Review Frames Dry Eye Disease as Complex Inflammatory and Genetic Disorder

Dry eye disease has undergone a major conceptual redefinition, transitioning from an assumed passive consequence of poor tear production into a recognized multifactorial disorder driven by tear film instability, hyperosmolarity, inflammation, and neurosensory abnormalities. A comprehensive narrative review spanning fifteen calendar years from 2012 through 2026 in PubMed, published in Frontiers in Medicine by researchers from King Khaled Eye Specialist Hospital and the University of Ferrara, evaluates the biological underpinnings governing this condition. Historically attributed simply to aqueous tear deficiency or rapid evaporation, clinical and experimental investigations have established that dry eye disease involves intricate interactions between epithelial barrier integrity, immune signaling cascades, and neural regulation. This evolving understanding explains why the disorder presents with substantial clinical heterogeneity and why traditional symptomatic approaches often prove insufficient. By systematically analyzing tear dynamics, inflammatory cascades, genetic factors, and therapeutic interventions, the authors describe how persistent molecular stress perpetuates ocular surface damage.

The global burden of dry eye disease is substantial, affecting hundreds of millions of people while impairing visual performance, workplace productivity, and overall quality of life. Reported prevalence figures display considerable variation according to age, gender, geographic region, environmental exposure, and specific diagnostic criteria. Global estimates range from 5 percent to 50 percent, reflecting substantial geographical differences that reach up to 42 percent in Africa compared to 8.1 percent in the United States. Advancing age increases disease risk, while environmental elements such as heat, low humidity, outdoor exposures, certain medications, job seniority, and contact lens wear further elevate susceptibility. Women are affected more frequently than men, particularly during pregnancy and menopause, with prevalence reaching up to 71.88 percent among post-menopausal cohorts. Furthermore, increasing prevalence is observed among younger populations, driven by prolonged digital screen usage that reduces blink frequency, accelerates tear evaporation, and aggravates symptoms.

At the center of disease pathogenesis are tear film instability and tear hyperosmolarity, recognized by the TFOS DEWS II classification as defining features that trigger ocular surface damage. Whether stemming from aqueous tear deficiency, meibomian gland dysfunction, or environmental drying, unstable tear dynamics increase tear osmolarity. This subjects corneal and conjunctival epithelial cells to severe osmotic stress, disrupting cellular activity and activating stress-response pathways. Compromised epithelial barrier integrity stimulates innate immune defenses, prompting the release of inflammatory mediators including interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and chemokines. These signaling molecules recruit immune cells to the ocular surface and stimulate resident antigen-presenting cells while accelerating dendritic cell maturation. Concurrently, epithelial injury generates oxidative stress that further amplifies inflammatory pathways and tissue destruction. This persistent innate immune activation drives continuous cytokine secretion, establishing a self-perpetuating vicious cycle of ocular surface inflammation and injury that persists even after the initial insult has resolved.

Adaptive immunity reinforces this inflammatory cycle through targeted lymphocyte responses and specialized intracellular stress sensing complexes. Activated dendritic cells migrate to regional lymph nodes to stimulate T lymphocytes, specifically promoting T helper 1 and T helper 17 lineages. Upon migrating to the ocular surface, T helper 1 cells secrete interferon-gamma, which accelerates goblet cell loss and downregulates mucin production, compromising tear film stability. Concurrently, T helper 17 cells release interleukin-17, inducing matrix metalloproteinases and exacerbating epithelial barrier disruption. Adhesion between intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 retains these inflammatory cells within affected ocular tissues. In parallel, the NLRP3 inflammasome serves as an intracellular multiprotein stress sensor triggered by hyperosmolarity, oxidative stress, and epithelial damage. Once activated, the NLRP3 pathway facilitates the maturation and release of interleukin-1 beta and interleukin-18, potent proinflammatory cytokines that exacerbate tissue damage and represent appealing targets for future intervention.

In tandem with immune signaling, neurosensory abnormalities represent an essential pathophysiological component of dry eye disease. Corneal sensory nerves govern reflex tear secretion, blink control, and trophic support for the ocular surface epithelium. When these nerves sustain structural injury from chronic inflammation, sensory perceptions and protective reflexes become altered without directly mirroring clinical signs. Systematic review and meta-analysis evidence demonstrates quantifiable alterations in corneal nerve parameters among dry eye patients, confirming the biological involvement of neural dysfunction in disease manifestation. This communication between inflammatory processes and neural circuits deepens disease complexity, as neural defects can amplify ocular surface stress.

The search for objective biological indicators has established candidate biomarkers across tear cytokines, tissue enzymes, and cellular proteins. Elevated levels of tear cytokines such as interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma correlate with ocular surface inflammation and disease severity. In the DREAM study, longitudinal changes in cytokine ratios over one year exhibited weak associations with clinical signs, suggesting potential as dynamic markers but lacking validation for diagnostic or prognostic decision-making. Matrix metalloproteinase-9, an enzyme linked to epithelial barrier breakdown, represents a clinically available point-of-care test incorporated into TFOS and ASCRS diagnostic algorithms. While indicating active ocular surface inflammation, matrix metalloproteinase-9 remains non-specific and cannot pinpoint etiology or direct treatment choices. Other markers, including lactoferrin and lysozyme reflecting lacrimal secretion, as well as cellular HLA-DR marking immune activation, face significant analytical barriers, including variable sampling methods and a lack of standardized diagnostic thresholds.

