Decoding Allergic Conjunctivitis: Latest Perspectives on Etiological Drivers and Immunopathological Mechanisms

Abstract

Allergic conjunctivitis (AC) is a common ophthalmic disease, ranging from mild, self-limiting forms to severe, vision-threatening conditions such as vernal keratoconjunctivitis and atopic keratoconjunctivitis. Its pathogenesis originates from the interplay between genetic predisposition and complex environmental factors, manifesting as a complex pathophysiological network. This review comprehensively elucidates recent advancements in the etiology and pathogenesis of AC. Key etiological drivers include Ig(Ig: Immunoglobulin) E-mediated reactions due to allergen sensitization, genetic susceptibility, and escalating environmental impacts, such as climate change, air pollution, and modern lifestyles influencing immune development and allergen exposure. Its pathogenesis is characterized by complex immune cell activation and crosstalk; dysregulation of lipid mediators; an intricate cytokine network predominantly driven by Th2(Th2: T helper 2) cytokines and alarmins that often signal via the JAK‒STAT(JAK‒STAT: Janus Kinase- Signal Transducer and Activator of Transcription) pathway; and a significant neuroimmune imbalance leading to neurogenic inflammation and persistent itch. Furthermore, epithelial barrier dysfunction, ocular surface microbiome dysbiosis, and epigenetic modifications are increasingly recognized as crucial regulatory factors. This review also highlights the ongoing challenges in addressing AC heterogeneity, pursuing personalized medicine, improving diagnostic methods, and developing effective preventive strategies, including allergen immunotherapy. Ultimately, integrating multidimensional data from cutting-edge research holds the promise of achieving more precise and personalized AC management, thereby improving outcomes for AC patients worldwide.

Graphical Abstract

Allergic conjunctivitis (AC) is one of the most common ophthalmic diseases, affecting up to 20–30% of the global population [1]. Its clinical spectrum ranges from mild, self-limiting seasonal/perennial AC (SAC/PAC) to severe forms, such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC), which can lead to corneal scarring and vision loss [2]. The pathogenesis of AC results from the interplay between genetic predisposition and complex environmental factors, manifesting as a complex network of multiple cell types and molecular mediators on the ocular surface [3–6]. In recent years, advances in research technologies (such as single-cell sequencing, multiomics analysis, and high-resolution imaging) have enabled our understanding of AC pathogenesis to reach unprecedented depth. Concurrently, environmental deterioration (climate warming and worsening air pollution) and lifestyle changes are considered significant factors driving the increasing prevalence of AC [7, 8]. This review delves into the latest advancements in the etiology and pathogenesis of AC in unprecedented detail (Fig. 1).

Fig. 1.

Graphical abstract. This illustration provides a comprehensive overview of the pathophysiology of allergic conjunctivitis (AC). The etiological drivers on the left show that AC is triggered by a combination of allergen sensitization, genetic predisposition, and environmental influences, including climate change, air pollution, and modern lifestyle factors. The central section delves into the pathogenesis, which is a complex network of vicious cycles where a compromised epithelial barrier serves as a "gateway" that leads to the activation of immune cells (e.g., mast cells, eosinophils, Th2 cells, and ILC2) and the amplification of inflammatory responses through cytokines (e.g., IL-4, IL-5, and IL-13) and signaling pathways (e.g., JAK-STAT). Concurrently, neuroimmune imbalance contributes to intractable pruritus, with epigenetic modifications regulating these processes at a deeper level. The right section offers therapeutic insights and future directions based on these mechanisms. These include targeted biologics, such as anti-IgE/IL-4Rα and JAK inhibitors; allergen immunotherapy (AIT), which can alter the disease course; and adjunctive strategies, such as barrier repair. These approaches are aimed at achieving precise, personalized patient management

Etiology and Relationships with Environmental Changes

Fundamental Causes: Allergen Sensitization and Re-exposure

The essence of AC is an abnormal immune response (type I and/or type IV hypersensitivity reactions) of the body to harmless environmental substances (allergens). Allergens (primarily airborne, such as pollen, dust mite feces, animal dander, mold spores, etc.) penetrate the conjunctival epithelial barrier and are captured, processed, and presented by antigen-presenting cells (APCs, mainly dendritic cells, DCs) to naïve T cells, inducing their differentiation into Th2 cells in the presence of a specific cytokine (e.g., IL1−4). By producing IL-4 and IL-13 and interacting with B cells (via CD240L‒CD40 signaling), Th2 cells promote B-cell class switching to plasma cells that produce allergen-specific IgE antibodies. The produced IgE antibodies subsequently bind to high-affinity IgE receptors (FcεRIs) on the surface of mast cells and basophils, sensitizing the body [9, 10]. When a sensitized individual is re-exposed to the same allergen, the allergen cross-links IgE bound to mast cells, triggering mast cell degranulation and releasing large amounts of preformed (e.g., histamine and tryptase) and newly synthesized (e.g., lipid mediators and cytokines) inflammatory mediators, leading to an immediate-phase reaction (symptoms appear within minutes). Subsequently, recruited inflammatory cells (such as eosinophils and Th2 cells) release more mediators, leading to a late-phase reaction (appearing hours later and lasting for days) and potentially leading to chronic inflammation [11–13].

Genetic Susceptibility

AC often coexists with other allergic diseases (such as allergic rhinitis, asthma, and atopic dermatitis) and exhibits familial aggregation, indicating that genetic factors play important roles in its pathogenesis. This genetic predisposition is termed "atopy" [14]. The genes involved are related mostly to immune responses (e.g., HLA3 genes and genes encoding cytokines and their receptor, such as IL4, IL5, IL13, IL33, and TSLP4) and epithelial barrier function (e.g., the FLG5 gene) [15–19]. For example, skin barrier dysfunction caused by FLG gene mutations is a significant risk factor for AKC and may also affect conjunctival barrier function [20–22].

Driving Role of Environmental Changes

Global warming leads to an extended plant growing season, altered geographical distribution, and increased production of pollen, which is also more allergenic under relatively high CO₂ concentrations [23, 24]. Extreme weather events (such as thunderstorms) can cause pollen grains to fragment into smaller microparticles that are easily inhaled and deposited on the ocular surface, triggering "thunderstorm asthma" and severe oculonasal symptoms [25, 26]. A study published in NATURE COMMUNICATIONS in 2022 predicted changes in future pollen seasons in the United States, indicating that they will start earlier, last longer, and be more intense. These changes directly increase the risk and intensity of population exposure to pollen allergens [27]. Air pollutants from urbanization and industrialization (such as particulate matter (PM2.5 and PM10), ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), volatile organic compounds (VOCs), etc.) can not only directly irritate the ocular surface, causing nonallergic inflammation, but also act as adjuvants, enhancing the body's immune response to allergens [7, 28–30]. Pollutants can damage the conjunctival epithelial barrier, making allergens more likely to penetrate; directly activate epithelial cells to release pro-inflammatory mediators and alarmins; adsorb and modify allergens, potentially enhancing their allergenicity; and promote oxidative stress, exacerbating the inflammatory response [30–32]. Numerous epidemiological studies have confirmed the association between air pollution exposure and the prevalence or symptom severity of AC [7, 33–35].For example, a 2024 study conducted in China revealed a link between exposure to common gaseous air pollutants and an increased risk of childhood conjunctivitis [36]. Modern lifestyles, such as excessive hygiene, antibiotic overuse, increased rates of cesarean section, westernized dietary patterns, and reduced contact with natural environments due to urbanization, may alter the colonization patterns of the gut and body surface (including the ocular surface) microbiota in early life, reducing the immune system's exposure to diverse microbial stimuli. According to the "hygiene hypothesis" and its subsequent evolutionary theories (such as the "old friends hypothesis" and "microbiome dysbiosis hypothesis"), this lack of early immune "education" may lead to imbalanced immune system development, predisposing individuals toward allergic (Th2-skewed) responses [37]. This result aligns with findings suggesting potential alterations in the ocular surface microbiome in individuals with AC [38, 39]. Modern humans spend most of their time indoors, making indoor air quality crucial for health. Indoor allergens (such as dust mites, pet dander, cockroaches, and molds) are the primary cause of perennial AC (PAC) [40, 41]. Chemicals released from building materials, furniture, and cleaning products (such as formaldehyde and VOCs) may also irritate the ocular surface or act as adjuvants [42]. Poor ventilation and humid environments (conducive to mold and dust mite proliferation) increase exposure to indoor allergens and irritants.

