泪液参与系统性免疫（英文）

Tear fluid participates in systemic immunity

摘要

泪液(或称眼泪、泪膜)作为一种重要的体液，对维持眼表的健康及免疫稳态具有关键作用。近年研究发现，泪液不仅参与眼部疾病的发生和发展，更在系统性疾病的免疫病理机制中发挥了深层作用，突破了既往科学界的固有认知。泪液中的免疫细胞(如T细胞、中性粒细胞、自然杀伤细胞、巨噬细胞)、细胞因子及免疫球蛋白可特异性地参与自身免疫性疾病(如干燥综合征、类风湿关节炎、系统性红斑狼疮、多发性硬化、Graves眼病)和系统性疾病(如阿尔茨海默病、糖尿病、移植物抗宿主病)。泪液成分的动态变化可反映全身免疫稳态失衡，其生物标志物(如外泌体携带的微RNA(microRNA，miR)-204、miR-200b-5p，蛋白质标志物β2微球蛋白等)在疾病早期筛查、诊断分层及治疗靶点发现方面展现出巨大潜力。泪液免疫成分分析可为系统性疾病提供创新性的诊断工具和治疗靶点，未来研究应致力于推动泪液检测技术的标准化与临床应用转化。

Abstract

Tear fluid, also referred to as tears or tear film, is an important biological fluid that plays a key role in maintaining ocular surface health and immune homeostasis. Recent studies have found that tear fluid not only participates in the occurrence and development of ocular diseases, but also exerts profound effects in the immune pathological mechanisms of systemic diseases, breaking through the inherent understanding previously held by the scientific community. Immune cells in tear fluid (such as T cells, neutrophils, natural killer cells, macrophages), cytokines, and immunoglobulins can specifically participate in autoimmune diseases (such as Sjögren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Graves’ ophthalmopathy) and systemic diseases (such as Alzheimer’s disease, diabetes mellitus, graft-versus-host disease). The dynamic changes in tear fluid components can reflect systemic immune homeostasis imbalance. Tear fluid biomarkers, such as exosomal microRNA (miR)-204, miR-200b-5p, and the protein marker β2-microglobulin, have shown great potential in early disease screening, diagnostic stratification, and therapeutic target discovery. Tear fluid immune component analysis may provide innovative diagnostic tools and therapeutic targets for systemic diseases. Future research should focus on promoting the standardization and clinical transformation of tear fluid testing technologies and their clinical application.

关键词

泪液 / 免疫 / 眼表免疫微环境 / 自身免疫性疾病 / 外泌体 / 微核糖核酸

Key words

tear fluid / immunity / ocular surface immune microenvironment / autoimmune disease / exosomes / microRNAs

Tears are a humor composed of water, mucus and lipid layers, acting as protection and lubrication of the ocular surface^[1]. Produced by lacrimal, meibomian, and goblet cells, tears contain immunomodulatory factors like transforming growth factor-beta (TGF-β) that help maintain ocular immune homeostasis^[2-5]. Tears also contain antimicrobial proteins (e.g., lysozyme, lactoferrin) that defend against pathogens and clear antigens via blinking^[6-8]. Furthermore, tear composition altered prior to the deterioration of immune response in numerous systemic diseases^[9], signifying its integral role in disease onset and progression^[10-11]. This article describes the functions of tear fluid in immune physiology and potential tear markers for multiple systemic diseases, aiming to extend the reach of immunotherapy and biomarker resources for clinical and experimental applications.

1 Physiological immune mechanism in tears

Tears constitute a dynamic immune microenvironment that reflects systemic immune status through resident immune cells, cytokines, and antibodies (Supplementary Figure 1, https://doi.org/10.57760/sciencedb.27698)^[12-14].

1.1 Immune cells

Tears contain T cells^[15], natural killer (NK) cells^[16], macrophages^[17], and neutrophils^[18] that regulate ocular immunity and reflect systemic immune activity^[19-20].

