Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Uveitis and Immunological Disorders_Pleyer, Forrester_2004

Foster, C. Stephen, MD

Professor of Ophthalmology

Massachusetts Eye & Ear Infirmary,

Harvard Medical School,

243 Charles Street,

Boston, MA 02114-3069, USA

Gordon, Lynn K., MD, PhD

Jules Stein Eye Institute,

100 Stein Plaza,

Los Angeles, CA 90095, USA

Heiligenhaus, Arnd, Prof. Dr.

St. Franziskus Hospital,

Hohenzollernring 74,

48145 Münster, Germany

Herbort, Carl P., MD, PD, MER Professor of Ophthalmology Department of Ophthalmology, University of Lausanne,

La Source Eye Centre, 2 Ave. des bergieres,

Lausanne 1004, Switzerland

Keitzer, Rolf, Dr.

Otto Heubner Center for Paediatric and Adolescent Medicine, Augustenburger Platz 1,

13353 Berlin, Germany

Kim, Alisa, MD

Jules Stein Eye Institute,

100 Stein Plaza,

Los Angeles, CA 90095, USA

Knop, Erich, Prof. Dr.

Augenklinik Charité,

Campus Virchow Klinikum,

Augustenburger Platz 1,

13353 Berlin, Germany

Knop, Nadja, Dr.

Augenklinik Charité,

Campus Virchow Klinikum,

Augustenburger Platz 1,

13353 Berlin, Germany

Kötter, Ina, Dr.

Universitäts-Augenklinik,

Schleichstraße 12,

72076 Tübingen, Germany

Lambiase, Alessandro, MD

Laboratory of Ophthalmology, Interdisciplinary Centre

for Biomedical Research (CIR),

“Campus Bio-Medico”, University of Rome, Rome, Italy

LeHoang, Phuc, MD, PhD

Professor of Ophthalmology Department of Ophthalmology, Pitié-Salpêtrière Hospital,

47 Bd. de l-Hôpital, Paris 75013, France

Levinson, Ralph D., MD

Assistant Professor of Ophthalmology

Jules Stein Eye Institute,

100 Stein Plaza, UCLA,

Los Angeles, CA 90095, USA

Mantovani, Alessandro, MD

Division of Ophthalmology,

Ospedale Valduce, Como, Italy

Micera, Alessandra, MD Interdisciplinary Centre

for Biomedical Research (CIR), Laboratory of Ophthalmology,“Campus Bio-Medico”, University of Rome, Rome, Italy

Mondino, Bartly, MD

Professor of Ophthalmology

Jules Stein Eye Institute,

100 Stein Plaza,

Los Angeles, CA 90095, USA

Muna, Ahmed, MD

Ocular Immunology and Uveitis Service,

Department of Ophthalmology,

Harvard Medical School,

243 Charles Street, Boston, MA 02114, USA

Pflugfelder, Stephen C., MD

Biological Sciences, Allergan Inc.,

2525 Dupont Drive, Irvine, CA 92612, USA

|Core Messages

∑Allergic conjunctivitis is inflammation of the ocular surface with IgE, cells, cytokines and mediators

∑Several chemokines/adhesion molecules, cytokines and neuropeptides are detectable in situ in allergic conjunctival tissues

∑Growth factors, and mainly nerve growth factor (NGF) and transforming growth factor b1 (TGF-b1), are also found to be increased in the blood, tears and tissues of patients with allergic conjunctivitis

∑A significant correlation is observed between plasma levels of NGF and the increased number of mast cells (MCs) and eosinophils (EOSs) in the tarsal and bulbar vernal keratoconjunctivitis (VKC) conjunctiva

∑Fibrosis can be observed in the conjunctiva of VKC (giant papillae formations) as a consequent manifestation of allergy

∑Overproduction and deposition of collagens and tissue remodelling in VKC may be due to imbalance of matrix metalloproteinases and their physiological inhibitors

∑Various growth factors (NGF, TGF-b1) and cytokines, produced by both inflammatory and stromal cells, have been proposed to cause tissue repair

∑VKC and atopic keratoconjunctivitis (AKC) diseases can compromise the cornea, with ulcers and scarring ultimately leading to visual loss