Pathogenesis

Immune Cell Activation and Complex Crosstalk

Although IgE-mediated mast cell activation and the release of histamine, tryptase, leukotrienes, and prostaglandins remain key drivers of the immediate reaction and early symptoms (itching, hyperemia, and edema) of AC, research continues to reveal the complexity of the inflammatory response (Fig. 2). As key effector cells in the initiation of AC, mast cell activation extends far beyond FcεRIs. Multiple signals, including complement fragments, neuropeptides, TLR6 ligands, and cytokines, can directly or synergistically activate mast cells [43–47]. The patterns of degranulation and mediator release induced by different stimuli (IgE vs. non-IgE stimuli) may vary. Bidirectional communication between mast cells and neurons (via SP/NK1R7 and NGF/TrkA8), epithelial cells (via alarmins), and ILC29s is crucial for inflammation amplification [48, 49]. Studies have utilized single-cell technologies to analyze mast cell subpopulations and their heterogeneity in allergic diseases [50]. Activated mast cells not only rapidly release preformed mediators from their granules, such as histamine (causing itching, vasodilation, and increased permeability), proteases (e.g., tryptase and chymase, which can activate PAR10s, degrade the matrix, and activate other cells), heparin, and TNF-α,11 but also synthesize them de novo and release large amounts of lipid mediators and cytokines/chemokines (e.g., IL-4, IL-5, IL-13, IL-8, and CCL122) within hours, thereby coordinating both immediate-phase and late-phase reactions [12, 46].

Fig. 2.

Immune cell activation and complex crosstalk. This figure illustrates the complex network of interactions between immune and structural cells on the ocular surface during allergic conjunctivitis pathogenesis. (1) Sensitization Phase (First Exposure): Allergens, such as pollen and dust mites, penetrate the conjunctival epithelial barrier. There, they are captured and processed by antigen-presenting cells (APCs), which are mainly dendritic cells (DCs). The APCs then present the antigens to naïve T cells in a microenvironment rich in cytokines, such as IL-4. This induces the differentiation of the T cells into type 2 helper T cells (Th2). These Th2 cells secrete IL-4 and IL-13, which interact with B cells and promote B cell class switching and differentiation into plasma cells. The plasma cells then produce large amounts of allergen-specific IgE antibodies. These IgE antibodies then bind to high-affinity IgE receptors (FcεRI) on the surfaces of mast cells and basophils, thereby sensitizing the body. (2) Effector Phase (Re-Exposure): Immediate phase reaction: When a sensitized individual is re-exposed to the same allergen, it cross-links IgE on the surface of mast cells. This triggers mast cell degranulation and the rapid release of pre-stored mediators, such as histamine and tryptase, as well as newly synthesized lipid mediators, such as prostaglandin D2 (PGD2) and cysteinyl leukotrienes (CysLTs). These mediators cause increased vascular permeability, vasodilation, and activation of sensory nerves. This leads to intense itching, congestion, edema, and other acute symptoms. Late phase reaction: Several hours after the immediate phase reaction, eosinophils, T helper 2 (Th2) cells, and basophils are recruited to conjunctival tissue by chemokines (such as eotaxins) and cytokines (particularly interleukin-5 [IL-5]). Eosinophils release cytotoxic proteins (such as ECP and MBP) from their granules, which directly damage corneal and conjunctival epithelial cells. Eosinophils are the main effector cells that cause corneal complications, such as shield ulcers, in vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC). Th2 cells continuously secrete IL-4, IL-5, and IL-13 as core coordinators of chronic inflammation. This further drives IgE production, eosinophil activation and survival, and leads to tissue remodeling, such as goblet cell hyperplasia, excessive mucus secretion, and fibrosis. Type 2 innate lymphoid cells (ILC2s) are key players in innate immunity. They can be rapidly activated by alarmins (such as TSLP and IL-33), which are released by damaged epithelial cells. This activation occurs independently of antigen recognition. ILC2s produce large amounts of IL-5 and IL-13. This rapidly amplifies the type 2 immune response in the early stage of inflammation. (3) Complex crosstalk: The arrows in the figure illustrate the intricate, bidirectional, and multifaceted regulatory relationships between cells, creating a self-amplifying inflammatory cycle. For instance, damaged epithelial cells release alarmins, which activate ILC2s and DCs. The mediators released by immune cells, such as mast cells and Th2 cells, then exacerbate damage to the epithelial barrier and activate sensory nerves (i.e., neuroimmune crosstalk)

Eosinophils, which are recruited from the blood to the conjunctival tissue under the influence of chemokines such as IL-5 and eotaxins (CCL11, CCL24, and CCL26), are the main effectors of pathological damage in VKC and AKC [51–54]. Activated eosinophils release their granular contents through exocytosis or cytolysis (formation of eosinophil extracellular traps, EETs): cationic proteins are cytotoxic, directly damaging corneal epithelial and stromal cells, leading to punctate erosions and shield ulcers; they also release growth factors (e.g., TGF-β13 and VEGF14) involved in tissue remodeling (fibrosis, angiogenesis) and produce lipid mediators and cytokines that further amplify inflammation [54, 55]. In addition to tissue damage caused by the release of granular proteins, the mechanisms and roles of eosinophil extracellular trap (EET) formation by eosinophils are gaining attention in ocular surface inflammation. EETs, which are composed of DNA,15 histones, and granular proteins, may contribute to pathogen clearance but can also exacerbate tissue damage and thrombosis [56, 57]. Eosinophils express various chemokine receptors (e.g., CCR163) and cytokine receptors (e.g., IL-5Rα, IL-4Rα, and ST172), enabling them to respond to complex microenvironmental signals [58, 59].

