Ocular allergy: implications for the clinical immunologist C. H. Katelaris, MD, PhD

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1 Ocular allergy: implications for the clinical immunologist C. H. Katelaris, MD, PhD Background: Allergic diseases of the eye are the most common conditions affecting the external ocular adnexa. The most common forms are primarily IgE-mediated and share features in common with other atopic conditions. Mast cell activation and release of mediators, particularly histamine, are central to the pathogenesis of seasonal and perennial allergic conjunctivitis. These conditions are self-limited without the occurrence of ocular surface damage. In contrast, vernal keratoconjunctivitis and atopic keratoconjunctivitis are complex diseases, involving both early- and late-phase allergic responses. They are characterized by severe chronic immune inflammation with T cell infiltration in the conjunctiva and may be sight-threatening. Objectives: To provide a brief overview of the ocular allergic conditions and summarize the current knowledge of immunopathogenetic mechanisms involved in initiating and driving these conditions. Data Sources: English-language articles were sought from a MEDLINE search from This yielded a number of scientific and review papers exploring recent advances in the understanding of the pathogenesis of the ocular allergic conditions. Conclusions: Recent advances in knowledge about the pathogenetic mechanisms involved in ocular allergy have led to a better understanding of treatment options and to the development of new treatment modalities, resulting in improved control of symptoms for patients. Ann Allergy Asthma Immunol. 2003;90(Suppl 3): INTRODUCTION Allergic diseases of the eye are the most common conditions affecting the external ocular adnexa. The most common forms are primarily IgE-mediated and share features in common with other atopic conditions: strong family history of atopic disease, recurrent episodes, and characteristic symptom complexes. The clinical presentation of the various forms of allergic conjunctivitis can vary greatly, from mild, intermittent symptoms with few signs to severe, vision-threatening conditions. All forms of the condition share in common a number of characteristics, including pronounced itching, a milky conjunctival appearance, stringy or ropy discharge, and, in severe cases, papillary hypertrophy of the tarsal conjunctiva. Ocular allergy presents in a number of forms. Their various manifestations are discussed in order of prevalence. CLINICAL SPECTRUM OF OCULAR ALLERGY Seasonal Allergic Conjunctivitis Seasonal allergic conjunctivitis (SAC) is the most common allergic ocular disease, accounting for approximately 80% of cases. It is most commonly associated with allergic rhinitis but may be the only manifestation of allergy in some individuals. The condition is an example of a classical type 1, immediate hypersensitivity reaction. Clinical presentation includes the cardinal feature of itching, as well as tearing, hyperemia, chemosis, and lid edema. The most common Institute of Immunology and Allergy Research, Westmead Hospital, Sydney, Australia. Received for publication July 23, Accepted for publication in revised form September 16, provokers of SAC are pollens, but other allergens may be responsible, depending on geographical location. Perennial Allergic Conjunctivitis The clinical picture of perennial allergic conjunctivitis (PAC) is identical to that of SAC, only symptoms occur on a year-round basis. The condition is provoked by a wide variety of allergens, but predominantly house-dust mite, animal dander, molds, and some pollens. PAC is more likely to be found in association with allergic rhinitis. Vernal Keratoconjunctivitis Vernal keratoconjunctivitis (VKC) is a chronic, bilateral, inflammatory disease that ranges in severity from mild irritation to severe, sight-threatening disease. 1 The onset of the disease is generally before the age of 10 years, and it is more common in boys with an atopic background at that stage. In later onset disease, there is a preponderance of females. It tends to be aggressive for several years, resolving during the later teenage years. There is a very definite geographic distribution of cases, the condition being more common along the Mediterranean Sea, in west Africa, and in the Middle East. 2 It is unusual in North America, western Europe, and Australia. There is a strong link with atopy; two-thirds of patients have a positive family history of allergy, whereas asthma or eczema is present in three-quarters of those with VKC. Despite its association with atopy, single allergen sensitivity is not the cause of the condition, and the eye symptoms in these individuals do not respond to allergen immunotherapy. Two types of VKC exist. The palpebral form is characterized by large, irregular hypertrophies of the conjunctival lining of the upper lid. There is a predominance of palpebral VOLUME 90, JUNE,