1.1 Introduction

Allergy or type I hypersensitivity is an immunoglobulin E (IgE) driven reaction that can take place in different organs. The effector phases of IgE-associated immune responses occur in three temporal patterns: (1) an acute reaction, which develops within seconds or minutes after allergen exposure; (2) a late phase reaction, which develops within a few hours after allergen exposure; and (3) a chronic inflammatory response, which can persist for days, months or years [1]. Allergic inflammatory disorders may result in ocular surface allergy, and in most cases ocular allergy is associated with other systemic allergies such as rhinoconjunctivitis [1]. The immunopathogenic mechanisms in allergic disorders involve a combination of IgE-mediat- ed and T-cell-mediated responses. Type-2 T- helper lymphocytes are predominant in inflamed allergic conjunctival tissues [2]. They are thought to play a prominent role in the development of allergic disorders by producing regulatory and inflammatory cytokines such as interleukin (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 and IL-5 (development of eosinophils, eosinophil chemotaxic, survival and degranulation) [1]. The IgE-medi- ated conjunctival allergic reaction can be reproduced easily by specific conjunctival provocation, which induces an early reaction followed by a predominant infiltration of eosinophils (EOSs) and mast cells (MCs), which are thought to play a pivotal role in disease pathogenesis [3]. EOSs and their proteins (ECP) are increased

and activated in tears and tissues of all allergic eye diseases even though the mechanisms of EOS recruitment to the ocular surface are not completely understood [4]. Tear fluid has also been found to contain a small quantity of histamine and tryptase [5], well-known products of MCs [1]. Interestingly, the conjunctival epithelium has also been considered to play a key role in ocular allergic disorders [6].

1.2

Chronic Allergic Eye Diseases

Chronic allergic ocular disease encompasses several disorders, such as seasonal atopic conjunctivitis, perennial atopic conjunctivitis, atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC) [7]. Seasonal atopic conjunctivitis (SAC) is a time-limited disease and in most cases conjunctivitis is only one manifestation of additional allergic reactions (rhinitis, hay fever or a hay fever like symptomatology, and in severe cases conjunctivitis is associated with different forms of pulmonary affection). Atopic keratoconjunctivitis is a severe, bilateral, ocular allergic disease affecting adults. A familial history for atopy and an association with systemic atopic dermatitis are common. Symptoms commonly include itching, burning,and tearing. Signs include involvement of mainly upper conjunctiva in the form of a papillary conjunctivitis. The corneal epithelium reveals mild to moderate inflammatory changes that can result in scarring and neovascularization leading to blindness. Many patients may develop associated staphylococcal blepharitis. Ocular complications include blepharoconjunctivitis, cataract, ocular herpes simplex and keratoconus. Vernal keratoconjunctivitis is essentially a chronic recurrent seasonal childhood disease (worldwide spread, especially in countries around the Mediterranean basin),which in approximately half the children’s population is associated with other allergic manifestations [8]. Unlike severe AKC, VKC tends to resolve spontaneously after several years. Genetic studies have not been performed that confirm a relationship of VKC with a particular genotype. The disease is mostly seasonal, lasting from the

beginning of spring (marked exacerbation of clinical symptoms) until autumn/winter (milder symptoms), even though for children the disease remains variably active the year around. Nevertheless, perennial cases that are persistent throughout the year are not rare, especially in patients living in warm subtropical or desert climates. Its predominance during the high pollen season highly strengthens the widely accepted hypothesis that VKC is an immunologically mediated hypersensitivity reaction to environmental antigens. The characteristic features of the two clinical forms of VKC, the giant papillae on the upper tarsal conjunctiva (tarsal VKC) or the gelatinous limbal infiltrates (limbal VKC), leave no doubt as to the diagnosis of vernal disease. All VKC forms are characterized by intense itching, tearing, mucous secretions and a severe photophobia that often forces children to live virtually in the dark. The commonly noted foreign body sensation is caused by conjunctival surface irregularity and copious mucous secretions, while the presence of pain is indicative of a compromised cornea, which can be present in the form of a superficial punctate keratitis, epithelial macroerosions or ulcers and plaque. According to the other allergic conjunctivitis, pronounced infiltration of lymphocytes, mainly of the Th2 subtype, EOSs and MCs has been reported for VKC [4, 6, 9]. In particular, Th2-derived IL-4 and IL-13, essential to IgE antibody production in tissue eosinophilia and asthma airway remodelling [1], have been reported in tears of both VKC and AKC as well as in patients with SAC,VKC and AKC, respectively [10].

