Development Of Allergic Conjunctivitis Research Articles

A nerve-goblet cell association promotes allergic conjunctivitis through the rapid antigen passage.

The penetration of allergens through the epithelial layer is the initial step in the development of allergic conjunctivitis. Although the pollinosis patients manifest symptoms in minutes after pollen exposure, the mechanisms of the rapid allergen transport remain unclear. In the present study, we found that the instillation of pollen shells rapidly induces a large number of goblet cell-associated antigen passages (GAPs) in the conjunctiva. Antigen acquisition by the stromal cells including macrophages and CD11b+ dendritic cells correlated with the surface GAP formation. Furthermore, a substantial amount of antigen was transported to the stroma during the first 10 minutes of the pollen exposure, which was sufficient for the full induction of an allergic conjunctivitis mouse model. This inducible rapid GAP formation and antigen acquisition was suppressed by topical lidocaine or trigeminal ablation, indicating that the sensory nervous system plays an essential role. Interestingly, pollen shell-stimulated GAP formation was not suppressed by topical atropine, suggesting that the conjunctival GAPs and intestinal GAPs are differentially regulated. These results identify pollen shell-induced GAP as a novel therapeutic target for allergic conjunctivitis.

Clarifying the effect of gut microbiota on allergic conjunctivitis risk is instrumental for predictive, preventive, and personalized medicine: a Mendelian randomization analysis.

Allergic conjunctivitis is an ocular immune disease which affects the conjunctiva, eyelids, and cornea. Growing evidence implicates the gut microbiota in balancing and modulating immunity response, and in the pathogenesis of allergic disease. As a result, gut microbial imbalance could be a useful indicator for allergic conjunctivitis. From the perspective of predictive, preventive, and personalized medicine (PPPM), clarifying the role of gut microbial imbalance in the development of allergic conjunctivitis could provide a window of opportunity for primary prediction, targeted prevention, and personalized treatment of the disease. In our study, we hypothesized that individuals with microbial dysbiosis may be more susceptible to allergic conjunctivitis due to an increased inflammatory response. To verify the working hypothesis, our analysis selected genetic variants linked with gut microbiota features (N = 18,340) and allergic conjunctivitis (4513 cases, 649,376 controls) from genome-wide association studies. The inverse-variance weighted (IVW) estimate, Mendelian randomization (MR)-Egger, weighted median estimator, maximum likelihood estimator (MLE), and MR robust adjusted profile score (MR.RAPS) were employed to analyze the impact of gut microbiota on the risk of allergic conjunctivitis and identify allergic conjunctivitis-related gut microbes. Ultimately, these findings may enable the identification of individuals at risk of allergic conjunctivitis through screening of gut microbial imbalances, and allow for new targeted prevention and personalized treatment strategies. Genetic liability to Ruminococcaceae_UCG_002 (OR, 0.83; 95% CI, 0.70-0.99; P = 4.04×10-2), Holdemanella (OR, 0.78; 95% CI, 0.64-0.96; P = 2.04×10-2), Catenibacterium (OR, 0.69; 95% CI, 0.56-0.86; P = 1.09×10-3), Senegalimassilia (OR, 0.71; 95% CI, 0.55-0.93; P = 1.23×10-2) genus were associated with a low risk of allergic conjunctivitis with IVW. Besides, we found suggestive associations of a genetic-driven increase in the Oscillospira (OR, 1.41; 95% CI, 1.00-2.00; P = 4.63×10-2) genus with a higher risk of allergic conjunctivitis. Moreover, MLE and MR.RAPS show consistent results with IVW after further validation and strengthened confidence in the true causal associations. No heterogeneity and pleiotropy was detected. Our study suggests that gut microbiota may play a causal role in the development of allergic conjunctivitis and provides new insights into the microbiota-mediated mechanism of the disease. Gut microbiota may serve as a target for future predictive diagnostics, targeted prevention, and individualized therapy in allergic conjunctivitis, facilitating the transition from reactive medical services to PPPM in the management of the disease. The online version contains supplementary material available at 10.1007/s13167-023-00321-9.

