MSc In Clinical Optometry: Principles Of Therapeutics, Unit 2 Part 2: Ocular Immune System PDF

MSc in Clinical Optometry: Principles of Therapeutics Unit 2: Part 2 OCULAR IMMUNE SYSTEM Description: This part will focus on the immune defence mechanisms of the eye and discuss the role of the immune system in the pathogenesis of specific ocular disorders Hours: Eight Learning outcomes Following...

MSc in Clinical Optometry: Principles of Therapeutics Unit 2: Part 2 OCULAR IMMUNE SYSTEM Description: This part will focus on the immune defence mechanisms of the eye and discuss the role of the immune system in the pathogenesis of specific ocular disorders Hours: Eight Learning outcomes Following successful completion of this module you should be able to:  Describe the innate and adaptive immune defence mechanisms that protect ocular tissues from pathogens  Discuss how specific immune defence mechanisms protect the eye against bacteria and viruses  Describe the immune mechanisms that lead to tissue damage in specific disorders of the eye and adnexa Introduction The first part of Unit 2 concentrated on the complex immune defence mechanisms that protect the body from pathogens. The specific characteristics of any immune response depend on whether the pathogen is intracellular or extracellular and its specific location within the body. The following chapter will describe in greater detail the immune defence mechanisms of the eye and discuss the role played by the immune system in the pathogenesis of specific ocular disorders. Immune privilege regional lymph nodes, provides the primary site for the The normal eye maintains immune privilege, which is initial immune response to intraocular antigens. hypothesised to be an evolutionary adaptation that serves to protect the eye. Sites of immune privilege 3. Cells lining the anterior chamber and (e.g. cornea, anterior chamber) exert limited subretinal space synthesise substances that inflammatory responses and modified innate and actively contribute to the immunosuppressive adaptive immunity. The factors that contribute to ocular microenvironment immune privilege include: These cells interact with the immune system to induce unusual suppression of the systemic immune system 1. Blood ocular barrier response to an antigen introduced into the eye. This is Fluid compartments of the eye (aqueous humour and known as Anterior Chamber Associated Immune vitreous) are separated from blood by zonula occludens Deviation (ACAID). junctions between endothelial cells in the blood vessels of the iris and retina and between epithelial cells of the The cornea and conjunctiva are exposed to the ciliary body and retina. The barriers restrict blood-born environment and are under constant assault from molecules and cells that participate in innate and foreign antigens. In defence, the temperature of the adaptive immunity from entering the eye. central cornea inhibits certain microbes and blinking mechanically removes antigens coupled with irrigation 2. Absence of lymphatic vessels by tears. Furthermore, the intact epithelial surface No patent lymphatic vessels have been demonstrated in prevents the influx of pathogens and the tears irrigate the anterior chamber, vitreous cavity or retina in the eye. mammals. The aqueous humour drains via the trabecular meshwork into the canal of Schlemm and Ocular immune response venous system instead of the lymphatic system. As well as the mechanisms that limit immune cell entry Antigen and APCs travel in the blood stream to the and induce immune suppression, the eye also contains spleen. As a consequence, the spleen, rather than active immune cells that detect foreign antigens. The Ocular Immune System study of the ocular immune response can be separated Conjunctiva along the major anatomical boundaries: The conjunctival immune system forms the conjunctival Mucosa Associated Lymphoid Tissue (MALT). A main  The ocular surface, including the conjunctiva player in the conjunctival epithelial immune response is and cornea the Langerhans cell, together with T and B cells. The  The collagen rich sclera Langerhans cell phagocytose the infectious or non-  The vascular uvea and the intraocular fluids infectious antigens and presents them on its surface in  The neural retina and retinal pigment the draining lymph nodes to activate other immune epithelium cells. The lateral part of the conjunctiva drains to the  The extraocular contents of the orbit preauricular lymph nodes and the nasal part to the sub- mental lymph nodes. In the sub-epithelial layer of the The following five sections will discuss in greater detail conjunctiva B and T cells are present, together with the typical immunological characteristics of each ocular PMNs, eosinophils and mast cells. In certain types of tissue and specific disorders will also be discussed. chronic infection, the lymphocytes aggregate in the subepithelial layer forming follicles (Figure 1). Tear film The tear film