{
  "abstract": "Background Genome-wide association studies (GWAS) have identified interferon regulatory factor 8 (IRF8) variants as risk loci for inflammatory bowel disease (IBD). While IRF8 is known to govern the differentiation of myeloid progenitors, the clinical and peripheral cellular consequences of IBD-associated IRF8 mutations in humans remain poorly understood.Methods We first identified the IRF8E395K/+ mutation in patients with IBD or intestinal colitis through whole-exome sequencing (WES) and database screening (Phenolyzer and DisGeNET). Single-cell RNA sequencing (scRNA-seq) was applied to peripheral blood mononuclear cells (PBMC) from mutation carriers and health controls, followed by analyses of IRF8-associated gene expression, cell population dynamics, Gene Set Enrichment Analysis (GSEA), and pseudotime trajectories. Finally, a mouse model carrying the orthologous mutation (IrfE393K/+) was established using CRISPR/Cas9-mediated gene editing.Results Here, we identify a family with high susceptibility to inflammatory bowel disease, in which affected members carry a shared heterozygous variant, rs746741171 (c.1183G>A) (IRF8 E395K/+) (IDDF2026-ABS-0109 Figure 1). Clinically, mutation carriers exhibit reduced colonic IRF8 protein expression, increased stool frequency, and heightened susceptibility to intestinal inflammation. ScRNA-seq profiling of PBMCs uncovered a marked expansion of low-density neutrophil (LDNs) as the most prominent cellular phenotype (IDDF2026-ABS-0109 Figure 2), despite only modest alterations in canonical IRF8 target genes (IDDF2026-ABS-0109 Figure 3). Neutrophils and monocytes from IRF8E395K/+ individuals displayed increased inflammatory signaling signatures. Mirroring the human phenotype, mice harboring the orthologous Irf8E393K/+ mutation showed heightened susceptibility to colitis (IDDF2026-ABS-0109 Figure 4), accompanied by increased LDNs in peripheral blood and enhanced neutrophil infiltration in colonic tissue (IDDF2026-ABS-0109 Figure 5). Conclusions Our findings established IRF8E395K/+ as a novel, functional risk allele that predisposes to intestinal inflammation and subsequent IBD development. It establishes that IRF8 mutation-driven reprogramming of PBMC fates, marked by LDN expansion, directly links this myeloid signature to IBD pathogenesis.Abstract IDDF2026-ABS-0109 Figure 1Abstract IDDF2026-ABS-0109 Figure 2Abstract IDDF2026-ABS-0109 Figure 3Abstract IDDF2026-ABS-0109 Figure 4Abstract IDDF2026-ABS-0109 Figure 5",
  "authors": [
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Mingyue Wu"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Kun Chen"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Lu Zhang"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Sirui Yu"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Yamei Shi"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Mei Yang"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Hong Yang"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Shaofeng Feng"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Mengni Zhang"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Shumin Wang"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Jun Ye"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Third Military Medical University, China"
      ],
      "name": "Jin Chai"
    }
  ],
  "title": "IDDF2026-ABS-0109 The IRF8e395k/+ mutation confers risk for inflammatory bowel disease with elevated low-density neutrophils",
  "uid": "93723d89-70ca-55a7-b6b9-48887037e4b8"
}