2 disease in the more temperate climates. The limbal form is associated with gelatinous nodules in the corneoscleral junction. Trantas dots, small white opacities full of inflammatory cells, can also be seen at the limbus. Corneal involvement includes development of shield ulcers and neovascularization. The symptoms of VKC vary. In mild disease, there may be slight itching and tearing, whereas in severe disease, there is severe tearing, photophobia, ocular grittiness, and mucus discharge. Corneal changes may result in severe blepharospasm, photophobia, and corneal ulceration. Although the disease tends to be self-limiting, optimal control is vital to prevent the structural changes that may occur, particularly in the cornea. Giant Papillary Conjunctivitis Giant papillary conjunctivitis (GPC) is, strictly speaking, not an allergic disease, but a condition that is the result of mechanical trauma on a background of an allergic diathesis. 3 It is typically associated with soft contact lens wear, 4 but has been reported in patients wearing soft, hard, and rigid, gaspermeable contact lenses, as well as in individuals with ocular prostheses and exposed sutures in contact with the conjunctiva. Those who sleep in disposable lenses are probably three time more likely to be affected than if lenses are removed daily. Patients with hay fever and asthma may be at greater risk for GPC. Symptoms of GPC include an accumulation of mucus in the inner canthus upon awakening, accompanied by tearing, itching, foreign body sensation, blurred vision, and lens intolerance. In its full-blown state, GPC is characterized by the production of giant papillae ( 0.3 mm) on the tarsal conjunctiva lining the upper lids. Atopic Keratoconjunctivitis Atopic keratoconjunctivitis (AKC) is usually seen in the second to fifth decades in those with atopic dermatitis. It is a bilateral, chronic allergic inflammation of the conjunctiva and eyelids. The condition is characterized by severe itching, burning, photophobia, and fissuring of the lateral aspect of the eyelids with scarring of the lids and loss of eyelashes in more severe cases. In rare cases, corneal damage and blindness may occur. Anterior polar cataracts develop in some patients. There is a risk of posterior subcapsular cataracts for those in whom steroids have been used to treat the ocular or skin disease. There is no seasonal exacerbation as ones sees with VKC, nor is there any racial or geographic predilection. 5 IMMUNE MECHANISMS IN OCULAR ALLERGY Over the last decade, our understanding of the mechanisms underlying ocular allergy has greatly increased. Central to the pathogenesis of all the conditions outlined above is mast cell activation and release of the major mediator, histamine. Tearfluid analysis of patients with any of the ocular allergic conditions reveals the presence of histamine and tryptase, a marker of mast cell activation. The essential difference between the more common SAC and PAC, and VKC and AKC, is that the former remain self-limited without ocular surface damage, whereas the latter are characterized by severe chronic immune inflammation with T cell infiltration in the conjunctiva. Allergic reactions in the nose and lungs are characterized by an immediate reaction due to mast cell degranulation and mediator release (early-phase reaction), and this is followed some hours later by cellular infiltration as a result of cytokine release and inflammatory cell recruitment (late-phase reaction). Uniquely, the most common allergic reactions in the eye, SAC and PAC, differ from that seen in the respiratory tract in that there is no progression from early phase to late phase. The reason for this difference is not known. By contrast, patients with the rarer conditions of AKC and VKC will have tissue damage elicited by the late-phase response. The late-phase response is characterized by activation of endothelial cells and leukocytes, both of which express adhesion molecules, and this allows leukocyte migration from the blood vessels to the tissue. Many of the products from the early-phase reaction such as histamine, platelet-activating factor, and leukotrienes will activate endothelial cells, which in turn become sources of cytokines and chemokines. Conjunctival Mast Cells In humans, mast cells are found in great numbers in the normal conjunctiva, which is estimated to contain 12,000/m 3. 