IL-18 Receptor Axis in Allergic Conjunctivitis: A Multi-Omics Study

Liyun Yuan^1,2Wangming Su³Liangpin Li⁴Yang Xiang⁴Zijiao Xu⁴Yuchuan Wang⁴Hua Xia^5*Xiaoyong Yuan^4*

• ¹Nankai University, Tianjin, China
• ²Nankai University School of Medicine, Tianjin, China
• ³The Second Hospital of Longyan, Longyan, China
• ⁴Tianjin Eye Hospital, Tianjin, China
• ⁵tianjin aier eye hospital, Tianjin, China

Purpose: 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.. Methods: 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 signalling dynamics. Key pathways were validated in an independent ovalbumin-induced AC mouse model using clinical scoring, qRT-PCR and Western blot analysis. Results: 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-γ (Ifng) expression. Cell–cell communication and pseudotime analyses indicated an allergic-state network characterised by enhanced NK cell–linked IFN-γ signalling to antigen-presenting cells and dynamic changes in NF-κB and JAK–STAT pathway activity. In the OVA-induced model, conjunctival IL-18, IL-18R1, IL-18RAP and phosphorylated NF-κB p65 were increased in AC versus controls and showed a stepwise rise across mild, moderate and severe clinical groups. Conclusions: Across human genetics, single-cell transcriptomics and in vivo validation, an IL-18 receptor/IFN-γ 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 signalling as a candidate pathway for future mechanistic and therapeutic studies.