contributes in four different ways to ocular surface defence: (i) the tear film and the mucin glycoproteins (which are secreted by conjunctival goblet cells), trap microorganisms and form a mechanical barrier, (ii) the regular washing of the ocular surface by the tears and the action of blinking removes trapped bacteria and foreign particles, (iii) tears contain polymorphonuclear leucocytes (PMN) and (iv) the tear film contains many antibacterial proteins. Among these proteins sIgA, IgG, and IgE antibodies, lysozyme, lactoferrin, transferrin, ceruloplasmin and complement are the most important (Table 1). Protein Function Ceruloplasmin Role in free radical removal. Blepharitis is a very common problem in which there is The complement pathway involves a combination of infection and inflammation around the several complement factors. The lashes, meibomian glands and tarsal conjunctiva. Complement classical complement pathway leads Experimental models of this disorder have implicated to cell lysis. activated T cells in the pathogenesis. The involved antigens are uncertain, but could be related to infective Secreted antibody, present in normal agents such as bacteria, in particular staphylococci, eyes. Neutralises viruses and inhibits which are the most commonly isolated bacterial sIgA bacterial adherence to ocular surface population in cases of blepharitis. epithelium. Normal levels very low. Increased in Cicatrisation and scarring occurs in some types of IgE conjunctival inflammation, including that seen in mucous allergic ocular surface disorders. membrane pemphigoid where symblepharon is not Antigen specific antibody, only present uncommon (Figure 2). The conjunctival scarring has IgG in pathologic circumstances. major effects on the accessory lacrimal glands and dryness ensues with major problems for the ocular Proteolytic enzyme. In the presence surface. This may be associated with scarring in other Lysozyme of complement, facilitates IgA mucous membranes such as the mouth. There are bacteriolysis. several causes, including an association with topical therapy (pseudopemphigoid). Immunohistochemical Chelation of iron and destabilisation of staining of conjunctival biopsies in pemphigoid typically bacterial membranes (bacteriostatic). Lactoferrin reveals a linear deposition of antibodies to the Needed for the working of lysozyme. basement membrane zone. Acute disease is Role in free radical removal. characterised by a sub-epithelial infiltrate consisting of macrophages, neutrophils and T cells (CD4+ and Transferrin Iron chelator and anti-oxidant effect. CD8+), with relatively few B cells. Increased expression of MHC Class II molecules occurs on macrophages, Table 1: Tear film proteins and their function fibroblasts, and other cells in active disease, suggesting 2 Ocular Immune System which in the presence of a steroid pressure response or herpetic infection can be very useful. In AKC and VKC, the inciting allergen is often not known. However, GPC, which resembles VKC in that giant papillae (Figure 3) are also a feature, occurs in response to an irritating stimulus such as a contact lens or ocular prosthesis and is not associated with atopy. their involvement in the process of antigen presentation to T cells. Allergic conjunctivitis can be divided into acute and chronic types. Acute allergy is a Type I hypersensitivity reaction that can be seasonal (seasonal allergic conjunctivitis (SAC)) in which pollen is a common allergen, or occur throughout the year causing perennial allergic conjunctivitis (PAC) in which house dust mite is a significant cause. It can be associated with atopic Pterygia (Figure 4) are commonly seen especially in hot asthma, eczema and/or allergic rhinitis. Allergic countries and may grow across the cornea and over the reactions to preservative agents in eye-drops may also visual axis. It is now thought that immune mechanisms occur. In acute allergy, there is an influx of mast cells may be involved in pterygium formation/perpetuation, in and eosinophils into the conjunctiva. The allergen binds contrast to the findings in pingueculae. The class II to IgE molecules on the surface of the mast cells, which MHC molecule HLA-DR (which is involved in antigen then release several inflammatory mediators including presentation to T cells) is abundantly expressed in histamine. Neither SAC nor PAC is sight threatening pterygium epithelial cells, whereas almost no and resolve when the inciting stimulus is removed. expression is found in pinguecula and normal There are no chronic sequelae. conjunctiva. A high value of Ki-67 and PCNA expression - both markers for increased cellular proliferation - Chronic allergic conjunctivitis includes vernal coexists in the same areas as HLA-DR antigen keratoconjunctivitis (VKC), atopic keratoconjunctivitis expression in pterygium, with increased numbers of (AKC) and giant papillary conjunctivitis (GPC). All of inflammatory cells. These data suggest that these