The protective role of conjunctival goblet cell mucin sialylation

Gel-forming mucins secreted by conjunctival goblet cells have been implicated in the clearance of allergens, pathogens, and debris. However, their roles remain incompletely understood. Here we show that human and mouse conjunctival goblet cell mucins have Alcian blue-detectable sialic acids, but not sulfates in the steady state. Interestingly, Balb/c mouse strain lacks this sialylation due to a point mutation in a sialyltransferase gene, St6galnac1, which is responsible for sialyl-Tn synthesis. Introduction of intact St6galnac1 to Balb/c restores the sialylation of conjunctival goblet cell mucus. Sialylated mucus efficiently captures and encapsulates the allergen particles in an impenetrable layer, leading to the protection of mice from the development of allergic conjunctivitis. Expression of ST6GALNAC1 and sialyl-Tn is upregulated in humans under conditions with chronic stimuli. These results indicate that the sialylated glycans on the ocular mucins play an essential role in maintaining the conjunctival mucosa by protecting from the incoming foreign bodies such as allergen particles.

Pollen shells and soluble factors play non-redundant roles in the development of allergic conjunctivitis in mice

PurposeWe aimed to clarify the role of particulate allergen exposure to the conjunctiva in the development of allergic conjunctivitis. MethodsWe administered ragweed pollen suspension, pollen extract, pollen shell, particulate air pollutants, and their combinations to the mouse conjunctiva five days a week without prior sensitization. Clinical signs were scored. Histological changes, cellular infiltrations, mRNA expressions, lymph node cell recall responses, and serum immunoglobulin levels were assessed. Immune cell-depleting antibodies and ST2 knockout mice were used to investigate the cellular and molecular requirements. ResultsPollen suspension, but not the extract or shell alone, induced robust eosinophilic conjunctivitis, accompanied by a proliferative response of epithelial cells. A combination of pollen extract and shell completely restored eosinophil accumulation. In addition, eosinophilic conjunctivitis was induced by a mixture of particulate air pollutants and pollen extract. Mechanistically, eosinophil accumulation was ameliorated by deficiency of the IL-33 receptor ST2 and abolished by depleting CD4+ T cells. Pollen shells, but not the extract, induced IL-33 release from conjunctival epithelial cells in vivo. ConclusionsOur results indicate the non-redundant roles for the allergens’ particulate properties and soluble factors in the development of allergic conjunctivitis.

Development of allergic conjunctivitis induced by Acanthamoeba excretory-secretory protein and the effect of resolvin D1 on treatment

ABSTRACT Purpose To evaluate whether allergic conjunctivitis (AC) could be induced by Acanthamoeba excretory-secretory protein (ESP) and analyze the therapeutic effect of resolvin (Rv) D1 and antiallergic agents. Methods Human conjunctival epithelial cells (HCVCs) were treated with 10 µg/well of ESP, and Th2 cytokines were measured using real-time PCR. C57BL/6 mice were treated with 10 µg/5 µL of ESP after sensitization, and conjunctivas isolated from the mice were stained with hematoxylin and eosin (H&E) for the analysis of eosinophils and periodic acid–Schiff (PAS) for the analysis of goblet cells. Cytokine levels in the eye-draining lymph nodes (dLNs) and spleens were measured using the enzyme-linked immunosorbent assay (ELISA). Then, the treatment effects of RvD1 and the antiallergic agents (olopatadine, bepotastine, and alcaftadine) on the HCVCs, mouse conjunctivas, dLNs, and spleens were assessed. Results Th2 cytokines were increased in the ESP-treated conjunctival cells. Mouse conjunctivas treated with ESP showed significant infiltration of eosinophils and goblet cells, and the dLN and spleen exhibited increased IL-4, IL-5 and IL-13 levels. All findings were significantly decreased upon treatment with RvD1 and the antiallergic agents. Conclusions Acanthamoeba could be used to establish an animal model of AC, which could be effectively treated with RvD1 or topical antiallergic agents.