Th2 cells and the cytokines they produce, namely, IL-4, IL-5, and IL-13, are considered core drivers of chronic inflammation and tissue remodeling in AC [60, 61]. The specific pathophysiological functions of these cytokines are detailed in Sect. 2.3. Pathogenic Th2 cell subsets (e.g., Th2 cells expressing IL-17RB or ST2) may play a more significant role in severe AC [62, 63]. Furthermore, while a Th2/Th1 imbalance is a classic theory in allergic diseases, recent research has focused on the potential role of Th17 cells in certain severe AC cases (especially those with corneal neovascularization or infectious complications), where IL-17 may promote neutrophil recruitment and tissue destruction [64, 65]. Functional defects in Regulatory T cells (Tregs), which normally produce immunosuppressive cytokines like IL-10 and TGF-β, are linked to the severity and chronicity of AC. These defects not only include reduced numbers or a decreased suppressive function but also may involve their conversion to a proinflammatory phenotype [66–68]. Th1718 cells (producing IL-17A, IL-17F, and IL-22) may be involved in AC under certain circumstances (such as bacterial infections or severe corneal neovascularization), where IL-17 can promote neutrophil recruitment and tissue destruction [69, 70]. Follicular helper T (Tfh) cells, through interactions with B cells in germinal centers, promote the production of high-affinity antibodies, including IgE, which is significant in allergic diseases. Tfh cells regulate B-cell differentiation and antibody affinity maturation by expressing specific surface molecules and secreting cytokines, such as IL-21 [71]. In allergic diseases, the dysfunction of Tfh cells may lead to excessive IgE production, thereby exacerbating allergic reactions [72]. Research indicates that the role of Tfh cells in allergic diseases is not limited to IgE production but also involves the regulation of germinal center responses. Tfh cells, through interactions with B cells, promote the formation and maintenance of germinal centers, which are crucial for antibody affinity maturation and the generation of memory B cells [73]. Th119 cells (producing IFN-γ20) are generally considered suppressed in individuals with allergies, but their role in chronic inflammation or specific subtypes may be more complex [74].

The role of type 2 innate lymphoid cells (ILC2s), a recent focus of immunological research, in the initiation, amplification, and chronification of AC has been further substantiated [75–77]. Located in the conjunctival lamina propria, these cells are important members of the innate immune system that can be rapidly activated by epithelial alarmins (particularly IL-33 and TSLP) following allergen exposure independent of antigen recognition to quickly produce large quantities of Th2-type cytokines (IL-5, IL-13, and IL-9). They play crucial roles in the initiation and amplification stages of the allergic reaction, potentially preceding the adaptive Th2 response. ILC2s engage in complex mutual regulatory networks with mast cells, eosinophils, epithelial cells, and other cells [78–81]. The mutual regulatory network between ILC2s and other cells (such as epithelial cells, mast cells, DCs, and Tregs) is highly complex. For example, IL-13 produced by ILC2s can act on the epithelium [82–84], whereas certain mediators produced by DCs or Tregs (such as IL-10, TGF-β, or retinoic acid) may inhibit ILC2 function [85, 86]. The role of ILC3s on the ocular surface remains unclear.

B lymphocytes, with the assistance of Th2 cells, undergo IgE class switching to produce large quantities of allergen-specific IgE, forming the material basis for allergic reactions. The presence of memory B cells accounts for the rapid production of IgE upon re-exposure. In addition to IL-4/IL-13-driven class switching, other signals (such as TLR agonists and certain viral infections) may influence IgE production in addition to B-cell IgE production [87, 88]. The local survival and maintenance mechanisms of plasma cells in the conjunctiva represent potential therapeutic targets.

In the complex pathological network of AC, various cell types, such as basophils, neutrophils, macrophages, dendritic cells, and conjunctival fibroblasts, play important roles. Although basophils constitute a small proportion of peripheral blood leukocytes, the IL-4 they release has diverse functions in regulating immune responses and is capable of influencing the activities of various immune cells, including T cells and B cells, thereby playing a role in allergic and autoimmune diseases [89]. Neutrophils play crucial roles in both acute and chronic inflammation. They not only participate in pathogen recognition and clearance but also promote the development of adaptive immune responses through interactions with other immune cells. In chronic inflammation, the interaction of neutrophils with other immune cells may lead to immune dysregulation, thereby exacerbating disease progression [90]. Furthermore, neutrophils are also considered drivers of immune dysregulation in certain autoimmune diseases, potentially influencing the functions of other immune cells through the formation and clearance of neutrophil extracellular traps (NETs) [91]. Macrophages and dendritic cells, as antigen-presenting cells, play important roles in the immune response of AC. Macrophages not only participate in antigen uptake and processing but also regulate the activities of other immune cells by secreting various cytokines and chemokines [92]. Dendritic cells, on the other hand, promote the initiation and maintenance of adaptive immune responses through interactions with T cells. Conjunctival fibroblasts are considered sentinel cells and local immunomodulators in infectious keratitis. They play important roles in the pathological process of infectious keratitis by recognizing pathogens, initiating innate immune responses, and promoting the recruitment and activation of inflammatory cells [93].

Fine-Tuned Regulation and Roles of Lipid Mediators

Lipid mediators are bioactive molecules produced from cell membrane phospholipids via the release of arachidonic acid (AA) by phospholipase A2 (PLA2), followed by metabolism through the cyclooxygenase (COX) or lipoxygenase (LOX) pathways. They play significant roles in the inflammation characteristic of AC.

Prostaglandin D2 (PGD2) is the major prostaglandin released by mast cells and exerts multiple effects by acting on its receptors, DP211 and DP2. Its DP1 receptor primarily mediates vasodilation and increased vascular permeability (leading to edema and hyperemia), whereas DP2 (CRTH2,22 a chemoattractant receptor-homologous molecule that is predominantly expressed on Th2 cells, ILC2s, eosinophils, and basophils) primarily mediates the chemoattraction and activation of Th2 cells, ILC2s, and eosinophils [94, 95]. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin synthesis by inhibiting COX enzymes, but their roles in AC treatment are limited, especially for symptom relief or postoperative inflammation. DP2 antagonists (e.g., fevipiprant) have undergone clinical trials for diseases such as asthma, and their potential in treating AC is worth exploring, although no drugs are currently approved [96, 97]. PGD2 synthase (e.g., H-PGDS23) is also a potential target.

Cysteinyl leukotrienes (CysLTs), including LTC4,24 LTD4,25 and LTE4,26 are produced mainly by mast cells, eosinophils, and macrophages. LTC4 synthase (LTC4S) and the receptors CysLT1/CysLT2 are key nodes. By acting on CysLT1 and CysLT2 receptors, they cause potent, transient vasoconstriction followed by sustained vasodilation and increased vascular permeability, promote mucus secretion, and chemoattract eosinophils, among other effects [98–101]. Although oral CysLT1 antagonists (e.g., montelukast) may benefit AC patients with concomitant rhinitis, high-quality evidence supporting their use as first-line therapies for AC is lacking, and ophthalmic formulations are not routinely used [102]. LTB427 is a potent chemoattractant for neutrophils and eosinophils, is produced mainly by neutrophils and macrophages, and may play a role in certain types of ocular surface inflammation [103–105] The development of drugs with better selectivity or dual targeting (e.g., simultaneously antagonizing CysLT1 and DP2) may be a future direction.

Platelet-activating factor (PAF), which is produced by various inflammatory cells, can increase vascular permeability and eosinophil chemotaxis and activation, with a potency even greater than that of histamine. Its receptor, PAF-R, mediates multiple proinflammatory effects [106–109]. PAF antagonists are not yet routinely used to treat AC.

