Ocular allergies in 2005

The wide spectrum of ocular allergies includes a variety of conditions affecting the ocular surface and all of its components, namely the conjunctiva, the cornea, the lids and the tear film. These conditions represent a common clinical problem and their treatment is a challenge for ophthalmologists in everyday practice. It is estimated that 10–15% of the general population suffer from this conditon. Furthermore, it is believed that in a small percentage of sufferers, ocular signs and symptoms may induce severe sight-threatening conditions that remarkably worsen quality of life.

The substantial progress of the last 10 years has improved our knowledge in understanding the natural history of allergic eye diseases. As ophthalmologists, we should carefully differentiate between conditions that induce clinical signs and ocular discomfort, but do not generally affect the cornea (seasonal or perennial forms of allergic conjunctivitis). It is also important to be aware of the long standing allergic inflammation and late sequelae induced by the severe forms of vernal and atopic keratoconjunctivitis.

Chronic inflammation with the participation of several inflammatory cells and mediators is the common denominator of all these diseases. Type-2 T-helper (Th2) lymphocytes are predominant in inflamed allergic conjunctival tissues. They are thought to play a prominent role in the development of allergic disorders by producing regulatory and inflammatory cytokines such as [1]:

•	Interleukin (IL)-3 (local differentiation of mast cells and eosinophils)
•	IL-4 (development of mast cells, immunoglobulin [Ig]E synthesis and vascular cell adhesion molecules)
•	IL-13 and IL-5 (development of eosinophils, eosinophil chemotaxic, survival and degranulation)

Mast cells (MCs) have always been regarded as the principal cell involved in the allergic reaction. The well-known effect induced by the crosslinking of IgE antibodies bound to high-affinity IgE receptors by the antigen involves the subsequent release of various preformed (histamine) and newly synthesized mediators that cause immediate MC degranulation. However, it is now known that these cells produce and release several other chemotactic factors, cytokines and chemokines. The cytokines/growth factors detected in situ in human MCs include IL-3, -4, -5, -6, -8, -10, -13 and -16, tumor necrosis factor-α, vascular endothelial growth factor, granulocyte/monocyte-colony forming factor, stem cell factor, nerve growth factor (NGF), fibroblast growth factor-β and macrophage inflammatory protein-1α [2]. Similarly, eosinophils and their toxic proteins are activated and increased in tears, conjunctiva and serum of all allergic eye diseases, and are also responsible for corneal damage in vernal keratoconjunctivitis (VKC). Other inflammatory cells, such as neutrophils, also participate in the allergic response and sustain inflammation through the recruitment of other inflammatory cells and mediators [1,3].

Chemokines and adhesion molecules have been found to exert a greater influence when associated with the selective infiltrate observed in ocular disorders. Chemokines have been shown to specifically attract and activate eosinophils, acting through chemokine receptor (CCR)-3 expressed on these cells. Increased eotaxin-1 and -2 preferentially recruit circulating eosinophils and attract them to the epithelium and subepithelial stroma causing eosinophil degranulation with release of epithelium-damaging proteins. In normal conjunctiva, intercellular cell-adhesion molecule (ICAM)-1 is downregulated and confined to the vascular endothelium. In contrast, ICAM-1/-3 expression is highly increased in active VKC biopsies and is expressed by vascular, epithelial, stromal and inflammatory cells [4–7].

Allergic inflammation is also associated with the release of neuropeptides, mainly substance P, which causes vasodilatation, increased vascular permeability and contributes to further release of histamine from MCs [8].

Growth factors (NGF and tumor growth factor [TGF]-β1) are increased in the blood, tears and tissues of patients with allergic conjunctivitis as well as in other allergic conditions [9,10]. Increased levels of TGF-β1, together with IL-1 and -6, in active VKC tissues and tears may be related to collagen hyperproduction. These data indicate that growth factors are synthesized, released and utilized by MCs, eosinophils and fibroblasts. Furthermore, this data also suggests that NGF and TGF-β1 may be viewed as additional markers of ocular allergic diseases [11].

Tissue remodeling and scarring are the consequences of chronic allergic disorders. Remodeling involves both the production and deposition of extracellular matrix (ECM) components, as well as the degradation and clearance of newly synthesized products. Three main overlapping phases have been identified in tissue response to injury: inflammation, granulation tissue formation (including fibroblast proliferation, migration and differentiation) and remodeling. This physiologic process can result in an exaggerated pathologic process ranging from tissue remodeling to extensive fibrosis. Fibroblasts represent the main target and effector cells of these processes due to their ability to migrate to the injured area, proliferate, produce ECM, differentiate into myofibroblasts and finally contract the tissue. Previously viewed as simple structural cells providing the cellular and ECM scaffold to tissues, fibroblasts are now recognized as regulatory cells exerting active roles in tissue homeostasis by producing cytokines and several growth factors with autocrine/paracrine activities. Vernal and atopic keratoconjunctivitis, the two major ocular allergies, represent clear examples where tissue remodeling plays a prominent role [3,11,12]. Another interesting and newly discovered aspect is the analysis of the ECM in VKC. This demonstrates a reduction in proteoglycans and a substantial increase in total collagen with an altered ratio between collagen Type I and III, due to a consistent increase in collagen Type III. Furthermore, high amounts of procollagens Type I and III in the tears during active tarsal VKC have also been reported. This increased deposition of collagen Types I, III and IV in the giant papillae may be viewed as a result of increased expression of cytokines and growth factors from either eosinophils, MCs and other inflammatory cells that are known to stimulate resident fibroblasts to overproduce ECM. Various growth factors and cytokines, produced by both inflammatory and stromal cells, have been proposed to cause tissue repair. However, the main profibrogenic factor remains TGF-β, which is responsible for the stimulation of ECM formation, the inhibition of its degradation and the chemoattraction of fibroblasts [11–13].

In contrast with these major advances in understanding the pathogenesis of ocular allergies, there are fewer improvements in the therapeutic approaches for these diseases. In fact, safe and effective topical eye drops are now available to treat the most common ocular allergies, such as seasonal or perennial allergic conjuntivitis, however, steroids appear to be the only effective drug for the rarest, most severe vernal and atopic disorders affecting the cornea.

The new generation of triple action topical eye drops with their therapeutic action on MCs, eosinophils and their antihistaminic activity have clearly been shown to improve ocular signs and symptoms in most patients with ocular allergies. Unfortunately, these compounds cannot completely control the severe inflammation of vernal and atopic keratoconjunctivitis. Therefore, these patients require the frequent use of steroid eye drops that may cause ocular side effects of glaucoma and cataract. New and promising agents such as cyclosporin eye drops and antileukotrienes could represent the next generation of antiallergic agents or compounds that could mediate mechanisms that may prove to have a relevant role in the future [14].

Novel immunotherapeutic tools should be directed to different targets including the shift of the ocular allergic response toward a Th1 lymphocyte mediated mechanism and the possible use of cytokine antagonists or growth factors