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Adhesion Molecules and Relationship to Leukocyte Levels in Allergic Eye Disease

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Adhesion Molecules and Relationship to Leukocyte Levels in Allergic Eye Disease Adhesion Molecules and Relationship to Leukocyte Levels in Allergic Eye Disease Annette S. Bacon,1'5 James I. McGill,5 David F. Anderson,13 Susan Baddeley,1 Susan L Lightman,2 and Stephen T. Holgate1 PURPOSE. TO evaluate the conjunctival expression of leukocyte cell adhesion molecules (CAMs) and their relationship to leukocyte patterns on the microvasculature in the different clinical subtypes of allergic eye disease. METHODS. Immunohistochemical analysis, using appropriate monoclonal antibodies, was applied to glycolmethacrylate-embedded biopsies of bulbar and tarsal conjunctival tissue. The proportion of total blood vessels expressing a particular CAM was derived and related to individual cell types identified by cell-specific markers, such as mast cells, eosinophils, neutrophils, T cells, and macrophages. Statistical analysis was used to correlate adhesion molecule expression and, ulti- mately, cell type. RESULTS. There was a basal expression of intercellular adhesion molecule-1 (ICAM-1) (21% bulbar, 18% tarsal), E-selectin (15% bulbar, 21% tarsal), and vascular cell adhesion molecule-1 (VCAM-1) (13% bulbar and tarsal) in normal controls. In seasonal and perennial (bulbar and tarsal conjunc- tival) allergic tissue, ICAM-1 and E-selectin were expressed in 40% to 78% of vessels; in chronic disease, they were expressed in 45% to 80% of vessels; and in vernal giant papillae, they were expressed in as many as 90% of vessels. There was also increased expression of endothelial VCAM-1 in all forms of allergic eye disease; the greatest values were found in vernal giant papillae (64%). Biopsies taken in winter from seasonal sufferers demonstrated a marked reduction in levels of all three CAMs compared with those taken in the pollen season. This is almost consistent with values found in normal conjunctiva. Positive correlations were found between the levels of ICAM-1 and E-selectin expression and the degree of granulocyte and lymphocyte infiltration, although VCAM-1 expression correlated most closely with eosinophil numbers. CONCLUSIONS. Increased levels of cell adhesion molecules on the microvasculature and the factors that regulate them are likely to be responsible for the infiltration of cells bearing their ligands and may perpetuate inflammation in the chronic forms of allergic eye disease. (Invest Ophthalmol Vis Set. 1998;39:322-330) llergic diseases1 of the conjunctiva are a common and ening keratopathy (atopic keratoconjunctivitis [AKC]) or lid heterogeneous group of disorders about which rela- changes (atopic blepharoconjunctivitis [ABC]). Giant papillary A tively little is known. Many atopic persons experience conjunctivitis (GPC) occurs in response to various types of self-limiting and often relatively mild seasonal (seasonal allergic ocular foreign body and has cellular features indicative of a conjunctivitis [SAC]) or perennial symptoms with acute exac- hypersensitivity reaction.1 erbations (perennial allergic conjunctivitis [PAC]). A small Cellular infiltrates characterize allergic conjunctivitis but number of others are more severely affected. Young patients have been reported to differ in quality and intensity between with active vernal keratoconjunctivitis (VKC) may demonstrate the two ends of the disease spectrum. SAC and PAC resemble gross lid involvement with giant papillae formation and the models of a type 1 hypersensitivity response, with well-docu- production of copious stringy mucus; acute pain and photo- mented mast cell degranulation occurring as a prelude to phobia accompany the formation of central corneal ulcers. In symptoms and the finding of high tear and serum levels of total older patients, chronic atopic conjunctivitis, usually in associ- and allergen-specific immunoglobulin E (IgE).2 In contrast, ation with facial eczema, is also characterized by sight-threat- there is increasing evidence that VKC and AKC may result from a more complex immunologic response involving predomi- nantly T lymphocytes, mast cells, and eosinophils.3"5 These From the 'First Medicine Department and the Southampton Eye chronic conjunctival responses are more commonly associated Unit, Southampton General Hospital, Southampton, United Kingdom; 2 with other major atopic disorders, such as asthma and eczema, and the Moorfields Eye Hospital and Institute of Ophthalmology, but the basis for disease severity and chronicity is poorly London, United Kingdom. Supported by the Medical Research Council (MRC) of the United understood. Kingdom grant G90052985B and the Sir Jules Thorne Trust. More is known about the processes involved in selectively Submitted for publication March 4, 1997; revised August 6, 1997; attracting