Shin, J. J. | Search bioRxiv

bioRxiv2026

Identification of Lupus Immune Complex-Driven Pathogenic Pro-inflammatory Monocytes and Macrophages in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease characterized by anti-nuclear antibody (ANA) production and inflammation, though the mechanisms by which ANAs induce inflammation and tissue injury are incompletely understood. Here, we identified distinct subsets of mononuclear phagocytes (MPs), including monocytes (Mo) and macrophages (M{Phi}), driven by lupus immune complex (IC), comprised of ANAs and their target antigens. scRNA-seq of human Mo incubated with U1-snRNP (snRNP) lupus IC revealed expansion of distinct pro-inflammatory Mo subsets with upregulation of inflammatory genes including those encoding cytokines, NLRP3, and transcription factors. These transcriptomic changes strongly correlated with protein expression, as determined by proteomic analysis. Mo developed similar pro-inflammatory transcriptomic changes in response to other lupus ICs containing anti-dsDNA and Ro60 antibodies. Interrogation of scRNA-seq datasets from the skin, kidney, and peripheral blood of lupus patients revealed the presence and expansion of pro-inflammatory Mo and M{Phi} populations exhibiting transcriptomic signatures similar to those observed in lupus IC-stimulated Mo. Some of these cells expressing the snRNP IC gene signature exhibited low expression of the type I IFN signature, suggesting that lupus IC and type I IFN signaling may independently affect Mo subsets. In lupus nephritis, infiltration of CD68+ M{Phi} expressing NLRP3 was associated with treatment outcomes. Inhibiting activation of the transcription factor ETS2, a master regulator of Mo/M{Phi}-driven inflammation, attenuated lupus IC-induced activation of pro-inflammatory Mo. Collectively, these findings provide novel insights into the role of lupus IC-driven pro-inflammatory MPs in the pathogenesis of SLE and highlight their relevance as therapeutic targets. Significance StatementSystemic lupus erythematosus (SLE or lupus) is a multi-systemic autoimmune inflammatory disease characterized by anti-nuclear antibody (ANA) production. Lupus immune complex (IC), consisting of ANAs and their target antigens, likely play a critical role in the pathogenesis of lupus through activation of mononuclear phagocytes (MPs), including monocytes (Mo) and macrophages (M{Phi}), which can produce an array of inflammatory molecules. Using transcriptomic and proteomic analyses, our study identified distinct pro-inflammatory Mo populations driven by lupus IC, along with expansion of similar pro-inflammatory Mo and M{Phi} subsets in the skin, kidneys, and peripheral blood of lupus patients. These findings provide novel insights into the pathogenic role of lupus IC-driven pro-inflammatory MPs and support a scientific rationale for therapeutically targeting these cells. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=155 HEIGHT=200 SRC="FIGDIR/small/700902v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1839430org.highwire.dtl.DTLVardef@175dd1dorg.highwire.dtl.DTLVardef@107b54forg.highwire.dtl.DTLVardef@11096b0_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Cell-stereotyped DNA repair outcomes are widespread during genome editing

Genome editing outcomes are governed by DNA repair pathways that vary with cell type and state. We developed scOUT-seq (single-cell Outcomes Using Transcript sequencing), a scalable approach that jointly profiles transcriptomes and matched multi-allelic editing outcomes ranging from homology directed repair (HDR) to inter-chromosomal translocations. We mapped editing outcomes in human CD34 hematopoietic stem and progenitor cells (HSPCs), mouse LSK HSPC equivalents, human upper airway organoids, and mouse multi-organ in vivo editing. Profiling 500,000 alleles across 74 cell types, scOUT-seq revealed that outcomes in most cell subtypes differ markedly from the bulk average. Various cell types shifted major repair classes, preferred different molecular sequences, and even enriched large structural variants, with distinctive patterns of allelic co-occurrence. Surprisingly, rare stem subtypes diverged from prevalent progenitors, and inhibitory neuron subtypes efficiently incorporated HDR alleles. These data suggest the potential for tailored therapeutic editing that may have been missed by bulk measurements.

genomics↗

bioRxiv2021

Minhee Analysis Package: An Integrated Software Package for Detection and Management of Spontaneous Synaptic Events

To understand the information encoded in a connection between the neurons, postsynaptic current (PSC) has been widely measured as a primary index of synaptic strength in the field of neurophysiology. Although several automatic detection methods for PSCs have been proposed to simplify a workflow in the analysis, repetitive steps such as quantification and management of PSC data should be still performed with much effort. Here, we present Minhee Analysis Package, an integrated standalone software package that is capable of detecting, sorting, and quantifying PSC data. First, we developed a stepwise exploratory algorithm to detect PSC and validated our detection algorithm using the simulated and experimental data. We also described all the features and examples of the package so that users can use and follow them properly. In conclusion, our software package is expected to improve the convenience and efficiency of neurophysiologists to analyze PSC data by simplifying the workflow from detection to quantification. Minhee Analysis Package is freely available to download from http://www.github.com/parkgilbong/Minhee_Analysis_Pack.

neuroscience↗