in the developing world, where limited resources beget curricula designed to balance state-of-the-art knowledge with practical and political considerations in region-specific contexts. Project-based biology teaching is particularly difficult to execute due to high infrastructural costs and limited teacher training. Here, we report our results implementing short, challenging, and low-cost biology courses to high school and college students in Bolivia, designed and taught in collaboration between scientists from developed nations and local science instructors. We find our approach to be effective at transmitting advanced topics in disease modeling, microscopy, genome engineering, neuroscience, microbiology, and regenerative biology. Importantly, this approach was unaffected by the students backgrounds, education level, socioeconomic status, or initial interest in the course, and increased participants interest in pursuing scientific careers. These results demonstrate efficacy of participatory learning in a developing nation, and suggest that such techniques could drive scientific engagement in other developing economies.

scientific communication and education↗