Objective:

Identify histamine-related genes associated with Sjögren’s syndrome–related keratoconjunctivitis sicca (KCS) and assess their potential diagnostic value.

Approach:

• Transcriptomic analysis: Researchers analyzed two public gene-expression datasets: blood samples from 30 patients with Sjögren’s syndrome and 30 healthy controls, and conjunctival samples from 7 patients with KCS and 19 healthy controls. They screened 1,183 histamine-related genes usi…
• Laboratory experiments: In immortalized human corneal epithelial cells exposed to hyperosmotic stress, researchers used small interfering RNA to suppress IFITM1 or CTSS and assessed cell viability and inflammatory markers.
• Additional analyses: Researchers examined immune-cell associations, pathways, predicted gene regulators, and computationally predicted gene-compound interactions.

Key Findings:

• IFITM1 and CTSS were selected by both machine-learning algorithms. Each had an area under the receiver operating characteristic curve greater than 0.90 for distinguishing KCS samples from controls.
• A diagnostic nomogram combining the genes had an AUC of 1.00 in the training dataset; the authors said this result requires confirmation in larger, independent cohorts.
• Under hyperosmotic stress, suppression of either gene was associated with better cell viability and lower expression of interleukin-6 and tumor necrosis factor alpha.
• IFITM1 was associated with antigen-presentation and major histocompatibility complex pathways; CTSS was associated with positive regulation of type 2 immune responses.
• Activated dendritic cells and T helper cells were increased in KCS samples compared with controls. IFITM1 correlated with activated dendritic cells, and CTSS with T helper cells.

Interpretation:

The study authors reported that IFITM1 and CTSS may have diagnostic value and are associated with ocular-surface inflammatory processes in KCS. They stated that further clinical and mechanistic validation is needed to establish diagnostic robustness and assess whether either gene is a viable therapeutic target.

Limitations:

• The transcriptomic datasets were small, particularly the KCS cohort of 7 patients.
• The diagnostic model has not been validated in an independent clinical cohort.
• Separate datasets were compared rather than patients being followed over time, so the study cannot determine whether either gene predicts progression to ocular surface disease.
• Functional experiments used cultured corneal epithelial cells; proposed regulatory mechanisms require direct experimental confirmation.
• The predicted gene-compound interactions do not establish therapeutic efficacy.

Conclusion:

The authors called for in vivo studies and multicenter clinical validation.

Sources:

• Eye Discovery (study source named in the provided context)