T cells in tears include CD4⁺, CD8⁺, and interleukin (IL)-17-producing T helper (Th17) subsets that contribute to ocular immune regulation^[21-24], in response to external stimuli^[18]. Beyond defense, T cells also modulate lacrimal gland (LG) function, influencing tear secretion and ocular surface homeostasis. Neutrophils exert dual pro-inflammatory and regulatory functions: they recruit Th17 cells via C-C motif chemokine ligand (CCL)2/CCL20 and can suppress T cell activity through CD11b, helping maintain immune balance^{[18, 25-26]}. NK cells contribute to immune surveillance and homeostasis; their depletion in conditions like Stevens-Johnson syndrome correlates with elevated IL-1α, IL-8, and ocular surface damage^[27-28].

Macrophages drive Th2-type inflammation in allergic conjunctivitis by releasing thymic stromal lymphopoietin (TSLP) and cytokines like IL-4 and IL-13, linking environmental triggers to ocular immune dysregulation^[29-31]. Together, these immune cells create a network whose activity in tears mirrors systemic immune status and provides actionable biomarkers for systemic diseases.

1.2 Antibody

Tears contain multiple antibodies, among which secretory immunoglobulin A (sIgA) is central to ocular immunity^[32]. In tears, immunoglobulin (Ig)A is converted to sIgA, which cooperates with antimicrobial molecules to neutralize pathogens and inhibit microbial growth^[33-34]. SIgA maintains ocular homeostasis through balanced pro- and anti-inflammatory activities. It promotes inflammation by inducing cytokines [e.g., IL-1, IL-6, and tumor necrosis factor (TNF)-α] and chemokines that recruit immune cells to combat infection^[35]. Conversely, it suppresses Th17 differentiation and IL-17A/interferon (IFN)-γ production, preventing excessive inflammation and preserving immune balance^[36], thereby averting excessive inflammation and maintaining immune equilibrium.

IgE’s Fc region binds strongly to mast cells, basophils, and endothelial cells, triggering degranulation and allergic responses upon antigen re-exposure^[15]. Although undetectable in healthy tears, IgE is markedly elevated in allergic conjunctivitis and atopic eye diseases^[37-38]. Moreover, tear IgE levels also correlate dynamically with corneal symptom severity^[39]. These findings highlight tear IgE as a promising biomarker for monitoring allergic eye disease. Tear IgG reflects systemic neurological disorders like multiple sclerosis (MS), characterized by oligoclonal IgG bands^[40]. Tear IgM varies by condition—elevated in viral conjunctivitis but reduced in diabetic keratitis—indicating disease-specific diagnostic value. β2-microglobulin (β2M), a component of major histocompatibility complex (MHC)-I, is significantly elevated in tears of primary Sjögren’s syndrome (SS) patients versus controls^[41-43]. Though its exact immune function is unclear, tear β2M serves as a useful biomarker for SS and broader immune dysregulation.

Together, tear biomarkers—sIgA, IgE, IgG, IgM, and β2M—offer non-invasive insights into systemic diseases. Pathological immune responses in tears of autoimmune diseases.

2 Pathological immune responses in tears of autoimmune diseases

2.1 SS

SS is an autoinflammatory disease that causes inflammation and damage to the exocrine glands, including the LG. Two main mechanisms underlie SS pathogenesis: The autoimmune epithelium hypothesis and ectopic germinal center formation^[44]. In the former, glandular epithelial cells aberrantly act as antigen-presenting cells (APCs) amid immune infiltration. The latter involves T and B cell aggregation in inflamed glands, forming ectopic germinal centers^[45].

SS-related dry eye disease (DED) features CD4⁺ T cell infiltration in the conjunctiva, indicating active T cell homing and local immune activation^[46]. Additionally, immune reactions mediated by Th1- and Th2-type CD4⁺ Th cells within the conjunctiva may trigger the release of proinflammatory cytokines, potentially harming the ocular surface.

Tears from SS patients show elevated TGF-β, IFN-γ, IL-2, IL-4, IL-12, IL-17, IL-33, and IFN-γ-induced protein (IP10). In CD25^-/- SS models, IFN-γ drives LG destruction by inducing epithelial apoptosis and upregulating IFN receptors. Eradicating LG inflammation in SS might involve regulating IFN-γ and IL-17. Moreover, IFN-γ also induces MHC-II on LG epithelia, enabling autoantigen presentation and perpetuating autoimmunity^[47]. IL-33 has recently emerged as a contributor to SS-induced ocular severity. Fold elevations of IL-33 in patients’ tears correlated positively with IL-4 and IL-5 levels. Through stimulating Th2 inflammation in dry eye progression, IL-33 may intensify the disease^[48].