Genetic epidemiology demonstrates that dry eye disease possesses a distinct polygenic architecture alongside environmental triggers. A comprehensive study examining 3,930 female twins estimated heritability at 29 percent for dry eye symptoms and 41 percent for clinically diagnosed disease accompanied by artificial tear use. Heritability estimates varied among specific clinical measures, reaching 58 percent for Schirmer test values and 40 percent for tear osmolarity, whereas tear break-up time showed no significant genetic heritability. Earlier candidate-gene studies examining inflammatory cytokines were limited by small sample sizes and inconsistent replication across diverse populations. More recently, a multi-ancestry genome-wide association preprint identified ten independent susceptibility loci across nine genomic regions linked to synaptic function and autoimmunity. Individual loci generally demonstrated small effect sizes, supporting a polygenic susceptibility model rather than single-gene causation. Genetic correlations were also identified between dry eye disease and systemic conditions including Sjögren’s disease and chronic pain, while human leukocyte antigen typing revealed associations such as HLA-B*40:01 in moderate-to-severe non-Sjögren disease.

Epigenetic mechanisms and gene-environment interactions offer explanatory biological links connecting inherited susceptibility to external triggers. Epigenetic modifications, including DNA methylation, histone remodeling, and non-coding RNA expression, alter gene regulation without modifying nucleotide sequences, playing documented roles in ocular surface inflammation. Environmental and behavioral exposures, such as digital screen time, low humidity, systemic medications, and atmospheric pollution, interact with individual genetic susceptibility to elevate disease risk, as evidenced by population studies from the Taiwan Biobank. Concurrently, systems biology and multi-omics platforms integrating transcriptomics, proteomics, and metabolomics have mapped complex biological networks governing immune dysregulation, oxidative stress, and epithelial damage. These approaches aim to define molecular signatures that differentiate biologically distinct disease endotypes. However, multi-omics tools remain predominantly exploratory discovery platforms. Their integration into routine clinical decision-making is currently limited by technical variability, high costs, complex computational requirements, and an absence of prospectively validated diagnostic or treatment-selection thresholds.

Therapeutic management of dry eye disease has increasingly shifted from empirical symptom relief toward phenotype-directed and mechanism-based interventions. Tear supplementation with artificial tears containing hyaluronic acid and trehalose remains foundational to improve lubrication, reduce friction, and prevent cellular osmotic stress. For evaporative disease associated with meibomian gland dysfunction, conventional lid hygiene is complemented by thermal pulsation systems such as LipiFlow, although systematic reviews note low certainty of evidence regarding superiority over standard care. Anti-inflammatory therapies occupy a central position: topical corticosteroids like loteprednol and fluorometholone provide rapid relief during acute inflammatory flares, while topical cyclosporine offers long-term management through T-cell inhibition. Lifitegrast counteracts the ICAM-1/LFA-1 interaction to reduce inflammatory cell recruitment. Additionally, newer therapies approved in the United States include varenicline nasal spray, which stimulates the trigeminal parasympathetic pathway to increase endogenous tear secretion, and perfluorohexyloctane ophthalmic solution, which suppresses tear evaporation in evaporative disease. Punctal cautery serves as an established tear conservation procedure for selected refractory presentations.

Investigational frontiers in dry eye care encompass regenerative stem cell therapies, nanomedicine drug delivery systems, and ocular surface microbiome research. Mesenchymal stem cell-based interventions are being evaluated for refractory disease due to their proposed immunomodulatory and tissue-repair capabilities, though clinical evidence remains insufficient for routine adoption. Nanotechnology formulations, including nanoparticle drug delivery platforms, seek to enhance drug bioavailability, prolong retention, and reduce dosing burdens, remaining predominantly in experimental stages. Exploratory investigations into the conjunctival microbiome have identified compositional variations between healthy individuals and dry eye patients; however, evidence has not established whether dysbiosis plays a causal role in disease pathogenesis or reflects secondary ocular surface disruption. Precision medicine in dry eye disease remains primarily phenotype-guided rather than truly biomarker-directed. While point-of-care tools like matrix metalloproteinase-9 provide adjunctive objective information, translating multi-omics profiles and genomic data into routine clinical practice requires prospective clinical validation to confirm that molecular stratification improves long-term patient outcomes.

Subject of Research: Pathophysiology, inflammatory biomarkers, genetics, and therapeutic approaches in dry eye disease

Article Title: Dry eye disease beyond tear deficiency: inflammation, biomarkers, genetics and precision medicine

Article References: Alaalm, L., Yu, A. C., Melloni, E., & Zauli, G. (2026). Dry eye disease beyond tear deficiency: inflammation, biomarkers, genetics and precision medicine. Frontiers in Medicine, 13, Article 1943129. https://doi.org/10.3389/fmed.2026.1943129

Image Credits: AI Generated

DOI: 10.3389/fmed.2026.1943129

Keywords: dry eye disease, tear film instability, tear hyperosmolarity, ocular surface inflammation, interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, interferon-gamma, interleukin-17, matrix metalloproteinase-9, NLRP3 inflammasome, ICAM-1/LFA-1 signaling, corneal nerves, meibomian gland dysfunction, lifitegrast, cyclosporine, varenicline nasal spray, perfluorohexyloctane, twin heritability, multi-omics profiling