EDITORIAL

ADVANCES AND GAPS IN OCULAR ALLERGIES

AVANCES Y RETOS EN ALERGIAS OCULARES

BONINI S, MD¹

The last decade brought a substantial progress in understanding the pathogenesis of allergic eye diseases. We have learned that the ocular allergic reaction is a chronic inflammation with the participation of several inflammatory cells and mediators. Type-2 T helper 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 IL-3 (local differentiation of mast cells and eosinophils), IL-4 (development of mast cells, IgE synthesis and vascular cell adhesion molecules) and IL-13, IL-5 (development of eosinophils, eosinophil chemotaxic, survival and degranulation (1). Mast cells (MCs) have always been regarded as the principal cell involved in the allergic reaction. In addition to the well known effect induced by the cross-linking of IgE antibodies bound to high affinity IgE receptors by the antigen and the release of various preformed (histamine) and newly synthesized mediators that causes immediate MC degranulation we have now learned that these cells produce and release several other chemiotactic factors, cytokines and chemokines. The cytokines/growth factors detected in situ in human MC include Interleukin (IL)-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-16, tumor necrosis factor-a (TNF-α), vascular endothelial growth factor (VEGF), granulocyte/monocyte-colony forming factor (GM-CSF), stem cell factor (SCF), nerve growth factor (NGF), fibroblast growth factor (β-FGF) and MIP-1α (2). Similarly, eosinophils and their toxic proteins are increased and activated in tears, conjunctiva and serum of all allergic eye diseases and are responsible of corneal damages. Other inflammatory cells such as neutrophils partecipate in the allergic response as well and sustaine the inflammation through the recruitment of other inflammatory cells and mediators (1,3).

Chemokines and adhesion molecules have been found strengthen associated with the selective infiltrate observed in ocular disorders. Chemokines have been shown specifically to attract and activate eosinophils, acting through chemokine receptor-3 (CCR3) expressed on these cells. Increased eotaxin-1 and Eotaxin-2 preferentially recruit circulating eosinophils and attract them to the epithelium and subepithelial stroma causing eosiniphil degranulation with release of epithelium-damaging proteins. In normal conjunctiva, the adhesion molecule ICAM-1 is down regulated and confined to the vascular endothelium. Otherwise, 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, and mainly NGF and TGF-β1 are also found 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-beta 1, together with IL-1 and IL-6, in active VKC tissues and tears might be related to collagen hyperproduction. Taken together, all these data indicate that growth factors are synthesized, released and utilized by mast cells, eosinophils and fibroblasts and may suggest that NGF and TGF-β1 might be view as an additional marker of the ocular allergic diseases (11).

Tissue remodelling and scarring are the consequences of chronic allergic disorders. Remodelling involves both production and deposition of extra cellular matrix (ECM) components, as well as 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 remodelling. This physiologic process can result in in an exaggerated pathological process ranging from tissue remodeling to extensive fibrosis. Fibroblasts represent the main target and effectors 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 2 major ocular allergies represent a clear example where tissue remodelling plays a prominent role (3,11,12). Another interesting and newly discovered aspect is the analysis of the extracellular matrix in vernal keratoconjunctivitis showing 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. Moreover, an high amount of procollagens type I and III in the tears during active tarsal VKC has been also reported. This increased deposition of collagen types I, III and IV in the giant papillae, might be view as a result of increased expression of cytokines and growth factors from either eosinophils, mastcells and other inflammatory cells which are known to stimulate resident fibroblasts to overproduce ECM. Various growth factors and cytokines, produced both by inflammatory and stromal cells have been proposed to cause tissue repair. However, the main pro-fibrogenic factor remains TGF-b , which is responsible for the stimulation of ECM formation, the inhibition of its degradation and the chemo attraction of fibroblasts (11-13).

In spite of these advances in understanding the pathogenesis of ocular allergies there are few aspects that need to be clarified. For instance, the therapeutic approach is now confined to control mediators from mast cells or the mast cell degranulation or to inhibit the activity of eosinophils and eosinophils derived products. At present no drugs are available to shift the ocular allergic response toward a Th1 mediated mechanisms or that could counteract the multifactorials events occurring in ocular allergic diseases. In addition, although we have a clear clinical and physiopathologic concept for each clinic entity included among the umbrella of ocular allergic diseases, the therapeutic approach is similar for the different clinical diseases. Possibly a new and standardized revision of the actual nomenclature could help to word a rationale therapeutic approach. Actually the topical therapy for chronic allergic ocular disorders, imply the use of steroids to quiet the disease and of MCs stabilizers or leukotriens inhibitors, mainly in association with steroid treatment. MC and EOS have been shown to participate in the development of allergic inflammatory disorders and tissue repair/fibrosis by modulating the activities of immune competent cells and of FBs and ECM homeostasis. MC and EOS effects exerted on FBs seems to be related to the production of different mediators and in turn FBs can promote local inflammation either by producing factors responsible for recruitment, adhesion and cell activation (3,14). This would imply that novel immuno-therapeutic tools directed to different targets, including antagonist of some cytokines or growth factors should be studied to develop new strategies in controlling especially MCs activation and EOs recruitment, and Th2 activity.

¹ Professor and Chairman. Department of Ophthalmology. University of Rome Campus BioMedico.
E-mail: S.Bonini@unicampus.it

REFERENCES

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