Research Article: IL-18 receptor axis in allergic conjunctivitis: a multi-omics study
Abstract:
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–specific mechanisms that could contribute to disease heterogeneity.
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.
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 Il18r1 and Il18rap were selectively upregulated in NK and T cells from allergic versus control mice and correlated positively with interferon-? ( Ifng ) expression. Cell–cell communication and pseudotime analyses indicated an allergic-state network characterized by enhanced NK cell–linked IFN-? signaling to antigen-presenting cells and dynamic changes in NF-?B and JAK–STAT pathway activity. In the OVA-induced model, conjunctival IL-18, IL-18R1, IL-18RAP and phosphorylated NF-?B p65 were increased in AC versus controls and showed a stepwise rise across mild, moderate and severe clinical groups.
Across human genetics, single-cell transcriptomics and in vivo validation, an IL-18 receptor/IFN-? 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.
Introduction:
Allergic conjunctivitis (AC) represents a significant global health challenge, affecting up to 40% of some populations and severely impairing quality of life through symptoms like ocular itching, tearing, hyperemia, and edema ( 1 , 2 ). The classic understanding of AC is rooted in a Type I IgE-mediated hypersensitivity reaction, which unfolds in a two-phase process ( 3 , 4 ). The immediate phase is triggered upon allergen re-exposure, causing IgE-sensitized conjunctival mast cells to degranulate and release a…
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