Specialized proresolving mediators (SPMs), such as lipoxins (LXA4, LXB4), resolvins (RvD series, RvE series), protectins (PD1/NPD1), and maresins, are derived from the metabolism of unsaturated fatty acids such as AA, EPA,28 and DHA.29 They actively inhibit neutrophil and eosinophil infiltration, promote macrophage efferocytosis of apoptotic cells, suppress proinflammatory cytokine production, and promote tissue repair [110–115]. Studies have shown that the production of SPMs may be insufficient in individuals with allergic inflammation or that the functions of their receptors (e.g., ALX/FPR302, GPR3132, and ChemR3223) may be abnormal. Supplementation with SPMs, their stable analogs, or drugs that promote endogenous SPM synthesis is considered a potentially new anti-inflammatory and proresolving strategy [114, 115]. Exploring the enhancement of endogenous proresolving pathways as a therapeutic strategy is an emerging research direction.

Complexity of Cytokine Networks and Signaling Pathways

Cytokines do not act in isolation but rather form complex networks. For example, TSLP can induce ILC2s and Th2 cells to produce IL-5 and IL-13; IL-33 potently activates ILC2s; and IL-4 and IL-13 can provide positive feedback by increasing the expression of certain chemokine receptors and increasing cell recruitment. Moreover, negative feedback regulation, such as IL-10-mediated inhibition of Th2 responses, occurs. Understanding the dynamic balance and imbalance of this network is crucial.

The core of AC is the predominance of a Th2-type immune response, leading to the overproduction of cytokines such as IL-4, IL-5, and IL-13. IL-4 drives IgE class switching and Th2 differentiation; IL-5 is a key driver of eosinophils; and IL-13 has broad functions, promoting IgE production, eosinophil recruitment, goblet cell hyperplasia and mucus hypersecretion, epithelial barrier disruption, and subconjunctival fibrosis and tissue remodeling (e.g., giant papillae formation) [60, 116–118]. IL-9, which is produced mainly by Th2 cells and ILC2s, can promote mast cell proliferation, survival, and activation, affecting not only mast cells but also ILC2 function and the airway epithelium [119–122]. IL-31, which is produced primarily by Th2 cells, and its receptor expressed on sensory nerves are considered an important cytokine pathways for inducing itch (especially in atopic dermatitis) by acting on the IL-31RA/OSMRβ33 receptor complex on sensory neurons; its role in AC-associated itch is also gaining attention [123–128]. Epithelial alarmins (TSLP, IL-33, and IL-25), as upstream initiators of the Th2 response, are increasingly recognized for their importance. They link environmental stimuli, innate immunity (especially ILC2s), and adaptive immunity (Th2 differentiation) [16, 76]. IL-10 and TGF-β are major immunosuppressive cytokines produced by Tregs and other cells; their insufficient production or functional defects may lead to uncontrolled inflammation [67, 68, 85]. IFN-γ (a Th1 cytokine) and IL-17 (a Th17 cytokine) are generally not dominant in classic AC models but may participate in regulating the nature and severity of inflammation under specific conditions (such as chronicity or complications) [129, 130]. GM-CSF,34 which is produced by epithelial cells, T cells, and other cells, can prolong eosinophil survival [131]. The roles of the chemokine family and their receptors in mediating the recruitment of specific immune cells to tissues have also been meticulously studied [51, 52, 65, 70, 120].

The actions of these cytokines are transmitted mostly by binding to their cell surface receptors and activating downstream signaling pathways. The JAK–STAT pathway is a key signaling hub for many AC-related cytokines, such as IL-4/IL-13 (activating STAT6 via JAK1/3/TYK235) and IL-5 (activating STAT1/5 via JAK2), providing a theoretical basis for JAK inhibitors [132–134]. Similarly, the NF-κB36 [135–137] and MAPK37 pathways also regulate proinflammatory gene transcription and cell activation. The calcineurin–NFAT38 pathway is crucial for T-cell activation and is the target of CNI39s (CsA, tacrolimus) [138, 139]. Understanding these signaling pathways provides a foundation for developing targeted drugs (such as JAK inhibitors).

Neuroimmune Imbalance

An imbalance in neuroimmune interactions in individuals with AC is a key mechanism leading to the amplification and persistence of symptoms, especially itching, a phenomenon known as neurogenic inflammation. Sensory neurons in the conjunctiva are not uniform; subpopulations expressing different ion channels (TRP40V1, TRPA1, TRPM8, etc.), receptors (histamine receptors H1/H4, PAR-2, IL-31R, TLRs, Mrgprs,41 etc.), and neuropeptides (SP, CGRP, VIP,42 etc.) may mediate different sensations (itching, pain, cold, and irritation) and participate in different types of neurogenic inflammation. Activated nerve endings not only transmit signals of itch, pain, and irritation to the central nervous system but also release neuropeptides antidromically at the periphery, primarily substance P (SP) and calcitonin gene-related peptide (CGRP) [140, 141]. SP acts on NK1 receptors on mast cells and other target cells to potently induce degranulation, increase vascular permeability, and promote inflammatory cell recruitment [142], while CGRP primarily causes potent vasodilation [143, 144]. Together, these processes form a neuro-immune positive feedback loop that drives neurogenic inflammation.In an inflammatory environment, various cells (including epithelial cells, mast cells, and fibroblasts) increase the production and release of nerve growth factor (NGF). By acting on high-affinity TrkA receptors and low-affinity p75NTR43 receptors on neurons, NGF promotes sensory neuron survival, growth, axonal sprouting (the nerve density may increase), and phenotypic changes (e.g., upregulation of TRPV1 and SP expression), leading to nerve hypersensitization (a reduced threshold and increased intensity of the response to stimuli) that more easily triggers itching and increases its severity [145–149]. NGF can also directly enhance mast cell reactivity ("priming"), increasing their sensitivity to stimuli such as IgE cross-linking or SP [150, 151]. Chronic inflammation leads to peripheral sensitization (a reduced threshold and enhanced response to stimuli at sensory nerve endings) and central sensitization (altered signal processing in the spinal cord and brain), resulting in amplified and persistent itching. NGF-driven nerve sprouting and phenotypic changes are important mechanisms of peripheral sensitization [152–154]. The activation of sensory neurons involves the opening of ion channels (such as TRPV1 and TRPA1), leading to Ca2 + influx, which in turn triggers the exocytosis of neuropeptides. Neuropeptides (like SPs) act on G protein-coupled receptors (like NK1R44s) on target cells (like mast cells), activating downstream signaling pathways (like the PLC-IP345/DAG46–Ca2 + pathway) and leading to cellular responses. In addition to histamine, nonhistamine-dependent itch pathways may be more important in chronic itch (as in AKC), involving the direct actions of TSLP, IL-31, neuropeptides, and proteases (via PARs) on sensory neurons. Tryptase release by mast cells is an important pruritogenic mechanism mediated by the activation of PAR-2 on neurons [48, 155–157]. Parasympathetic nerves (via acetylcholine/muscarinic receptors) and sympathetic nerves (via norepinephrine/adrenergic receptors) may also modulate ocular surface immune responses and tear secretion; their roles in AC require further investigation.