Features of Diseases of the Anterior Part of the Eye in Patients after COVID-19

There are quite systematic data of the ophthalmic manifestations in SARS-CoV-2, on the presence of conjunctivitis in patients with COVID-19, as well as on the detection of viruses in the lacrimal fluid and eye tissues. And, although ophthalmic manifestations are considered rather rare for COVID-19 and are not included in the list of important for diagnosis, there is not enough reliable data on the inflammatory processes of the eye’s anterior part and their connection with COVID-19, as well as those arising against the background of the treatment.Purpose. To study the development of inflammatory diseases of the anterior part of the eye in patients who have undergone the new coronavirus infection COVID-19.resu. In the Department of Infectious and Allergic Eye Diseases of the Helmholts National Medical Research Center of Eye Diseases, 88 patients with confirmed transferred new coronavirus infection COVID-19 of varying severity were observed. The main method of laboratory diagnostics is the detection of SARS-CoV-2 RNA in swabs from the nasopharynx, the patient’s sputum. Serodiagnostics of COVID-19 includes the determination of IgG-, IgM-antibodies to SARS-CoV-2 in the blood in an enzyme-linked immunosorbent assay.Results. Acute conjunctivitis associated with COVID-19 is quite rare and is an early sign of the disease. In the complex nonspecific topical therapy of viral conjunctivitis in COVID-19, along with etiopathogenetic systemic treatment, local eye medications with immunomodulatory and antiviral activity should be used. Conjunctivitis during a pandemic may be the only sign of COVID-19. The development of allergic conjunctivitis in COVID-19 is possibly associated not only with the effect of a viral agent, but also depends on the toxic effect of drugs used in the complex treatment of this disease. The increase in the number of patients with episcleritis after the postponed coronavirus infection needs further detailed study, with the analysis of laboratory data from this group of patients and the accumulation of clinical material.Conclusion. Ophthalmic manifestations in COVID-19 are very different, affecting various structures of the eye, occur at different periods — both during the course of the disease and after clinical recovery, and, of course, need further consideration, study and structuring.

Inflammatory-promoting roles of thymic stromal lymphopoietin and interleukin-4 in allergic conjunctivitis mice

Background Researches showed that thymic stromal lymphopoietin (TSLP) is an interleukin-17-like inflammatory factor and plays important roles in the pathogenesis and development of allergic diseases.However, the study whether TSLP plays roles in allergic conjunctivitis is rare. Objective This study was to investigate the expression change of TSLP and IL-4 in ocular surface tissue and cervical lymph node in the mice with allergic conjunctivitis induced by artemisia annua, a common plant in China, and to explore the role of TSLP and IL-4 in the pathogenesis and development of allergic conjunctivitis. Methods Twenty female BALB/c mice aged 6-8 weeks were randomized into normal control group and model group.Antigen solution was prepared using 400 μl extracting solution of artemisia annua pollen with 400 μl antigen solvent.The mouse models of allergic conjunctivitis were established by injection of 50 μl antigen solution in footpad followed by ocular topical administration of extracting solution once a day from day 10 to 12 after injection, and no any intervention was given in the normal control group.The mice were sacrificed and eyeballs were obtained 13 days after modeling, and corneal epithelium, conjunctiva and cervical lymph nodes were harvested for the detection of TSLP mRNA and IL-4 mRNA by real-time PCR.Immunochemistry was employed to assay the expression of TSLP and IL-4 proteins in corneal, conjunctival and subconjunctival tissues. Results Ocular inflammatory signs appeared 0.5 hours after ocular topical administration of extracting solution, including eyelid edema, conjunctival congestion, tears, scratching eyelids, etc.The symptoms lasted for 6-24 hours, with the model successful rate 80%.Real-time PCR indicated that the expression of IL-4 was absent in corneal epithelium in both model group and normal control group.The relative expression levels of TSLP mRNA in the corneal epithelium, conjunctiva and cervical lymph nodes in the model group were more (1.63±0.20) times, (2.71±0.48) times and (1.48±0.05) times than the normal control group, showing significant differences between the two groups (t=4.44, 14.16, 5.01, all at P<0.05). Compared with the normal control group, the relative expression levels of IL-4 mRNA in the model group increased (2.94±0.39) times and (1.74±0.09) times, with significant differences between the two groups (t=9.92, 14.54, both at P<0.05). Immunochemistry assay showed that the expression of TSLP protein in the corneal and conjunctival epithelial cells were enhanced in the model group compared with the normal control group.In addition, an intensive expression of IL-4 protein was seen in subconjunctival tissue in the model group, while the expression of IL-4 was absent in the normal control group. Conclusions TSLP is mainly expressed in the cornea, conjunctiva and cervical lymph nodes of the mice with allergic conjunctivitis, suggesting that TSLP promotes the inflammatory process of cornea and conjunctiva; IL-4 is mainly expressed in conjunctiva, showing IL-4 participates in conjunctival inflammatory process.TSLP and IL-4 play synergistic roles in promoting the inflammatory process of ocular surface in the mice with allergic conjunctivitis, which may be new therapeutic targets. Key words: Conjunctivitis, allergic/immunology; Allergens/adverse effects; Thymic stromal lymphopoietin; Interleukin-4; Epithelial cells, eye; Disease models, animal; Mice, inbred BALB/c