6 In the quiescent eye, most are in the substantia propria, whereas in the allergic state they are found in more superficial layers. Neutral proteases are a major constituent of the mast cell secretory granules, the most abundant being tryptase and chymase. Mast cells have been classified according to their neutral protease content. Tryptase-containing human mast cells (MCt) predominate in the mucosa of the nose, lungs, and gut, whereas the predominant mast cell in connective tissue (in the skin and conjunctiva) contains both tryptase and chymase (MCtc). Ocular allergy begins with the development of hypersensitivity to an allergen. Subsequent exposure to the allergen results in cross-linking of IgE on the surface of conjunctival mast cells, triggering a complex series of intracellular biochemical events resulting in the release of preformed mediators from the mast cell granule. Histamine is one of the major preformed mediators and is responsible for many of the signs and symptoms associated with the acute ocular allergic response. Itching is the result of stimulation of H 1 receptors in the conjunctival tissues. Chemosis and lid edema are caused by exudation of plasma from postcapillary venules via H 1 receptors. Erythema is mediated by H 1 and H 2 receptors on blood vessels, as well as by an indirect mechanism via stimulation of nerve endings. Although histamine is very important, it is not the whole story; many other chemicals are released and exert effects. Tryptase has the ability to potentiate the effect of histamine, activate eosinophils and mast cells, and attract eosinophils and neutrophils. Newly formed mediators result from mobilization of phospholipase A 2 that causes the release of arachidonic acid from mast cell membrane phospholipids. A variety of prostaglan- 24 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

3 dins have been identified in ocular tissues. Prostaglandin D 2 is the main prostaglandin released and may be an important mediator in ocular allergy, because when it is applied to the eye, it causes redness, chemosis, and mucus discharge. The leukotrienes LTC 4,LTD 4, and LTE 4 have all been identified in tears after conjunctival challenge. They probably act synergistically with prostaglandin D 2 to enhance vascular permeability. Mast cells are known to produce a wide variety of cytokines, all of which have distinct roles in allergic responsiveness, and many have overlapping functions. Interleukin (IL)-4, IL-5, IL-6, tumor necrosis factor (TNF)-, andstem cell factor have been localized to mast cells in normal and allergic conjunctiva. 7 Macleod et al 8 have shown that IL-4 and IL-13 are preferentially associated with MCtc and IL-5 and IL-6 to MCt subsets, suggesting that differences in protease content may also reflect functional differences as a result of differing cytokine profiles. The combined findings of increased IL-5 in MCt subsets and their increased number in VKC may explain why such an intense eosinophilic reaction is seen in that disease. Mast cells may also induce IgE production by B cells independently of T cell help, a mechanism that may explain the observation of local IgE production in allergic conjunctivitis. 9 Because mast cells play a central role in the development of ocular allergy, mast cell modulation has been a target for the development of antiallergic drugs, particularly mast cell stabilizers. In vitro studies have demonstrated that different mast cell types respond to nonimmunologic stimulation and drugs differently. For instance, although both cutaneous mast cells and conjunctival mast cells share the same phenotype, their secretory responses differ according to which secretagogue is used; both respond to calcium ionophore A 23187, anti-human IgE, compound 48/80, and concanavalin A, but only cutaneous mast cells respond to substance P, demonstrating that in addition to the phenotype, local environment is critical to determining the behavior of various mast cell types. 10 In a similar fashion, antiallergic agents have differing effects on various mast cell populations. Although cromolyn has been shown to be an effective mast cell-stabilizing agent in rodent mast cells in vitro, it is a poor inhibitor of IgE-dependent histamine release from human lung mast cells and shows no inhibition of mediator release from human cutaneous mast cells. 