different populations of inflammatory cells to in- accepted November 3, 1997. flamed tissue. Under appropriate inflammatory conditions, Proprietary interest category: N. cells migrate at microvenular sites and begin rolling on the Reprint requests: James I. McGill, Consultant Ophthalmic Sur- 6 geon, Southampton Eye Unit, Southampton General Hospital, Tremona endothelium, as a result of adhesion molecule-ligand bonds Road, Southampton, United Kingdom SOl6 6YD. that form between two resistant shearing forces.7 First, this Investigative Ophthalmology & Visual Science, February 1998, Vol. 39, No. 2 322 Copyright © Association for Research in Vision and Ophthalmology Downloaded from jov.arvojournals.org on 09/25/2021 IOVS, February 1998, Vol. 39, No. 2 Adhesion Molecules in Allergic Conjunctivitis 323 process involves P-selectin,8 a preformed glycoprotein released upper tarsus, and at least one other major atopic disorder. The from Weibel-Palade bodies on the endothelial cell surface VKC group was restricted to patients younger than 16 years within minutes of contact with histamine or leukotrienes from who had itching and mucus discharge, hyperemia, infiltration, activated mast cells.9 The ligand for P- and E-selectin is the papillae of any size, keratopathy, and limbal inflammation. A sialyl Lewis-X family of molecules predominantly expressed on diagnosis of GPC could be made only if the patient had a neutrophils, eosinophils, and monocytes.8 Later E-selectin is history of contact lens wear or exposure to a suture or pros- produced as a result of cytokine-induced gene transcription thesis, conjunctival hyperemia, and large or giant papillae. 10 and protein synthesis. E-selectin (CD62E) is expressed on All patients had active disease requiring treatment, but, for endothelial cells 4 to 6 hours after stimulation with interleu- the purpose of this study, none had been administered topical 1 kin-1/3 (EL-1/3), tumor necrosis factor-a (TNFo!), or interferon-y. ' corticosteroids for at least 3 months, sodium cromoglycate for Intercellular adhesion molecule-1 (ICAM-1) (CD54), a 1 month (except two patients with AKC who had discontinued member of the immunoglobulin superfamily, is expressed with this drug for 1 week only), and either oral corticosteroids or increased intensity on the luminal surface of the vascular en- H^antihistamines for 3 months. All patients gave their in- dothelium 6 to 28 hours after interaction with IL-1/3, TNFa, or formed consent, and the study was approved by the ethical interferon-y.1 '"'3 Its two cellular ligands are the integrins committees of the Moorfields Eye Hospital and the Southamp- LFA-1 (CDlla/CD18) and Mac-1 (CDllb/CD18), present on ton University Hospitals and followed the Declaration of Hel- granulocytes, monocytes, and lymphocytes.14 Subjects with sinki. The history and examination were recorded according to ongoing allergic skin disease express increased amounts of a detailed protocol described previously.26 ICAM-1 and E-selectin on the skin microvasculature.15 After Biopsies were taken in season from 14 patients with SAC exposure to allergen, atopic persons may also be induced to (mean age, 41.8 ± 6.2 years), and 7 subjects (mean age, 26 ± express ICAM-1 and E-selectin on the endothelial surface of the 4.8 years) were biopsied out of season. There were 8 patients 15 16 microvasculature of skin, bronchial mucosa, and conjunc- with PAC (mean age, 35.5 ± 7.3 years), 12 with AKC (mean 17 tiva. age, 38.9 ± 14.1 years), 10 with ABC (mean age, 46.2 ± 16.2 Vascular-cell adhesion molecule-1 VCAM-1 (CD 106) is an years), 10 with VKC (mean age, 21.3 ± 5.4 years), and 8 with additional member of the immunoglobulin superfamily. It is GPC (mean age, 430 ± 99 years). induced late (24-28 hours) after the interaction of TNFa and Controls consisted of nonatopic patients, 12 of whom IL-4 or IL-13 with endothelial cells18 and after allergen chal- were undergoing routine cataract surgery under general anes- lenge is expressed in bronchi by 24 hours.19 Its integrin ligand thetic. These patients were administered only two to four very late antigen-4 (CD29d/CD49) is predominantly expressed drops of 0.5% chloramphenicol prophylaxis before surgery, on T lymphocytes, eosinophils, and basophils.20 Patients with and the conjunctiva was uninflamed. Five controls volunteered perennial rhinitis express increased levels of ICAM-1 and for biopsy under local anesthetic in the absence of other ocular VCAM-1,21 whereas those with steady state asthma express problems. E-selectin, ICAM-1, and VCAM-1 on the bronchial microvascu- lature.19 Conjunctival Biopsy The differential expression of cell adhesion molecules Tissue was biopsied from the central one third of the upper (CAMs) under various inflammatory conditions is thought to be tarsal conjunctiva, using a standard 3-mm trephine, under plain responsible for the preferential
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