Airborne particulate matter (PM2.5) and the prevalence of allergic conjunctivitis in Japan

ObjectiveExposure to particulate matter less than 2.5μm in diameter (PM2.5) is associated with asthma and respiratory symptoms, but little is known about the influence of PM2.5 on allergic conjunctivitis. The purpose of this study was to examine the association of PM2.5 with outpatient attendance for allergic conjunctivitis. MethodsWe conducted a time-series analysis of the association between outpatient attendance for allergic conjunctivitis and PM2.5 levels from May to July (non-pollen season) and from August to October (the autumnal pollen season) in 2012. Air pollution data (including the levels of PM2.5, oxidants, nitric oxide, nitrogen dioxide, nitrogen oxide, carbon monoxide, methane, non-methane hydrocarbons, and total hydrocarbons) and data on the daily weather conditions (temperature, wind speed, and humidity) were collected at a centrally located monitoring station in Tokyo. We calculated weekly average values for the daily number of outpatient visits, as well as the air pollution and weather data, and used the weekly average values for analysis. ResultsThere was a significant association between the number of outpatient visits for allergic conjunctivitis and the PM2.5 level (r=0.62, p=0.0177) from May to July, while no correlation was found between the number of outpatient visits and any variable assessed from August to November. Multivariate analysis also showed that PM2.5 was a significant predictor of the number of outpatient visits from May to July (odds ratio=9.05, p=0.0463), while there were no significant predictors of the number of outpatient visits from August to October. From May to July, PM2.5 showed a negative correlation with humidity (r=−0.53, p=0.0499). ConclusionsThese findings suggest a possible role of PM2.5 in the development of allergic conjunctivitis during the non-pollen season. This association between PM2.5 and allergic conjunctivitis may have broad public health implications in relation to allergic diseases.

Specific IgE for wheat in tear fluid of patients with allergic conjunctivitis

Context: Allergy to hydrolyzed wheat protein in facial soap has become a major social issue in Japan. It has been reported that the most frequent early symptoms of allergy to hydrolyzed wheat protein in soap are allergic conjunctivitis and rhinitis, while wheat-dependent exercise-induced anaphylaxis can be induced by long-term use.Objective: We evaluated the relation between tear fluid levels of specific IgE for wheat and the features of allergic conjunctivitis.Methods: A prospective, non-randomized, cross-sectional study was conducted in 103 patients with moderate to severe allergic conjunctivitis (allergic group) and 20 age- and sex-matched healthy control subjects (control group). Specific IgE for wheat was measured in tear fluid with an immunochromatography assay, and a skin prick test (SPT) was also performed. Symptoms (sneezing, rhinorrhea, nasal obstruction, ocular itching, and lacrimation) were assessed in each subject along with the activities of daily living (ADL) score and the total ocular symptom score for allergic conjunctivitis. A severity score (0, 1, 2, or 3) was assigned for various changes of the palpebral and bulbar conjunctiva, as well as for limbal and corneal lesions associated with allergic conjunctivitis.Results: The IgE positive rate and specific IgE score were both higher in the allergic group than in the control group (71.8% versus 40.0% and 1.9 ± 0.7 versus 1.4 ± 0.5). A positive SPT for wheat was also more frequent in the allergic group than in the control group (6.8% versus 0.0%). Within the allergic group, patients with a positive SPT had higher specific IgE scores than patients with a negative SPT (3.3 ± 0.5 versus 1.8 ± 0.6, p < 0.001). In the allergic group, the wheat IgE level in tear fluid was correlated with the severity of allergic conjunctivitis symptoms, including ocular itching (r = 0.665), tearing (r = 0.672), and the total ocular symptom score (r = 0.204). Wheat IgE in tear fluid was also correlated with the severity of rhinitis symptoms, including sneezing (r = 0.610), nose blowing (r = 0.640), and nasal obstruction (r = 0.677). Furthermore, the tear fluid wheat IgE score was correlated with five objective features of allergic conjunctivitis (p < 0.05).Conclusions: These results suggest that wheat allergy may be involved in the development of allergic conjunctivitis.

