{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T18:15:00Z","timestamp":1770142500110,"version":"3.49.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Anti-interferon-\u03b3 autoantibodies (AIGAs) immunodeficiency syndrome is an emerging adult-onset immunodeficiency causing opportunistic infections. However, its comprehensive immune landscape remains elusive. This study presents the first single-cell RNA sequencing (scRNA-seq) analysis of AIGAs immunodeficiency syndrome, aiming to delineate its pathogenic mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed scRNA-seq on peripheral blood mononuclear cells (PBMCs) from 8 AIGAs immunodeficiency syndrome patients (4 infective, 4 stable phase) and 3 healthy controls. Findings were validated by flow cytometry in an expanded cohort (15 patients vs. 10 controls).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Single-cell RNA sequencing of PBMCs from patients with AIGAs immunodeficiency syndrome identified a comprehensive immune subset profile, including effector memory CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, naive CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, regulatory T cells, GNLY\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      Tem, GZMK\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      Tem, naive CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, naive B cells, memory B cells, plasma cells, ISG\n                      <jats:sup>+<\/jats:sup>\n                      atypical B cells, monocytes, and NKT cells. ScRNA-seq analysis revealed a significantly higher proportion of Th1 cells (16.62% vs. 6.94% in controls) and ISG\n                      <jats:sup>+<\/jats:sup>\n                      B cells (2.95% vs. 0.53%), alongside a lower proportion of plasma cells (9.30% vs. 17.79%) and memory B cells (9.54% vs. 27.35%). Flow cytometry consistently confirmed the increase in Th1 cells (21.84% [14.87\u201327.57] vs. 11.96% [7.19\u201315.74]) and decreases in marginal zone B cells (2.87% [1.71\u20134.45] vs. 8.60% [6.77\u201315.65]), memory B cells (13.85% [5.72\u201320.23] vs. 22.96% [16.39\u201333.83]), and class-switched B cells (6.11% [2.39\u20139.10] vs. 10.18% [5.35\u201315.77]). Transcriptome analysis demonstrated upregulated expression of interferon-response and HLA genes (e.g., HLA-DQB1, HLA-DQA1, HLA-DRB1), whereas IRF1 was downregulated across all subsets; functional enrichment analyses further highlighted significant activation in IFN signaling and B cell activation pathways. CellChat and pseudotime analyses indicated that CD4\n                      <jats:sup>+<\/jats:sup>\n                      Tem and CD14\n                      <jats:sup>+<\/jats:sup>\n                      monocytes drive sustained Th1 inflammation and monocyte hyperactivation through enhanced pro-inflammatory and antigen-presenting interactions, with T-cell differentiation skewed toward terminal effectors and B-cell development disrupted by ISG\n                      <jats:sup>+<\/jats:sup>\n                      B cell emergence, premature plasma cell formation, and IGLC3-biased class switching, collectively delineating the interferon-mediated immunopathology of AIGAs immunodeficiency syndrome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In summary, this first single-cell atlas maps AIGAs immunodeficiency syndrome as a Th1-skewed, IFN-\u03b3-driven disorder sustained by CD4\n                      <jats:sup>+<\/jats:sup>\n                      Tem\u2013CD14\n                      <jats:sup>+<\/jats:sup>\n                      monocyte crosstalk. It combines T-cell activation, expanded Th1 and ISG\n                      <jats:sup>+<\/jats:sup>\n                      B cells, and loss of memory\/plasma B cells to drive autoantibody generation. Skewed T- and B-cell trajectories and polygenic up-regulation of interferon\/HLA genes provide a clear mechanistic rationale for targeted therapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1659383","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T06:30:49Z","timestamp":1770100249000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Upregulation of interferon-\u03b3 activation in patients with anti-interferon-\u03b3 autoantibodies immunodeficiency syndrome: insights from single-cell analysis"],"prefix":"10.3389","volume":"16","author":[{"given":"Si-qiao","family":"Liang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue-mei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-na","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Si-yao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-mei","family":"Hong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ni","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeng-tao","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Ning","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-chan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-yi","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1111160","article-title":"Adult-onset 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