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.

Keywords: Biomarker; chemokines; cytokines; dry eye disease; growth factors; tear-soluble factors.

Figure 1

(a) Overview of tear-soluble factor status in DED patients as reported across various publications in the last decade. Y-axis represents the Importance score, which shows the prominence of soluble factors identified within the articles used in this study. X-axis lists the biomarkers in the decreasing order of Importance score (the gradient color bar has a red color, which indicates a significant increase or increase; white for no change in the status; and blue for a decrease or significant decrease). (b) List of tear-soluble factors identified under each major class in tears of DED patients. Factors that were reported to be measured in at least three publications are indicated by a black dot. Factors that were observed to significantly increase in three publications or more are indicated by a red triangle. Factors that were observed to significantly decrease in three publications or more are indicated by a blue inverted triangle

Figure 2

Bar plot of 38 top hit (≥3 publications with consistent report) soluble factors identified in DED. Differential levels of soluble factors in tears of DED subjects. Numbers inside colored bars indicate the number of publications for each analyte. A dark blue color box indicates significantly decreased levels of analytes, light blue indicates decreased levels of analytes, green indicates no change, light pink indicates increased levels, and red corresponds to significantly increased levels of analytes as reported in the last 10 years across publications

Figure 3

Chord plot illustrating the relationship between types of DEDs and their associated analytes in major subclasses. DED: Dry eye disease, DED-ADED: Aqueous deficient, DED-EDED: Evaporative, DED-MGD: Meibomian gland dysfunction related dry eye, DED-SJS: Steven–Johnson syndrome-related dry eye, DED-SS: Sjögren’s syndrome associated dry eye, Rx-Sx-DED: Treatment or surgery induced dry eye disease

Figure 4

Sankey plot illustrating the status of various tear analytes in seven types of DEDs. The thickness of the line indicates the presence of an analyte in the number of publications followed by their status (increase significantly, increase, no change, decrease and decrease significantly) in DED, DED-ADED, DED-EDED, DED-MGD, DED-SJS, DED-SS, Rx-Sx-DED

Figure 5

A schematic summary of the most studied soluble factors in DED over the last 10 years. The red arrow indicates that the listed factors have higher levels in the tears of DED subjects, whereas the blue arrow indicates reduced levels of those factors in the disease condition