Epithelial Barrier Breakdown

The disruption of the conjunctival epithelial barrier plays a dual role in the pathogenesis of AC, acting as an "open gate" and "adding fuel to the fire". A compromised barrier facilitates easier penetration of allergens, pollutants, and microbial products, thereby initiating or exacerbating immune responses. Concurrently, damaged epithelial cells themselves also release more proinflammatory mediators (such as IL-8 and GM-CSF) and alarmins (TSLP and IL-33), further amplifying inflammation. Factors contributing to barrier disruption (including inflammatory mediators, eosinophil products, proteases, mechanical damage, and environmental pollutants) have been discussed in detail in the previous sections. Maintaining and repairing the integrity of the epithelial barrier is crucial for controlling AC. Research has increasingly focused on the specific molecular mechanisms of barrier disruption, such as the downregulation, mislocalization, or altered phosphorylation status of specific tight junction (TJ) proteins (e.g., claudin-1 and occludin) [158, 159]. Increased epithelial cell apoptosis and decreased proliferative and repair capacities can also lead to barrier damage. The functional state of limbal stem cells is crucial for maintaining the corneal epithelial barrier and may be compromised in patients with severe forms of AC, such as AKC [160, 161]. Therefore, protecting and repairing the epithelial barrier has become an increasingly recognized ancillary strategy in AC treatment, for example, through the use of eye drops containing ingredients such as hyaluronic acid, trehalose, or components that promote tight junction formation.

Ocular Surface Microbiome Dysbiosis

In recent years, research into the relationship between the microbiome and AC has gradually emerged but remains exploratory. Some studies have utilized high-throughput sequencing technologies (such as 16S rRNA47 sequencing) to compare the conjunctival or tear microbial composition of AC patients with that of healthy controls. The results have been inconsistent, possibly due to variations in study design, sample collection methods, sequencing technologies, and geographical and population differences. Some studies have reported a potential decrease in α diversity (species richness and evenness within a community) in AC patients [162]. Regarding β diversity (compositional differences between communities), most studies have reported differences between AC groups and healthy groups [163]. How these alterations in the microbial composition (dysbiosis) affect AC is not yet fully understood. Potential mechanisms include the following: (1) changes in microbial metabolites (such as short-chain fatty acids (SCFAs) and lipopolysaccharide (LPS)) may affect the function of local immune cells (e.g., Tregs and ILCs) or the integrity of the epithelial barrier; (2) a reduction in the abundance of commensal bacteria may decrease resistance to pathogen colonization (colonization resistance); and (3) an increase in the abundance of certain bacterial species may directly promote inflammatory responses. Current research is mostly descriptive and correlational, and causal relationships have not yet been established. Future research requires larger-scale longitudinal cohorts combined with multiomics technologies (metagenomics, metatranscriptomics, and metabolomics) and functional experiments (such as the use of germ-free mouse models) to elucidate the precise role of the ocular surface microbiome in AC pathogenesis and to explore the possibility of intervention by modulating the microbiome (e.g., the use of probiotics, prebiotics, or fecal microbiota transplantation, although ocular application presents significant challenges).

Epigenetic Modifications

AC has a clear genetic predisposition, and an individual's risk of developing the disease is influenced by multiple genes and environmental factors. Genome-wide association studies (GWASs) have identified several gene loci associated with the risk of general allergic diseases (including AC), many of which are located within or near genes involved in immune regulation, Th2 differentiation, epithelial barrier function, or inflammatory signaling. For example, variations in genes such as IL4/KIF3A,48 IL13, TSLP, the HLA region, and FLG have been repeatedly reported to be associated with an allergy risk [164–170]. However, large-scale GWASs specifically targeting AC (especially its different subtypes) are relatively scarce, and more work is needed to discover AC-specific genetic risk factors.

As a key epigenetic mechanism, DNA methylation influences gene expression and thus plays an important role in the onset and progression of allergic diseases. For example, in childhood allergic diseases, nasal DNA methylation is considered to have strong predictive power and can be used to effectively diagnose allergies in children [171]. Furthermore, alterations in DNA methylation are also associated with multiple phenotypes of allergic diseases that often co-occur with the disease [172]. In the study of allergic diseases, DNA methylation is not only used as a diagnostic tool but also considered a potential therapeutic target. A high-throughput methylation analysis of immune cell subtypes or whole blood can identify disease-specific epigenetic variations [173]. If these variations are consistently correlated with disease parameters, they could serve as clinical biomarkers for the disease or treatment response. Moreover, the role of DNA methylation in allergic diseases is also reflected in its response to environmental factors. Environmental factors influence gene expression and susceptibility to allergic diseases by affecting DNA methylation [174]. For example, the association between smoking and allergic diseases such as asthma is partly mediated by changes in DNA methylation [175], and similar mechanisms may exist on the ocular surface. In summary, the role of DNA methylation in allergic diseases is multifaceted; it not only contributes to the pathogenesis and development of these diseases but also offers new perspectives and methods for their diagnosis and treatment. Future research needs to further explore the specific mechanisms of DNA methylation in allergic diseases to develop more effective diagnostic and therapeutic strategies.

Histone modification, a key epigenetic regulatory mechanism, plays an important role in modulating allergic responses by affecting chromatin structure and gene expression levels [176]. The role of histone deacetylases (HDACs) in allergic diseases is particularly prominent. Studies indicate that HDACs regulate cellular processes by removing acetyl groups from lysine residues of target proteins. Small-molecule HDAC inhibitors have produced therapeutic effects on animal models of various inflammatory diseases, but in some cases, they may exacerbate atherosclerosis and weaken host defense capabilities [177]. Furthermore, HDAC1 plays a critical role in allergic reactions; its expression is stimulated by allergens and is associated with increased levels of Th2 cytokines [176]. Changes in histone acetylation are also related to the inhibition of mast cell function and the regulation of food allergy responses. Research has shown that histone deacetylase inhibitors such as trichostatin A (TSA) can alleviate food allergy symptoms by altering transcriptional processes in mast cells, thereby inhibiting IgE-mediated mast cell activation [178]. Additionally, the KAT6A49 inhibitor WM-1119 inhibits IgE-mediated mast cell activation and allergic inflammation by reducing the levels of histone H3 lysine 14 acetylation (H3K14ac) and H3K27ac [179].

In individuals with allergic conjunctivitis, MicroRNAs (miRNAs) modulate the intensity and nature of immune responses by influencing the differentiation, proliferation, and function of immune cells. Studies have shown that miRNAs play a significant role in regulating inflammatory responses, especially in allergic diseases [180]. In individuals with allergic conjunctivitis, miRNAs can affect immune responses by regulating Th2 cell polarization and the release of inflammatory mediators. Specific miRNAs, such as miR-21, miR-146a, and miR-155, have been shown to be upregulated in patients with allergic diseases and are associated with the increased secretion of Th2 cytokines [181]. Furthermore, miRNAs can influence immune cell activation and function by regulating cytokine expression and signaling pathways [182]. The role of miRNAs in allergic conjunctivitis is not limited to intracellular gene regulation but also involves intercellular signaling. Research has shown that extracellular miRNAs can serve as noninvasive biomarkers for disease diagnosis and the prediction of treatment efficacy [183]. Additionally, miRNAs can participate in the pathological process of allergic conjunctivitis by affecting the immune responses of epithelial cells [184]. In summary, miRNAs play multifaceted roles in the immune regulation of allergic conjunctivitis. They not only are potential biomarkers but also may become new therapeutic targets for allergic conjunctivitis in the future. In-depth research into the specific mechanisms of miRNAs in allergic conjunctivitis is expected to provide new insights and approaches for the diagnosis and treatment of this disease. Many studies utilize high-throughput sequencing to identify AC-specific miRNA expression profiles and explore their potential as biomarkers or therapeutic targets. For example, a 2022 study analyzed the miRNA profile in the tears of VKC patients [185].