Past study^[49] indicated that SS patients with dry eye bore substantially elevated tear fluid concentrations of CCL5, IP-10, and macrophage inflammatory protein (MIP) such as MIP-1a and MIP-1b. These cytokines attract Th1 cells, NK cells, macrophages, and dendritic cells expressing specific receptors like chemokine C-C-motif receptor (CCR)5 and C-X-C motif chemokine receptor (CXCR)3, which accumulate in ocular and conjunctival tissues. Subsequently, IL-8 strongly stimulates T lymphocytes, neutrophils, and eosinophils^[47], potentially damaging the LG and ocular surface via cytotoxic effects and apoptotic processes resulting from the extensive T cell infiltration and activation.

Cathepsin S has been noted to be elevated in SS patient tears, recently postulated as a disease biomarker. In an experimental SS mouse model, cathepsin S suppression resulted in reduced autoantibody titers and lymphocyte accumulation in LG, as well as suppressed presentation of SS-related autoantigen, alpha-fodrin, and dampened autoantigen-specific T cell responses in vitro^[50].

In summary, tear cytokines, immune cells, and cathepsin S collectively drive SS immunopathology.

2.2 Rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease that drives ocular surface inflammation through both systemic and local immune pathways.Regardless of RA type, dry eye is the prevalent ophthalmic indicator. Unlike SS, RA patients’ dry eye may result from localized damage to the tear layer. In RA-nonSS tear samples, tear levels of IL-1α, IL-6, IL-8, and TNF-α are elevated—unlike in RA-SS—suggesting distinct local inflammatory profiles^[51]. IL-1α, IL-6, and TNF-α inhibitors yield notable therapeutic benefits for RA management. Notably, RA-SS patients exhibited markedly reduced lacrimal duct IL-1α and IL-6 levels, while RA-nonSS patients demonstrated no significant changes in these cytokines^[52]. Available studies indicate RA patients demonstrate evaporative component alterations, inclusive of reduced goblet cells and disordered meibomian glands. Notably, TNF inhibitor therapy increases conjunctival goblet cell density and mucin production, improving dry eye symptoms in RA patients^[53].

Tears from RA patients show elevated IL-17, chemokines (CCL3-5), and proinflammatory cytokines (e.g., TNF, IL-6, IL-8), despite normal serum IL-17 levels—indicating localized ocular inflammation^[54-56]. In sum, RA drives ocular surface damage through local cytokine/chemokine elevation (e.g., TNF-α, IL-6, IL-17, CCL3-5), supporting targeted anti-cytokine therapy and mucin restoration for dry eye management.

2.3 Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterized by autoantibodies (e.g., anti-double stranded DNA, anti-Smith) that contribute to multi-organ inflammation, including ocular surface damage^[57-58]. SLE patients show reduced meibum secretion and immune cell infiltration in ocular tissues^[59]. Tears from SLE patients show elevated proinflammatory cytokines, including TNF-α, IFN-γ, IL-6, IL-8, and IL-17^[60]. While IL-2, IL-4, and IL-23 are reduced, immunomodulatory TGF-β and IL-10 are detectable^[61]. In SLE-SS, IL-17 correlates with tear instability and reduced tear secretion; in SLE-nonSS, IL-6 associates with tear film breakup. Specifically, SLE-nonSS patients commonly develop mixed-type dry eye, driven by meibomian gland dysfunction and increased tear evaporation^[62]. Interestingly, SLE-SS tears contained notably higher levels of TNF-α, IL-6, and IL-17 when compared to SLE-nonSS tears^[63]. Due to their proinflammatory properties, IL-17 family members can both amplify tissue damage and offer protection against infections^[64].

Primarily, SLE causes ocular surface disease through meibomian gland dysfunction and distinct tear cytokine profiles, with SLE-SS and SLE-nonSS showing different inflammatory signatures.