1.3

Effector Cells and Cytokine Release

Allergic conjunctivitis is due to direct exposure of the ocular mucosal surfaces to environmental allergens. The pathogenesis of allergic conjunctival disorders is multifactorial and not fully understood. Ragweed represents the primary responsible allergen (75% of cases of rhinoconjunctivitis). Conjunctival symptoms include itching, tearing, and perhaps burning. Clinical examination may reveal various forms of im-

munologic reaction, all of these presenting as various forms of “red eye”. Photophobia and blurred vision may also occur. Clinical signs include milky or pale pink conjunctivae with vascular congestion, which may progress to conjunctival swelling (chemosis). The immunology hypersensitivity reactions include mast cell degranulation, eosinophils, and other inflammatory cells and modulators. The hallmark and effector cells of allergic phenomena are mast cells and eosinophils.

Mast cells (MCs) are bone-marrow-derived tissue cells containing prominent cytoplasmic granules. They have a clear and pivotal role in allergy, but also take part in wound healing and native immunity [11]. In type I hypersensitivity reactions,MCs elicit the early stages of the allergic inflammatory response. In fact the crosslinking of IgE antibodies bound to high-affinity IgE receptors by the antigen and the release of various preformed (histamine) and newly synthesized mediators causes immediate MC degranulation. In addition, the later release of chemiotactic factors, cytokines and chemokines, from activated MCs also induces the onset of the late-phase reaction, characterized by tissue infiltration and activation of various inflammatory cells and notably the eosinophils. The cytokines/growth factors detected in situ in human MCs include interleukin (IL)-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-16, tumor necrosis factor-a (TNF-a), vascular endothelial growth factor (VEGF), granulocyte/monocytecolony forming factor (GM-CSF), stem cell factor (SCF), nerve growth factor (NGF), fibroblast growth factor (b-FGF) and MIP-1a [12]. In particular, by releasing IL-5, GM-CSF, TNF-a, and tryptase, MCs promote eosinophil recruitment, activation and survival into the tissue [12].

Eosinophils (EOSs) are blood granulocytes produced in the bone marrow under the influence of IL-3, IL-5 and GM-CSF that infiltrate the tissues in various pathological situations, such as parasitic infections, allergic inflammation and neoplastic diseases [13]. EOSs possess cytoplasmic granules that, among non-EOS-specific mediators, contain characteristically preformed basic proteins, namely EOS peroxidase (EPO), EOS-derived neurotoxin (EDN), major basic

protein (MBP), and EOS cationic protein (ECP). Recently, it has been reported that EOSs maintain their ability to release ECP even after repeated stimulation, implying that mature EOSs may not require a significant ECP resynthesis [14]. In addition, their secretory granules contain several preformed cytokines such as GMCSF, IL-2, IL-6, IL-4, IL-5, transforming growth factor b (TGF-b),NGF and TNF-a. The presence of EOSs in inflammation and allergy has been recognized as the critical element inducing the inflammatory process and causing tissue damage, even though more recently EOS presence has also been associated with tissue repair. Another recent observation is that an MC-EOS cross-talk exists that may amplify the local allergic inflammatory response [12]. MCs enhance EOS survival and functional activity by TNF-a and tryptase and EOSs cause histamine, GM-CSF and PGD2 release from MC by MBP and SCF. Moreover, other mediators such as GM-CSF, IL-3, g-IFN and NGF also take part in this cellular cross-talk [12]. Early studies have shown a role for different growth factors in the growth and survival of both MCs and EOSs [12].

1.4

Chemokines and Adhesion Molecules

Chemokines and adhesion molecules have been found to strengthen associated with the selective infiltrate entity observed in these ocular disorders, controlling the specific cell recruitment in the conjunctiva [15, 16]. Chemokines have been shown specifically to attract and activate EOSs [17], acting through chemokine receptor-3 (CCR3) expressed on EOSs [17]. Increased eotaxin-1 and eotaxin-2 (a recently discovered chemokine that is functionally very similar to eotaxin-1) preferentially recruit circulating EOSs,attracting them to the epithelium and subepithelial stroma and inducing EOS degranulation with release of epithelium-damag- ing proteins [17]. A recent study showed that cultured conjunctival FBs produce eotaxin-1 in response to IL-4, IL-13 and TNF-a, strongly supporting the hypothesis of a real contribution of FBs in allergic status [18]. These EOS-derived

compounds have been shown to be highly concentrated in tears of all allergic patients, likewise representing a diagnostic marker, mainly localized in corneal ulcers and highly toxic to corneal epithelial cells. In normal conjunctiva, the adhesion molecule ICAM-1 is downregulated and confined to the vascular endothelium. Otherwise, ICAM-1/-3 expression is highly increased in active VKC biopsies and not confined to the lower levels, but expressed by vascular, epithelial, stromal and inflammatory cells [19]. ICAM-1 is necessary to monocyte, lymphocyte and neutrophil adhesion to activated endothelium. Several proinflammatory cytokines contribute ICAM-1 induction [19].