Although research on the specific mechanisms of lncRNA50s in allergic conjunctivitis is currently limited, the existing studies indicate that lncRNAs play significant regulatory roles in other allergic diseases. For example, in allergic rhinitis (AR), the lncRNA FOXD3-AS1 was found to inhibit endoplasmic reticulum stress and epithelial barrier dysfunction by destabilizing the CHOP mRNA51 [186]. Furthermore, the lncRNA GAS5 is upregulated in exosomes from AR patients and inhibits Th1 differentiation while promoting Th2 differentiation by downregulating EZH252 and T-bet [187]. These studies suggest that lncRNAs may influence the pathological processes of allergic diseases by regulating immune cell differentiation and function. Similar mechanisms may also exist in allergic conjunctivitis. lncRNAs might participate in the onset and development of the disease by affecting the function of conjunctival epithelial cells or the activation of immune cells. Further research needs to focus on identifying and validating specific lncRNAs and their mechanisms of action in allergic conjunctivitis. In summary, the role of lncRNAs in allergic diseases is increasingly recognized, and their potential functions in allergic conjunctivitis warrant in-depth exploration. These findings will not only help reveal the pathological mechanisms of this disease but also provide targets for the development of new therapeutic strategies.

Challenges and Future Prospects

The high heterogeneity of AC requires a change in treatment strategies, shifting from a one-size-fits-all approach to individualized care. In recent years, the development of biologics and small molecule drugs that target key immune pathways has brought precision medicine to the treatment of severe AC, particularly refractory VKC and AKC. To develop the best treatment plans for patients, ophthalmologists need to understand the mechanisms, target populations, and clinical evidence of these emerging therapies (Table 1). Anti-IgE therapy (omalizumab) is one of the earliest biologics used to treat allergic diseases. It blocks the binding of free IgE in serum to the FcεRIs on the surface of mast cells and basophils. This interrupts the allergic cascade at its earliest stage, preventing allergen-induced inflammation [188]. Although omalizumab is not approved for AC treatment, numerous case reports and small studies have demonstrated that it can significantly improve ocular signs and symptoms and reduce reliance on glucocorticoids in patients with refractory VKC or AKC who have significantly elevated total serum IgE levels and have not responded to conventional treatments [189, 190]. Dupilumab (anti-IL-4Rα) is a game-changing drug for treating moderate to severe AC, particularly AKC associated with atopic dermatitis (AD) [191]. By blocking the IL-4Rα receptor subunit common to IL-4 and IL-13, dupilumab can simultaneously inhibit IgE production, eosinophil recruitment, goblet cell hyperplasia, and epithelial barrier dysfunction. Multiple clinical studies and real-world data show that dupilumab significantly improves skin symptoms and effectively alleviates ocular itching, tearing, congestion, and corneal epithelial defect healing in patients with moderate to severe AD and AKC [192–194]. This has become an important treatment option for these patients. Anti-IL-5/IL-5Rα therapy, such as mepolizumab and benralizumab, is one option. These drugs offer a precise approach for patients with severe asthma characterized by eosinophilic infiltration. A key biomarker in clinical selection is peripheral blood eosinophil count. For patients with VKC or AKC and significantly elevated blood eosinophil counts who have not responded well to other treatments, targeting IL-5/IL-5Rα can effectively reduce eosinophil levels. This alleviates eosinophil-mediated corneal toxicity and improves clinical outcomes. Although large-scale randomized controlled trials for AC are limited, existing evidence supports the value of its application in specific patient subgroups [195–198]. JAK inhibitors, such as tofacitinib and ruxolitinib, represent another promising treatment path. Their broad-spectrum inhibition of multiple cytokine pathways makes them potentially effective for treating severe AC with different immune phenotypes. For ophthalmologists, the development of topical JAK inhibitors is particularly appealing. Topical JAK inhibitor eye drops could deliver potent anti-inflammatory and antipruritic effects to the ocular surface with the efficacy of glucocorticoids but without the long-term risks, such as elevated intraocular pressure and cataracts, associated with steroids. Currently, several topical JAK inhibitors are in the clinical trial stage, offering the potential for a safer, more effective, and stronger local treatment option for AC patients [199–202]. Future challenges and opportunities lie in utilizing biomarkers (e.g., IgE, ECP,53 specific cytokines, and alarmins in tears/serum) to precisely select these targeted drugs and achieve "tailor-made" personalized treatment. This would maximize therapeutic efficacy and improve the visual health and quality of life of the millions of AC patients worldwide (Table 2).

Table 1.

Comparison of allergic conjunctivitis subtypes: Clinical features, immunopathologic signatures, and therapeutic approaches

AC Subtype	Key Clinical Features	Key Immunopathologic Signatures	Dominant Immune Cells/Molecules	Recommended/Potential Targeted Therapies
SAC	There is seasonal recurrence of mild to moderate itching, congestion, edema, and tearing without corneal involvement	The predominant reaction is the IgE-mediated type I immediate-phase response, and the inflammation is usually self-limiting	mast cells、IgE、histamine 、PGD2、CysLTs	Antihistamines, mast cell stabilizers, NSAIDs、 AIT
PAC	Perennial attacks are associated with indoor allergens and are usually milder than SAC attacks, but they are persistent	There is persistent low-grade type I hypersensitivity, which is possibly accompanied by a late-phase inflammatory response	Mast cells, IgE, histamine, eosinophils (mild)	Antihistamines, mast cell stabilizers, NSAIDs, AIT, Glucocorticoids (short-term)
VKC	It is severe, chronic, and recurrent. It is more common in children. It involves giant papillary formations and corneal involvement, including punctate erosions, shield-shaped ulcers, and pannus	There is prominent Th2 inflammation, eosinophilic infiltration, neuroimmune imbalance, and epithelial barrier dysfunction	Eosinophils (significantly)、Th2 cells、ILC2s、IL-4/5/13、TSLP、IL-33、NGF	Glucocorticoids, calcineurin inhibitors (CNIs), anti-IL-4Rα (e.g., dupilumab), anti-IL-5, and JAK inhibitors (emerging)
AKC	It is severe, chronic, and progressive. It is more common in adults and is often accompanied by atopic dermatitis and corneal complications, such as scarring, perforation, and vision loss	Severe Th2 inflammation, eosinophilic infiltration, and severe damage to the epithelial barrier function may be associated with Th1/Th17 responses and neuroimmune imbalance	Eosinophils (significantly), Th2 cells, ILC2s, Th1/Th17 cells (possibly), and various inflammatory mediators	Glucocorticoids, calcineurin inhibitors (CNIs), anti-IL-4Rα (such as dupilumab), anti-IL-5, and JAK inhibitors (emerging), More aggressive systemic treatment is needed

Table 2.