2.4 MS

Currently, cerebrospinal fluid (CSF) is the predominant diagnostic MS indicator due to intrusive collection and infeasibility of repetition. Considering the brain-eye connection, tears could potentially serve as a novel noninvasive source of sample^[65].

MS patients show altered tear acyl-carnitine profiles, suggesting metabolic dysregulation linked to immune activity Elevated tear histidine, aspartic acid, and serine—serine being linked to inflammation-driven ceramide synthesis—are also observed in MS^[66]. Tear levels of alpha-1 antichymotrypsin (AACT), an inflammation-responsive protease inhibitor, are elevated in MS and may reflect disease-related immune activity^[67].

Tears contain extracellular vesicles (EVs) of neuronal and microglial origin, supporting a molecular link between the central nervous system (CNS) and ocular surface in MS. EVs from MS patients’ tears and CSF share—70% identical proteins involved in inflammation and immune signaling, indicating a molecular bridge between the 2 fluids^[68]. EV cargo analysis further reveals enrichment of proteins driving T cell activation and phagocyte recruitment, reinforcing tears as a window into CNS inflammation in MS^[69].

Together, tear-based lipids, amino acids, and EVs reflect CNS immune activity in MS, supporting their potential as noninvasive diagnostic biomarkers.

2.5 Graves’ ophthalmopathy

Graves’ ophthalmopathy (GO) adversely affects the extraocular muscles and periorbital fat, impairing visual acuity^{[38, 70]}. Tear cytokines are promising biomarkers for GO. Kishazi, et al^[71] found significantly elevated IL-6, TNF-α, IL-8, IL-10, IL-12p70, and IL-13 in GO patients versus controls, with levels of TNF-α, IL-6, IL-8, and IL-13 correlating with clinical activity scores (CAS). Altered tear IL-7 levels across disease states. These findings support cytokines as potential non-invasive indicators of GO activity, though validation of sensitivity and specificity is needed^[72].

Tear-derived exosomes also show diagnostic potential: GO patients have approximately twice the tear exosome concentration of controls^[73], with elevated levels of exosomal vitamin D-binding protein (VDBP), C-reactive protein (CRP), chitinase-3-like protein 1 (CHI3L1), matrix metalloproteinases (MMP)-9, and vascular cell adhesion molecule (VCAM)-1. Exosomes from GO patients further induced higher secretion of IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) in orbital fibroblasts than those from controls, suggesting functional relevance^[74]. Their microRNA (miRNA) cargo may mediate intercellular signaling (Supplementary Table 1, https://doi.org/10.57760/sciencedb. 27698).

Together, tear cytokines and exosomes offer promising non-invasive biomarkers for assessing GO activity.

3 Pathological immune responses in tears of systemic diseases

3.1 Alzheimer’s disease

Pathological markers associated with Alzheimer’s disease (AD) include amyloid B-protein (Aβ) plaques, neurofibrillary tangles (NFTs), local inflammation, and ganglion cell degeneration^[75]. The rising prevalence of AD necessitates novel diagnostic methods employing less invasive, user-friendly techniques such as tear tests.

AD is notable for tau and Aβ protein accumulation in ocular tissues, mirroring their presence in cerebral and blood tissues^[76]. Gijs, et al^[77] scrutinized standard AD biomarkers in tear fluid from individuals with varying degrees of cognitive impairment. Five pathological criteria related to amyloid proteins (triple assay for Aβ-38, Aβ-40, and Aβ-42) and Tau proteins (duplex assay for t-Tau and p-Tau) were established. The studies^[78-79] revealed that only Aβ40 could be effectively detected in tears, due to Aβ42’s poor detectability precluding quantification of its ratio with Aβ40. This could be due to both tau and amyloid-(A) depositions being present in the ocular tissue of the condition.

The miRNA content significantly deviates from healthy individuals, indicating a potential biomarker for AD. Previously, researchers have related alterations in tear volume and tempo to AD development. Notably, miR-200b-5p is exclusive to patients with AD’s tears, potentially serving as an early AD indicator. This miRNA is ubiquitously found in mature mouse exosomes, making tear fluid readily accessible. Moreover, miRNA expression can be altered quickly due to cell death, influenced by several degenerative processes linked to AD. Notably, AD is linked to elevated risk of ocular degeneration, involving heightened retinal degeneration and choroidal thinning^{[78, 80]}.