1.5

Neuropeptide and Growth Factor Involvement

Allergic inflammation might also follow the release of neuropeptides, mainly substance P, as observed in VKC [20], which cause characteristic features of allergic inflammation, including vasodilatation, increased vascular permeability and a contribution to further release of histamine from MCs. Specifically, tryptaseand his- tamine-releasing factors might greatly contribute to SP release and to amplifying the chronic allergic reaction, triggering nerves to release neuropeptides by binding to proteaseactivated receptors.

Fig. 1.1. A possible cross-talk between mast cells (MCs),eosinophils (EOS) and fibroblasts (FBs) during the early and late phase of allergic reactions. MCs and EOS effects exerted on FBs seem to be related to the release of either fibrogenic or fibrolytic mediators in-

fluencing tissue repair/fibrosis. Furthermore, FBs influenced MCs and EOS by increasing their survival and functional activity and contributing to the local inflammation

Growth factors, and mainly NGF and TGF-b1 [21], are also found increased in the blood, tears and tissues of patients with allergic conjunctivitis. NGF involvement in allergic disorders was postulated after the discovery of an increased NGF plasma level in patients with VKC, which correlated with increased total IgE levels and ECP [22]. A significant correlation was also observed between plasma levels of NGF and the increased number of MCs and EOSs in the tarsal and bulbar VKC conjunctiva [22]. The discovery of the increased NGF plasma levels in VKC prompted the investigation of the presence of NGF in other allergic rhinoconjunctivitis [23]. The fact that NGF levels correlated with total IgE antibody titre strengthens support for the hypothesis of a link between NGF and an allergic response in the visual system [24].Additional evidence of an involvement of NGF and NGF receptors in allergic ocular disorders has come from a newly described ocular allergic condition, named inflamed juvenile conjunctival nevus (IJCN [25]). In the conjunctiva of IJCN patients increased EOSs and MCs have been found to synthesize and release NGF as well as express its specific receptor [25]. The increase in the local NGF expression has been correlated to an incremented number of MCs and EOSs [25]. TGF- b1 has been reported in several active VKC patients, mainly as a source of EOSs, without significant differences between the tarsal and the limbal forms [26]. Increased levels of TGF- b1,together with IL-1 and IL-6,in active VKC tissues and tears indicate a local production of these cytokines, mainly of EOS derivation [26]. Moreover, these increased levels of TGF-b1, IL-1 and IL-6 might be related to collagen hyperproduction [26]. Taken together, all these data indicate that growth factors are synthesized, released and utilized by MCs, EOSs and FBs, and that NGF and TGF-b1 might be viewed as an additional marker of ocular allergic conditions as a result of their relevant association with allergic ocular disorders (Fig. 1.1).

1.6

Tissue Remodelling

and the Contribution of Fibroblasts

Tissue remodelling and formation of giant papillae are some of the consequences of chronic allergic disorders,including the eye [1,21]. Remodelling involves both production and deposition of extracellular matrix (ECM) components, as well as degradation and clearance of newly synthesized products [21].Any inflammatory reaction can induce tissue damage and a resulting healing process, which is a very complex event involving interactions of both inflammatory and structural cells [1]. Three main overlapping phases have been identified in tissue response to injury, which can continue for months to years: inflammation, granulation tissue formation – including fibroblast (FB) proliferation,migration,differentiation and remodelling. This process can be physiological and well balanced or can result in an exaggerated pathological process, which includes remodelling and/or fibrosis [21]. FBs 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 (myoFBs) and finally to contract the wound [21]. Previously viewed as simple structural cells providing the cellular and ECM scaffold to tissues, FBs are now recognized as regulatory cells exerting active roles in tissue homeostasis,by producing cytokines and several growth factors with autocrine/paracrine activities [12]. Several in vitro studies suggest that myoFBs may play a role in fibrosis, remodelling, and repair processes associated with IgE-medi- ated hypersensitivity, at least in other organs where chronic allergic conditions might develop [21]. MyoFBs are specialized cells thought to rise locally from FBs and displaying the contractile protein a-smooth muscle actin (a-SMA). MyoFBs represent the main transient cellular phenotype responsible for wound contraction and their deletion, via apoptosis, or as recently hypothesized via their phenotypical reversion to FBs, is necessary to terminate successfully the repair process.Although somewhat controversial, prolonged survival of myoFBs