{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T06:31:34Z","timestamp":1765866694463,"version":"3.48.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"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>Purpose<\/jats:title>\n                    <jats:p>The pathophysiology of allergic conjunctivitis (AC) is not fully explained by the traditional Th2-centric model. This study aimed to identify AC-associated candidate genes and delineate immune pathways, with a focus on cell-type\u2013specific mechanisms that could contribute to disease heterogeneity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed an integrative multi-omics strategy, using three genomic analyses (FUSION, MAGMA, UTMOST) on human GWAS data to identify AC-associated candidate genes. These candidates were then investigated using single-cell RNA sequencing data from a mouse model of AC to map immune cell communication and signaling dynamics. Key pathways were validated in an independent ovalbumin-induced AC mouse model using clinical scoring, qRT-PCR and Western blot analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      This approach identified nine high-confidence AC-associated candidate genes, including key components of the IL-1 and Toll-like receptor families. In the AC mouse model, the IL-18 receptor components\n                      <jats:italic>Il18r1<\/jats:italic>\n                      and\n                      <jats:italic>Il18rap<\/jats:italic>\n                      were selectively upregulated in NK and T cells from allergic versus control mice and correlated positively with interferon-\u03b3 (\n                      <jats:italic>Ifng<\/jats:italic>\n                      ) expression. Cell\u2013cell communication and pseudotime analyses indicated an allergic-state network characterized by enhanced NK cell\u2013linked IFN-\u03b3 signaling to antigen-presenting cells and dynamic changes in NF-\u03baB and JAK\u2013STAT pathway activity. In the OVA-induced model, conjunctival IL-18, IL-18R1, IL-18RAP and phosphorylated NF-\u03baB p65 were increased in AC versus controls and showed a stepwise rise across mild, moderate and severe clinical groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Across human genetics, single-cell transcriptomics and\n                      <jats:italic>in vivo<\/jats:italic>\n                      validation, an IL-18 receptor\/IFN-\u03b3 axis in NK and T cells emerges as a reproducible module associated with AC and its severity. These findings extend the immunopathological framework of AC beyond a purely Th2-driven process and nominate IL-18R-linked signaling as a candidate pathway for future mechanistic and therapeutic studies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1704591","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T06:27:46Z","timestamp":1765866466000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["IL-18 receptor axis in allergic conjunctivitis: a multi-omics 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