Clinical and Experimental Immunomodulation

Clinical and Experimental Immunomodulation

Roles of CD4+CD25+ T cells in the development of experimental murine allergic conjunctivitis

CD25+ regulatory T (T reg) cells play a suppressive role in experimental autoimmune uveoretinitis as well as experimental airway inflammation but their involvement in the development of allergic conjunctivitis (AC) remains unclear. We therefore investigated whether T reg cells play a role in the development of experimental AC (EC). BALB/c and C57BL/6 mice were actively immunized with ragweed (RW). The mice were treated with an anti-CD25 Ab (PC61) or control normal rat IgG (nrIgG) either 2 days prior to active immunization or during the induction phase (days 0, 2, 4, 6 and 8). Ten days after active immunization, the mice were challenged with RW-containing drops. Twenty-four hours after the challenge, the conjunctivas were harvested for histological analysis of eosinophil infiltration, and the spleens were harvested for cell culture for splenocyte transfer. Cultured splenocytes were transferred into syngeneic mice, and 4 days after the transfer, the recipient mice were challenged with RW. Twenty-four hours after the challenge, conjunctivas were collected for histological analysis. Pretreatment with PC61 did not affect EC in either strain of mice; however, treatment with PC61 during the induction phase significantly suppressed EC in C57BL/6 mice. In contrast, transfer of RW-primed splenocytes from mice treated with PC61 induced EC that was significantly more severe regardless of strain and treatment protocol. The finding that T reg cells play a suppressive role in the development of EC in splenocyte transfer experiments suggests that modulation of T reg cells may be a possible therapy for AC.

Interleukin-4–Mediated Infiltration of Eosinophils into the Conjunctiva and Its Suppression by Interferon-γ

Purpose: Interleukin (IL)-4 is a T helper (Th)2 cytokine that plays an important role in the development of allergic reactions. It has been suggested that IL-4 is responsible for the infiltration of eosinophils into the conjunctiva during the development of allergic conjunctivitis. However, it is still unclear whether IL-4 is able to induce this eosinophilic infiltration on its own. We investigated whether subconjunctival injection of IL-4 can induce eosinophils to infiltrate into the conjunctiva. Methods: Brown Norway rats were subconjunctivally injected with IL-4, eotaxin, or phosphate buffered saline (PBS), and the conjunctivas were harvested for histologic analysis (including immunohistochemistry) 6, 12, 18, and 24 hr later. The harvested conjunctivas were also subjected to reverse transcription-polymerase chain reaction (RT-PCR) analysis to examine chemokine expression. In a separate experiment, the effect of coadministering interferon-γ (IFN-γ) along with IL-4 was examined. Results: The subconjunctival injection of IL-4 induced eosinophil infiltration into the conjunctiva in a dose-dependent manner. IL-4 was as potent as eotaxin. The eosinophilic infiltration started 6 hr after the injection and persisted for up to 24 hr after the injection. Other infiltrating cell phenotypes were noted but were also observed in conjunctivas injected with PBS alone. RT-PCR analysis demonstrated that IL-4 injection did not upregulate chemokine RNA expression in the conjunctiva. Coinjection of IFN-γ suppressed the infiltration of eosinophils into the conjunctiva induced by IL-4 injection. Conclusions: The subconjunctival injection of IL-4 specifically induces eosinophils to infiltrate into the conjunctiva. In addition, IFN-γ in the conjunctiva can counteract this effect of IL-4.

The effect of topically applied secretory leukocyte protease inhibitor on the eosinophil response in the late phase of allergic conjunctivitis

Purpose. This study examined the effects of secretory leukocyte protease inhibitor (SLPI), a protease inhibitor in tears, in allergic conjunctivitis. Methods. Conjunctiva of male Hartley guinea pigs sensitized with ovalbumin were treated with SLPI or the vehicle 10min before antigen challenge or simultaneously. The animals were sacrificed after antigen challenges of 0-24 h duration, and the inhibition of eosinophil conjunctival migration and degranulation by SLPI was analyzed histochemically. The effects of SLPI on mast cell chymase and tryptase were also examined. Results. Treatment of sensitized guinea pigs with SLPI suppressed the conjunctival recruitment and degranulation of eosinophils after antigen challenge for 6 h, inhibiting the development of allergic conjunctivitis. The effects of SLPI were observed at concentrations =0.1µM, with a peak at 5µM. SLPI inhibited chymase in a dose-dependent manner, but had no effect on tryptase. Conclusion. The topical SLPI application may be therapeutic in allergic conjunctivitis.