11 Thus, for the study of pharmacologic actions of possible therapeutic agents, it is essential that experiments be performed on mast cells that are species- and tissue-specific. Epithelial Cells There is much experimental evidence to suggest that conjunctival epithelial cells contribute to the pathogenesis of human allergic ocular disease by production of pro-inflammatory mediators. Gamache et al 12 have demonstrated secretion of TNF-, IL-6, IL-8, and granulocyte-macrophage colonystimulating factor from conjunctival cells in response to stimuli. Supernatants from activated mast cells containing TNF- induce intercellular adhesion molecule-1 expression on conjunctival epithelial cells but, although adhesion molecule expression is known to be necessary for eosinophil attachment, eosinophil migration to the site of inflammation needs the direction provided by chemoattractant gradients. Conjunctival and corneal epithelial cells in culture can express very specific eosinophil attractants such as monocyte chemoattractant factors and RANTES. Eosinophils Eosinophil infiltration is the hallmark of allergic ocular disease, and although their presence in the conjunctiva confirms the diagnosis of ocular allergy, their absence does not exclude the diagnosis, as they may be residing in deeper tissues. The number of eosinophils is not significantly increased in SAC, whereas it is in AKC and VKC. Eosinophils are activated by interaction with other inflammatory cells and mediators, and they release basic, highly charged polypeptides including major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin, and eosinophil peroxidase. MBP and ECP are involved in corneal damage that may occur in VKC and AKC. In addition to these unique eosinophil products, eosinophils also release leukotrienes, prostaglandins, cytokines, and chemokines, which promote eosinophil survival and chemoattraction. 6 IMMUNOPATHOLOGY OF VKC The exact mechanisms leading to the development of VKC are not completely understood but almost certainly involve both types I and IV hypersensitivity. Immunohistochemical studies of biopsy specimens of the conjunctiva and cornea have been revealing. Both mast cells and eosinophils are found in larger numbers and more superficially than in SAC. Large numbers of MCtc and eosinophils are found in the epithelium, along with basophils. The substantia propria also contains elevated numbers of MCtc and eosinophilic MBP granules, which are also deposited widely throughout the conjunctiva. Histamine levels are consistently elevated in tears from patients with VKC. This is attributable to the extensive mast cell degranulation and a deficiency in histaminase, the enzyme that breaks down histamine. 13 Tears also contain allergen-specific IgE and IgG antibodies. A unique profile of T cells is found in the biopsy specimens from VKC patients, supporting the type IV contribution. CD4 T-cell clones from specimens of tarsal conjunctiva have helper function for IgE synthesis in vitro and produce IL Fibroblasts from the tarsal conjunctiva can be induced to proliferate by histamine and epithelial-derived growth factor. This may contribute to the sight-threatening possibility in this condition. 15 IMMUNOPATHOLOGY OF AKC AKC is a very serious, sight-threatening form of allergic conjunctivitis. Although the involvement of mast cells, IgE antibody, and eosinophils is similar to SAC or PAC, lymphocyte involvement is probably the cause of its chronicity and VOLUME 90, JUNE,

4 sight-threatening possibilities. Biopsy specimens reveal that mast cells, basophils, eosinophils, and lymphocytes are all elevated in the conjunctiva. In the epithelium, there is goblet cell and epithelial cell proliferation as well as evidence of upregulation of antigen presentation. In contrast to normal tissue, immunohistochemical staining reveals increased RANTES, granulocyte-macrophage colony-stimulating factor, and IL-3. Amplification of the immune response seen in AKC is probably attributable to the increase in CD4 T cells. 16 In the substantia nigra, increased numbers of mast cells are seen, as well as eosinophils and mononuclear cells. There are also increased numbers of fibroblasts and collagen, both of which are important contributors to the sight-threatening aspect of AKC. Tear fluid shows increases in IgE and eotaxin compared with normal tears. 