Tear biomarkers in dry eye disease: Progress in the last decade

Abstract

Dry eye disease (DED) is a commonly occurring, multifactorial disease characterized by reduced tear film stability and hyperosmolarity at the ocular surface, leading to discomfort and visual compromise. DED is driven by chronic inflammation and its pathogenesis involves multiple ocular surface structures such as the cornea, conjunctiva, lacrimal glands, and meibomian glands. The tear film secretion and its composition are regulated by the ocular surface in orchestration with the environment and bodily cues. Thus, any dysregulation in ocular surface homeostasis causes an increase in tear break-up time (TBUT), osmolarity changes, and reduction in tear film volume, all of which are indicators of DED. Tear film abnormalities are perpetuated by underlying inflammatory signaling and secretion of inflammatory factors, leading to the recruitment of immune cells and clinical pathology. Tear-soluble factors such as cytokines and chemokines are the best surrogate markers of disease severity and can also drive the altered profile of ocular surface cells contributing to the disease. Soluble factors can thus help in disease classification and planning treatment strategies. Our analysis suggests increased levels of cytokines namely interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-9, IL-12, IL-17A, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α); chemokines (CCL2, CCL3, CCL4, CXCL8); MMP-9, FGF, VEGF-A; soluble receptors (sICAM-1, sTNFR1), neurotrophic factors (NGF, substance P, serotonin) and IL1RA and reduced levels of IL-7, IL-17F, CXCL1, CXCL10, EGF and lactoferrin in DED. Due to the non-invasive sample collection and ease of quantitively measuring soluble factors, tears are one of the best-studied biological samples to molecularly stratify DED patients and monitor their response to therapy. In this review, we evaluate and summarize the soluble factors profiles in DED patients from the studies conducted over the past decade and across various patient groups and etiologies. The use of biomarker testing in clinical settings will aid in the advancement of personalized medicine and represents the next step in managing DED.

Therapeutic Targets in the Management of Dry Eye Disease Associated with Sjögren’s Syndrome: An Updated Review of Current Insights and Future Perspectives

“…As surrogate markers of disease severity, there are elevated concentrations of IL-1β, IL-2, IL-4, IL-6, IL-9, IL-12, IL-17A, IFN-γ, and TNF-α cytokines, and CCL2, CCL3, CCL4, and CXCL8 chemokines. The levels of MMP-9, FGF, VEGF-A, IL1RA, sICAM-1, and sTNFR1 soluble receptors, NGF, substance P, and serotonin neurotrophic factors were also increased, while the concentrations of IL-7, IL-17F, CXCL1, CXCL10, EGF, and lactoferrin were reduced, in DED patients compared with healthy controls [ 25 , 26 ].…”

Developing an improved optical biosensing system based on gold nanoparticles acting as interferometric enhancers in Lactoferrin detection

“…29 The elimination of harmful free radicals and inhibition of the formation of several toxic compounds by Lactoferrin makes it a potential biomarker for the diagnosis of relevant diseases, such as Alzheimer's Disease (AD), 30,31 Inflammatory Bowel Disease (IBD), 32 as well as tear biomarker for dry eye. 33–35…”

The Problem With Dry Eye Trials

“…Not surprisingly, studies have similarly demonstrated different tear inflammatory profiles among patients with symptoms and signs of dry eye. 4 This likely explains why symptomatically, some individuals prefer cyclosporinebased products whereas others prefer lifitegrast. 5 As a community, we need to better subtype dry eye into categories based on treatable mechanisms.…”

“…Furthermore, as we have learned from the field of uveitis, there are many different pathologic patterns of ocular inflammation, each requiring a different optimal therapy. Not surprisingly, studies have similarly demonstrated different tear inflammatory profiles among patients with symptoms and signs of dry eye . This likely explains why symptomatically, some individuals prefer cyclosporine-based products whereas others prefer lifitegrast .…”