Measurement of interleukin-4 and histamine in superficial cells of conjunctiva in patients with allergic conjunctivitis.

Interleukin 4 (IL-4) may play a role in the development of allergic disease. We questioned whether IL-4 related phenomenon occurred on the surface of the conjunctiva during allergic conjunctivitis. Ten patients with cedar pollen-allergic conjunctivitis and 10 patients with postsurgical conjunctivitis were enrolled in this study. Cells were collected by brush cytology from the upper palpebral conjunctiva. After the cells were cultured for 24 hours, the levels of IL-4, IgE, and histamine were measured in the supernatants. An ELISA was used for histamine and a highly sensitive sandwich ELISA for IL-4 and IgE. Conjunctival cells were also stained and fixed by May-Grunwalds stain solution. The number of superficial cells, especially lymphocytes, were compared in the two groups. The total number of cells collected by brush cytology did not differ in allergic vs., postsurgical conjunctivitis. Lymphocytes were similarly present in such specimens. The levels of IL-4 (p = 0.01) and histamine (p = 0.02) significantly increased in the specimens from patients with allergic conjunctivitis, although IgE was not detected in both groups. There was a correlation between the level of IL-4 and histamine (p = 0.0001). Conjunctival cells in allergic conjunctivitis produced a larger amount of IL-4 and histamine for cedar pollen compared to the postsurgical conjunctivitis. As with other allergic diseases, IL-4 may play a role similar to that of histamine in the development of allergic conjunctivitis.

Respiratory syncytial virus and allergic conjunctivitis

The pathogenesis of allergic conjunctivitis is largely conjectural. We investigated the possible involvement of respiratory syncytial virus (RSV), a ubiquitous respiratory pathogen, in the development of allergic conjunctivitis through immune mechanisms. A new technique of brush cytology was used to obtain conjunctival cells from 30 patients with allergic conjunctivitis and 20 control subjects. Samples were assayed for the presence of RSV sequences with the reverse-transcription polymerase chain reaction and the nested polymerase chain reaction. Specific primers and inner primers were synthesized on the basis of RNA sequences previously identified. RSV sequences were detected in 7 of 30 (23%) patient samples and 1 of 20 (5%) control samples. Our results proved that polymerase chain reaction could detect RSV sequences in conjunctival samples. RSV may be a significant pathogenic factor in allergic conjunctivitis. (J A LLERGY C LIN I MMUNOL 1995;95:663-7.)

Respiratory syncytial virus and allergic conjunctivitis.

The pathogenesis of allergic conjunctivitis is largely conjectural. We investigated the possible involvement of respiratory syncytial virus (RSV), a ubiquitous respiratory pathogen, in the development of allergic conjunctivitis through immune mechanisms. Brush cytology technique was used to obtain conjunctival cells from 30 patients with allergic conjunctivitis and 20 controls. Samples were assayed for the presence of RSV sequences with the reverse transcription polymerase chain reaction (RT-PCR) and the nested polymerase chain reaction (nested PCR). In order to further investigate the relation of RSV and allergic conjunctivitis, we performed an animal study. BALB/c mice were either infected with live RSV or sham infected intranasally. The mice were exposed to ovalbumin (OVA) with alum adjuvant. At differing intervals, levels of OVA concentration in serum and IgG-anti-OVA antibody were measured by ELISA and IgE-anti OVA antibody in serum was assessed by passive cutaneous anaphylaxis. RSV sequences were detected in 7 (23%) of 30 patient samples and 1 (5%) of 20 control samples. IgG and IgE antibody responses to OVA in serum were demonstrable only in RSV-infected mice immunized with OVA and alum. Our results proved that PCR could detect RSV sequences in conjunctival samples. RSV may be a significant pathogenic factor in allergic conjunctivitis.