In essence, existing studies suggest the potential use of tear miRNAs, along with Aβ and tau proteins, as novel biomarkers for AD.

3.2 Diabetes mellitus

Tears from diabetics contain cytokines associated with oxidative damage and chronic inflammation. Th1 cells primarily induce proinflammatory cytokines, contrasting with Th2 cells releasing primarily anti-inflammatory cytokines^[81]. Th1 cytokines (IFN-γ, TNF-α, IL-2, and IL-8) stimulate cellular immunity, inducing inflammation and cytotoxicity. Th2 cytokines (IL-4, IL-5, IL-10, and IL-13) protect against diabetes via regulatory functions. Diabetes mellitus (DM) tears exhibit diminished secretion of IL-4, IL-5, and IL-10 and elevated production of IFN-γ, TNF-α, IL-2, and IL-8^[82]. Diabetic retinopathy (DR) may arise from release of inflammatory proteins and cell death stimulated by epidermal growth factor (EGF), reflecting LG activity. The tears of diabetes patients display significantly elevated EGF levels due to reduced reflexive tears and deactivation of the EGF receptor (EGFR) signaling pathway during wound healing^[83].

Proteomic studies^[84-85] show that tear proteins in DR are enriched in factors involved in antigen processing, proteolysis, oxidative stress, and cytokine response. MMP-3 and MMP-9 levels are increased in tears of DR, which can act as pro-apoptotic agents to accelerate the apoptosis of retinal neurons and endothelial cells^[86]. Additionally, elevated tear IL-2 and IL-8 in DR reflect ongoing inflammation and are linked to disease severity^[87-88].

3.3 Graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) manifests as ocular dryness, typically appearing 3 to 6 months post-transplantation due to mucosal epithelial fibrosis, LG obstruction, inflammation, and immune cell invasion^[89-90].

Tear fluid in ocular cGVHD shows elevated IL-4, IL-5, IL-6, IFN-γ, and lymphotoxin (LT)-α^[91]. IFN-γ, a T cell-associated cytokine, is crucial in shaping the pathology of graft-versus-host disease (GVHD). While promoting GVHD via upregulation of chemokine receptors, it also induces apoptosis in activated donor T cells, curtailing the disease’s progress^[91-92]. Notably, tear LT-α levels are lower in ocular cGVHD patients than in controls and inversely correlate with symptom severity^{[90, 93]} signify that a comparative analysis between oGVHD patients with varied LT-α levels could illuminate its mechanism.

The summary of the ocular immune mechanisms of systemic diseases is shown in the Supplementary Figure 2 (https://doi.org/10.57760/sciencedb.27698).

4 Conclusion

Tears can serve as an essential source of biomarkers for systemic diseases and as an auxiliary screening tool for ophthalmic diagnosis. Compared to blood or CSF, tears offer unique advantages for non-invasive disease detection. Their easy, painless collection enables point-of-care testing, home use, and deployment in low-resource settings^[94]. Unlike blood, tear fluid lacks blood cells that might obscure or degrade biomarkers, offering a clearer view of molecular signatures. Furthermore, the adaptability of tear sampling to immediate-result point of care (POC) tests enhances patient compliance, thereby sidestepping the delays associated with lab-based blood analysis.

Yet, tear fluid biomarkers also face hurdles. Reproducibility and stability pose concerns, with variations in collection methods, experimental conditions, and population differences yielding inconsistent results. Moreover, the biological relevance of tear biomarkers demands deeper scrutiny—while proteomics identifies candidates, their mechanistic ties to disease pathology often remain murky, complicating clinical prioritization. Small tear volumes, environmental factors, and the effects of medication further complicate analysis. These obstacles suggest that, while promising, the complete replacement of blood tests by tear fluid awaits large-scale.

While tears are unlikely to fully replace blood tests in the foreseeable future, their unique strengths in early detection, dynamic monitoring, and non-invasive profiling position them as an indispensable adjunct in the evolving landscape of precision medicine. The goal is not competition but synergy—harnessing tears and blood as complementary lenses to illuminate the full spectrum of human health and disease.Funding and financials.

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