Current and emerging targeted therapeutic strategies for allergic conjunctivitis

Therapeutic Class	Example Drug	Mechanism of Action	Key Pathological Target	Clinical Application/Prospects
Anti-IgE	Omalizumab	It combines with serum-free IgE to prevent binding to the FcεRI receptor on mast cells	Block the initiation of the allergic cascade reaction	For high IgE levels (e.g., VKC or AKC)
Anti-IL-4/IL-13	Dupilumab	Block the IL-4Rα receptor common to IL-4 and IL-13	Inhibit Th2 differentiation, IgE production, eosinophil recruitment, and mucin secretion	It is a core therapy for AC dominated by type II inflammation (e.g., VKC or AKC)
Anti-IL-5/IL-5R	Mepolizumab	Reducing eosinophils can be achieved by neutralizing IL-5 or blocking its receptor	Inhibit the maturation, recruitment, and activation of eosinophils	It is potentially applicable to severe AC subtypes with significantly elevated eosinophils
JAK inhibitor	Tofacitinib / Ruxolitinib	Inhibit the JAK-STAT signaling pathway	Broad-spectrum inhibition of multiple cytokine signals, including IL-4, IL-5, IL-13, IL-31, etc	It can be administered orally for refractory AD-related eye diseases, and the development of topical preparations has broad prospects

Currently, the diagnosis of AC primarily relies on the patient’s medical history and clinical signs, and the severity assessment is relatively subjective. More objective and quantitative tools are needed to aid in the diagnosis, grading, monitoring of disease activity, and evaluation of the treatment response. A tear analysis (tear proteomics/cytokinomics), which involves analyzing proteins, cytokines, inflammatory mediators, miRNAs, etc., in tears, holds promise for identifying biomarkers that reflect the inflammatory status of the ocular surface. Impression cytology can be used to examine conjunctival epithelial cell phenotypes (such as goblet cell density and HLA-DR expression) and infiltrating immune cells. In vivo confocal microscopy (IVCM) allows the noninvasive observation of corneal and conjunctival microstructures and assessment of inflammatory cell infiltration, nerve morphology, epithelial barrier status, etc. High-resolution anterior segment optical coherence tomography (AS-OCT) can be used for quantitative assessments of conjunctival edema, giant papillae size, corneal thickness, and lesion depth. The application of these advanced technologies in research is increasing, and they may gradually enter clinical practice in the future.

Environmental control (such as avoiding known allergens, using air purifiers, maintaining indoor cleanliness, and wearing protective eyewear during the pollen season) remains a cornerstone of AC management. Allergen-specific immunotherapy (AIT), including subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), is the only treatment modality capable of altering the natural course of allergic diseases and inducing long-term immune tolerance. AIT has proven effective for patients with allergic rhinitis accompanied by AC, reducing both ocular and nasal symptoms and decreasing medication needs. This conclusion is strongly supported by numerous landmark clinical studies. Large-scale, long-term SCIT studies confirmed significant alleviation of ocular and nasal symptoms in patients with allergic rhinoconjunctivitis during treatment. These studies also demonstrated a reduction in the use of symptomatic medications. More importantly, the studies demonstrated that the efficacy persisted for several years after three to five years of treatment. This truly demonstrates the unique advantage of SCIT in altering the natural course of the disease [203, 204]. Similarly, multiple large-scale, randomized, double-blind, placebo-controlled trials on SLIT have provided solid evidence for treating ocular allergies with AIT. Specifically, standardized SLIT tablets for grass pollen, ragweed, and dust mites have been proven to significantly improve total ocular symptom scores and reduce the need for rescue medications during allergy season. These high-quality clinical data translate the theory of immune tolerance from basic immunology into clinical benefits, reinforcing AIT's position as a first-line etiological therapy [205–213].In recent years, an increasing number of studies have focused on the application of SLIT in patients with isolated or predominantly ocular allergic symptoms, as its convenience and safety profile are superior to those of SCIT. Optimizing AIT regimens (such as selecting appropriate allergens, doses, and treatment durations), exploring new administration routes (e.g., intradermal, intralymphatic, and epicutaneous), and developing more effective and safer vaccine adjuvants or recombinant/modified allergens are research directions in the field of AIT.

Conclusions

Research on allergic conjunctivitis is currently in an era of increased knowledge and technological innovation. Our understanding of the pathogenesis of AC has deepened to include epigenetic regulation, the heterogeneity of cell subpopulations, and fine-tuned interactions within molecular networks, with increasing attention being given to the driving roles of environmental factors (Fig. 3). Therapeutically, precisely targeted biologics and JAK inhibitors have led to revolutionary changes in the treatment of patients with moderate to severe AC, but the scientific exploration of complementary therapies such as traditional Chinese medicine and dietary supplements is also flourishing. The future direction lies in integrating multidimensional information to achieve a precise diagnosis, personalized treatment, and effective prevention of AC. Despite numerous challenges, with the continuous deepening and translation of basic and clinical research, we believe that we can provide better solutions for hundreds of millions of AC patients worldwide, significantly improving their visual health and quality of life.

Table 3.

Key pathogenic mechanisms and therapeutic implications in allergic conjunctivitis

Core Pathological Mechanism	Key Involved Cells/Molecules	Clinical Manifestations/Pathological Features	Therapeutic Targets	Therapeutic Strategies	Notes/Comments
IgE-mediated Type I Hypersensitivity	Mast cells, IgE, histamine, tryptase, PGD2, CysLTs	Immediate-phase symptoms: Intense itching, hyperemia, edema, tearing	FcεRI, H1/H4 receptors, COX, LOX, CysLT1/2 receptors, DP1/2 receptors	Antihistamines, mast cell stabilizers, NSAIDs, leukotriene receptor antagonists, anti-IgE biologics (e.g., Omalizumab)	Core initiation step of AC pathogenesis and the main driver of immediate-phase symptoms
Th2 Cell-dominated Inflammatory Response	Th2 cells, ILC2s, IL-4, IL-5, IL-13, TSLP, IL-33	Chronic inflammation, eosinophil infiltration, giant papillae formation, excessive mucus secretion, tissue remodeling	IL-4Rα, IL-5, JAK-STAT pathway, TSLP, IL-33	Glucocorticoids, JAK inhibitors, anti-IL-4Rα biologics (e.g., Dupilumab), anti-IL-5 biologics (e.g., Mepolizumab)	Key driver of chronic and severe AC; a target for multiple biologics
Eosinophil Activation Damage	Eosinophils, EETs, cationic proteins	Corneal punctate erosions, shield ulcers, corneal scarring, pannus, tissue fibrosis	IL-5, CCR3, IL-5Rα	Glucocorticoids, anti-IL-5 biologics (e.g., Mepolizumab, Reslizumab)	Primary cells causing pathological damage in severe AC such as VKC and AKC
Neuroimmune Imbalance	Sensory neurons, SP, CGRP, NGF, IL-31, PAR-2	Persistent itching, nerve sensitization, nerve proliferation, neurogenic inflammation	H1/H4 receptors, NK1 receptor, TrkA receptor, IL-31R, PAR-2	Antihistamines, neuromodulators (potential), IL-31R antagonists (potential)	Key mechanism explaining chronic itching and symptom persistence
Epithelial Barrier Dysfunction	Conjunctival epithelial cells, TJ proteins	Increased permeability to allergens/pollutants, inflammation amplification, ocular surface dryness	TJ protein repair, epithelial cell regeneration	Barrier repair agents (e.g., hyaluronic acid, trehalose), environmental control, reduction of irritants	The "gateway" for AC onset and an "amplifier" of inflammation
Lipid Mediator Dysregulation	PGD2, CysLTs, PAF, SPMs (e.g., lipoxins, resolvins)	Vasodilation, edema, eosinophil chemotaxis, impaired inflammation resolution	DP2 receptor, CysLT1 receptor, PAF receptor, SPM synthesis pathways/receptors	DP2 antagonists (potential), leukotriene receptor antagonists, SPM supplements/promoters (emerging strategy)	Important regulators of the inflammatory response beyond histamine, representing a new therapeutic direction
Epigenetic Modification	DNA methylation, HDACs, miRNAs, lncRNAs	Abnormal gene expression, dysregulated immune modulation, disease susceptibility	DNMTs, HDACs, miRNAs, lncRNAs	Epigenetic drugs (potential), biomarker development	Explains the mechanism by which genetic susceptibility and environmental factors influence gene expression; has diagnostic and therapeutic potential
Ocular Surface Microbiome Dysbiosis	Ocular surface microbiota	inflammation promotion, impaired barrier function	Microbiome balance	Microbiome modulation (e.g., probiotics, prebiotics—future direction)	An emerging research field that may affect local immune homeostasis
Immune Tolerance Defects	Tregs, IL-10, TGF-β	Uncontrolled immune response, persistent inflammation, disease chronicity	Treg function, IL-10/TGF-β pathway	AIT	A fundamental therapy to alter the natural course of the disease

Fig. 3.