17 IMMUNOPATHOLOGY OF GPC Contact lens deposits in combination with physical trauma may lead to the development of GPC. However, the majority of contact lens wearers do not develop GPC, so additional mechanisms must be involved. There is increasing evidence that suggests that a complex immunologic reaction consisting of both humoral and cell-mediated immunity occurs in those who develop GPC. Regardless of the involvement of immediate hypersensitivity reactions, non IgE-mediated responses definitely contribute to the immunopathology of GPC as is seen with the mixed inflammatory infiltrate. Biopsy studies in normal individuals reveal polymorphs and lymphocytes only in the epithelium. In GPC patients there is a mixed inflammatory infiltrate consisting of mast cells in the epithelium and substantia propria. Ultrastructural studies provide evidence of mast cell degranulation. Eosinophils and basophils are also seen in epithelium and substantia propria. The cellular infiltrate is less pronounced compared with that seen in VKC. A number of differences are seen in the tear fluid of patients with GPC compared with normal individuals. The changes, although less dramatic, are similar to those found in VKC. Evidence of mast cell participation in the process is found in the elevation of tryptase and histamine. Eosinophil degranulation is evident by elevation in ECP and MBP. Participation of the arachidonic acid pathway is seen with increased LTC 4 levels. Montan and van Hage-Hamsten 18 have demonstrated the elevation in ECP seen in both VKC and GPC, although subjects with VKC generally have higher levels. ECP appears to be a useful marker of severity of the condition. It is hypothesized that trauma plays an important role in the development of GPC. Neutrophil chemotactic factors are released from injured conjunctival tissues, as has been demonstrated in an experimental model by Elgebaly et al. 19 This group has also demonstrated elevation of neutrophil chemotactic factors in patients with GPC, but not in asymptomatic lens wearers or normal individuals. For some time it has been considered that leukotrienes may be important mediators in conjunctival inflammation. Sengor et al 20 have indeed shown elevation of LTC 4 levels in the tears of GPC patients even when minimal symptoms are present, suggesting this may be a useful marker for disease prediction. Measurements of complement have been performed, revealing elevated tear C3 and factor B in both VKC and GPC, with evidence that C3 is locally produced in conjunctival tissue. The generation of C 3a anaphylatoxin by nonimmune mechanisms may contribute to basophil and mast cell activation with release of inflammatory mediators. 21 More recent evidence suggests that T cells play an important role in the pathogenesis of GPC. Using immunochemical techniques, Metz et al 22 have investigated the prevalence of T cells and their subsets. They found that in the common allergic diseases, there were increased numbers of T cells in the epithelium and subepithelium of the tarsal conjunctiva when compared with controls. In contrast to controls, there were many more CD4 T cells in both the epithelium and subepithelium. Extending their work on T cell characteristics in chronic allergic conditions, Metz et al 23 have published data on T cell cytokine profiles. Using in situ hybridization to identify cytokine messenger RNA, they have shown increases in IL-3, IL-4, and IL-5 in VKC and increases in IL-3 and IL-4 in GPC, demonstrating a Th 2 -like pattern in the two conditions. In contrast, AKC shows a Th 1 pattern. CONCLUSION The different types of ocular allergy provide a fascinating insight into the various immune mechanisms affecting the conjunctiva. Although these conditions differ in their clinical and histologic appearance, the basic triggering mechanisms are similar. SAC and PAC are classic examples of type 1 hypersensitivity responses. In SAC the condition lasts a few hours and has no associated cellular response. In contrast, VKC and AKC are complex conditions characterized not only by type I hypersensitivity but also type IV responses and are chronic inflammatory conditions, which in their severe form can be sight-threatening. New insights into the immunopathogenetic mechanisms driving the conditions will hopefully lead to the development of more effective pharmacologic agents to control the inflammatory processes involved. REFERENCES 1. Collum LM. Vernal keratoconjunctivitis. Acta Ophthalmol Scand. 1999;77: Leonardi A, Smith LM, Secchi AG. 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