Dryness, irritation, burning, light sensitivity, and fluctuating vision are common concerns for people with Sjögren's syndrome. This systemic autoimmune disease can affect exocrine glands, including the lacrimal and salivary glands. Keratoconjunctivitis sicca (KCS), an inflammatory dry eye condition affecting the ocular surface, is one of its major ocular manifestations.
Depending on the diagnostic criteria applied, approximately 75%–90% of patients with Sjögren's syndrome may develop KCS. Severe disease can involve persistent corneal epithelial defects, corneal ulceration, neovascularization, and even irreversible visual impairment.
Clinicians typically evaluate KCS using symptom assessments, tear secretion tests, tear film break-up time, and ocular surface staining. However, ocular manifestations vary widely among patients with Sjögren's syndrome: some report few typical dry eye symptoms, whereas others develop marked or progressive ocular surface damage. What molecular changes might help explain this variability and the development of ocular surface inflammation?
Researchers from the Eye & ENT Hospital of Fudan University and collaborating institutions examined this question in a study published in Eye Discovery , focusing on histamine-related genes. Although commonly associated with allergic reactions, histamine also participates in inflammation, immune regulation, and cytokine production. In the ocular surface microenvironment, histamine-related signaling may contribute to inflammatory cell infiltration, impaired epithelial barrier function, increased vascular permeability, and altered tear film homeostasis. However, the specific molecular links between histamine-related processes and Sjögren's syndrome-associated KCS remain incompletely understood.
The researchers analyzed two transcriptomic datasets from the Gene Expression Omnibus (GEO). GSE84844 comprised whole-blood samples from 30 patients with Sjögren's syndrome and 30 healthy volunteers; GSE176510 comprised conjunctival samples from 7 patients with KCS and 19 healthy controls. The team compared differentially expressed genes associated with the two conditions and cross-referenced them against 1,183 histamine-related genes to identify potential candidates.
Two machine learning methods—least absolute shrinkage and selection operator (LASSO) and support vector machine–recursive feature elimination (SVM-RFE)—both identified IFITM1 and CTSS as candidate genes. In the analyzed dataset, each gene achieved an area under the receiver operating characteristic curve (AUC) above 0.90, indicating an ability to distinguish KCS samples from controls within that dataset. A two-gene diagnostic nomogram reached an AUC of 1.00 in the training set. These findings indicated a promising prediction and diagnosis values of IFITM1 and CTSS in the future, which could make the intervention of the transfer from SS to KCS possible.
Further analyses associated IFITM1 with antigen processing and presentation, the major histocompatibility complex (MHC), and autoimmune-related pathways. CTSS was associated with the positive regulation of type 2 immune responses. Immune-infiltration analysis suggested increased representation of activated dendritic cells and T helper cells in KCS samples. IFITM1 correlated more strongly with activated dendritic cells, whereas CTSS was more closely associated with T helper cells. These associations suggest a possible connection between the candidate genes and ocular surface immune activity; they do not establish a causal mechanism.
The team also conducted preliminary experiments in human corneal epithelial cells. Under hyperosmotic stress, siRNA-mediated knockdown of either CTSS or IFITM1 was associated with better preservation of cell viability and lower expression of inflammatory cytokines, including IL-6 and TNF-α, compared with control cells. These in vitro findings support further investigation of the genes' possible roles in ocular surface inflammatory injury, but do not demonstrate clinical efficacy or establish them as therapeutic targets.
Professor Jianjiang Xu, corresponding author of the paper from the Eye & ENT Hospital of Fudan University, said: "The clinical manifestations of Sjögren's syndrome-associated KCS vary greatly. Symptoms and routine ocular surface examinations alone are not enough to explain why different patients develop different degrees of inflammation and injury. By combining transcriptomic data with cell experiments, we hope to connect histamine-related signaling, immune cell involvement, and corneal epithelial inflammation. IFITM1 and CTSS should not yet be regarded as mature clinical diagnostic markers or therapeutic targets, but they provide molecular clues worth further investigation for understanding the progression from Sjögren's syndrome to keratoconjunctivitis sicca."
The study adds histamine-related pathways to the discussion of immune-inflammatory mechanisms in Sjögren's syndrome-associated KCS. The findings connect IFITM1 with interferon-related responses and activated dendritic cells, and CTSS with antigen presentation and T helper cell responses. Further work-including independent validation and mechanistic studies—will be needed to determine whether these candidates can contribute to disease stratification, monitoring, or therapeutic research.
ARTICLE INFORMATION
Ning Lyu, Dandan Wang, Yiqin Dai, Lei Guo, Yidan Fan, Zhaoyuan Lyu, Jiayu Gu, Jianjiang Xu.
Investigation of Histamine-Related Key Genes in the Progression from Sjögren's Syndrome to Keratoconjunctivitis Sicca.
Fulltext Link: https://doi.org/10.1016/j.edisc.2026.100069 .
About Eye Discovery
Eye Discovery is an open-access, peer-reviewed international academic journal, with ISSN 3117-4167. It is published quarterly by Elsevier and serves as the official journal of Eye & ENT Hospital of Fudan University, China.
Eye Discovery is dedicated to creating a high-end platform for ophthalmologists, scientists, and scholars worldwide to focus on innovative achievements in ophthalmology and interdisciplinary fields, and to promote academic dissemination and exchange.
Website: https://www.sciencedirect.com/journal/eye-discovery
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