Summary of research progress on the pathogenesis of allergic conjunctivitis. This figure illustrates the current understanding of the pathogenesis of allergic conjunctivitis (AC), presenting a complex network of pathophysiological processes influenced by genetic, immunological, neurological, and epigenetic factors. 1. Epithelial Barrier Dysfunction: The damaged conjunctival epithelial barrier acts as a "gateway" and "amplifier." It makes it easier for allergens and irritants to penetrate and initiate an immune response. The barrier also actively releases alarmins, such as thymic stromal lymphopoietin (TSLP) and IL-33. These alarmins directly activate downstream innate and adaptive immune cells. 2. Immune network imbalance: The core feature is the dominance of type 2 immune responses. Alarmins and allergens jointly activate an immune cell network that includes mast cells, eosinophils, Th2 cells, and ILC2s. These cells mediate the acute and chronic inflammatory manifestations of allergic conjunctivitis (AC) by releasing large amounts of type 2 cytokines (IL-4, IL-5, and IL-13), histamine, and lipid mediators. 3. Neuroimmune imbalance: Inflammatory mediators, such as histamine and tryptase, and cytokines, such as IL-31, directly activate sensory nerve endings, causing itching. At the same time, activated neurons release neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP), which further activate mast cells and create a "neurogenic inflammation," forming a vicious cycle. Additionally, increased nerve growth factor (NGF) leads to neural hypersensitivity and hyperplasia, an important mechanism for chronic and intractable itching. 4. Upper-level regulatory mechanisms: Dysbiosis of the ocular surface microbiota: Changes in the normal ocular surface microbial community may affect the "education" and maintenance of homeostasis of the local immune system, thereby promoting allergic (Th2-biased) responses. 5. Epigenetic modifications: Environmental factors can regulate the expression of key inflammatory genes by altering DNA methylation, histone modifications (e.g., the role of HDACs), and the expression profiles of non-coding RNAs (e.g., miRNAs and lncRNAs). This establishes a connection between genes and the environment, influencing an individual's susceptibility to AC (Table 3)

Abbreviations

AA

Arachidonic Acid

AC

Allergic Conjunctivitis

AD

Atopic Dermatitis

AIT

Allergen Immunotherapy

AKC

Atopic Keratoconjunctivitis

ALX/FPR

Annexin A1 Receptor/Formyl Peptide Receptor

APC

Antigen-Presenting Cell

AR

Allergic Rhinitis

AS-OCT

Anterior Segment Optical Coherence Tomography

CCL

Chemokine (C–C motif) Ligand

CCR

C-C Chemokine Receptor

CGRP

Calcitonin Gene-Related Peptide

ChemR

Chemokine-like Receptor

CNI

Calcineurin Inhibitor

COX

Cyclooxygenase

CRTH2

Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells

CysLT

Cysteinyl Leukotriene

DAG

Diacylglycerol

DC

Dendritic Cell

DHA

Docosahexaenoic Acid

DNA

Deoxyribonucleic Acid

ECP

Eosinophil Cationic Protein

EET

Eosinophil Extracellular Trap

EPA

Eicosapentaenoic acid

EZH2

Enhancer of Zeste Homolog 2

FcεRIs

High-Affinity IgE Receptor

FLG

Filaggrin

GM-CSF

Granulocyte-Macrophage Colony-Stimulating Factor

GPR

G Protein-Coupled Receptor

GWAS

Genome-Wide Association Study

HDAC

Histone Deacetylase

HLA

Human Leukocyte Antigen

H-PGDS

Hematopoietic Prostaglandin D Synthase

IFN-γ

Interferon-gamma

Ig

Immunoglobulin

IL

Interleukin

ILC2

Type 2 Innate Lymphoid Cell

IP3

Inositol 1,4,5-trisphosphate

IVCM

In Vivo Confocal Microscopy

JAK‒STAT

Janus Kinase- Signal Transducer and Activator of Transcription

KAT6A

K(lysine) Acetyltransferase 6A

KIF3A

Kinesin Family Member 3A

lncRNA

Long Noncoding Ribonucleic Acid

LOX

Lipoxygenase

LPS

Lipopolysaccharide

MAPK

Mitogen-Activated Protein Kinase

miRNA

Micro Ribonucleic Acid

mRNA

Messenger Ribonucleic Acid

Mrgprs

Mas-related G protein-coupled receptors

NET

Neutrophil Extracellular Trap

NFAT

Nuclear Factor of Activated T cells

NF-κB

Nuclear Factor-Kappa B

NGF/TrkA

Nerve Growth Factor/ Tropomyosin-related Kinase A

NSAID

Nonsteroidal Anti-Inflammatory Drug

NTR

Neurotrophin Receptor

OSMRβ

Oncostatin M Receptor Beta

PAC

Perennial Allergic Conjunctivitis

PAF

Platelet-Activating Factor

PAR

Protease-Activated Receptor

PGD2

Prostaglandin D2

PL

Phospholipase

rRNA

Ribosomal Ribonucleic Acid

SAC

Seasonal Allergic Conjunctivitis

SCFA

Short-Chain Fatty Acid

SCIT

Subcutaneous Immunotherapy

SLIT

Sublingual Immunotherapy

SP/NK1R

Substance P/ Neurokinin-1 receptor

SPM

Specialized Pro-resolving Mediator

ST

Suppression of Tumorigenicity

Tfh

Follicular Helper T cell

TGF-β

Transforming Growth Factor-beta

Th1

T helper 1

Th2

T helper 2

Th17

T helper 17

TJ

Tight Junction

TLR

Toll-Like Receptor

TNF-α

Tumor Necrosis Factor-alpha

Treg

Regulatory T cell

TRP

Transient Receptor Potential

TSA

Trichostatin A

TSLP

Thymic Stromal Lymphopoietin

TYK2

Tyrosine Kinase 2

VEGF

Vascular Endothelial Growth Factor

VIP

Vasoactive Intestinal Peptide

VKC

Vernal Keratoconjunctivitis

VOC

Volatile Organic Compound

Author Contribution

J. B. and Y.W. wrote the main manuscript text. J. B. and J.Y. provide financial support. L. T. and J. Y. helped revise the manuscript. All authors reviewed the manuscript.

Funding

This work was supported by grants from National Natural Science Foundation of China (82201144, 82171018), the R&D Program of Beijing Municipal Education Commission(KZ20231002543), the Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (PWD&RPP-MRI, JYY2023-6), and the program for Youth Beijing Scholar 2020 (022).

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.