have in addition to the mast cell and eosinophil immunopathological mechanisms may contribute in the influx seen in SAC and PAC, a T cell mediated pathogenesis of pterygium and that increased HLA-DR response. This is principally of the TH2 type in VKC and GPC, whereas in AKC there is a marked TH1 response, coupled with increased IL-2 and IFN- secretion. Conjunctival epithelial cells also become involved in the inflammatory process and may play a role in T cell interactions, with resulting fibrosis and scarring of the conjunctiva. Both VKC and AKC occur in people with other signs of atopy such as eczema and asthma and both are potentially sight threatening due to corneal involvement and the consequences of scarring of the affected conjunctiva. People with AKC are also at risk of herpetic corneal infection, which may be bilateral. This is a major problem if they need topical corticosteroids to control the inflammatory process. In both VKC and AKC, topical steroids may be needed, but topical cyclosporin, which reduces the cytokine production by T cells and eosinophils, has been shown to be effective in both. In AKC, it can be used to spare the steroids, 3 Ocular Immune System antigen expression seems to be correlated with the growth rate of the lesion. Cornea In contrast to the conjunctiva, the cornea is avascular. As a consequence, the main cellular corneal defence arises from the cells at the surrounding limbus and from the anterior chamber. The limbus contains both lymphocytes and Langerhans cells. These cells can be rarely found in the corneal stroma, but their number increases significantly and is clearly visible in infectious and non-infectious pathologies (e.g. stromal infiltrate around a corneal foreign body) as illustrated in Figure 5. Non-infectious immune-related responses of the cornea regrafting) where the systemic immune system has mainly occur in the area immediately adjacent to the been in prior contact with ocular antigens. In these limbus. These include disorders such as Mooren’s ulcer situations, as in other vascularised organ and Terrien’s marginal degeneration. Corneal transplantation, the immune system responds to attack involvement can also occur in conditions where the foreign antigens, T cells and macrophages infiltrate the nearby sclera is involved, such as Wegener’s tissue and secrete a variety of cytokines and corneal granulomatosis and acne rosacae. graft rejection can ensue. In order to improve the survival of corneal grafts in high-risk situations, two Viral infections, for example herpes simplex, may strategies have been shown to help – that of HLA involve the corneal epithelium and are easily treated matching of donor and recipient particularly of the DR with topical anti-viral agents. However, in some patients subtypes and use of immunosuppressive therapy. Both there is an immune response and immune cells invade cyclosporin and mycophenolate have been shown to the underlying stroma and may be associated with a uveitis. Herpes zoster infection can also cause a uveitis, but immune reactions can also occur in the cornea causing a nummular keratitis (Figure 6), which may require topical steroids to suppress the symptoms and local inflammatory response. A typical example of the relative lack of inflammatory response in the cornea occurs following corneal transplantation (Figure 7). Corneal transplantation may be necessary to deal with corneal opacification due to infection, dystrophy, degeneration or trauma. The success rate is about 90% at five years after first-time grafting due to the avascularity of the cornea and lack of immune activation. However, this is reduced in high- risk patients (for example, where there is neovascularisation of the cornea or cornea/iris touch (peripheral anterior synechiae) or in patients requiring 4 Ocular Immune System reduce the risk of graft rejection in these high-risk eyes, cells and macrophages, with a predominance of CD4+ T but use of the drugs for twelve months following the cells, some of which are activated and express the IL-2 corneal graft seems to be required. When graft receptor. Clusters of B cells are found in perivascular rejection does occur, topical steroids are the mainstay areas and neutrophils, macrophages, and plasma cells of treatment, but systemic corticosteroid therapy may are also seen. In necrotising disease, the integrity of the also be required. eye is threatened and the nearby cornea can also be involved and can perforate. Urgent treatment with high Immunology of the sclera dose corticosteroids and immunosuppressive agents The sclera, as the cornea, is mainly composed of such as cyclosporin and cyclophosphamide are collagen fibres, but in contrast to the cornea, the sclera required. is opaque and is covered by the more vascularised episclera. Scleritis can be subdivided according to its Immunology of the uvea localisation (anterior and posterior scleritis), its cause The uvea (Figure 10) consists of the iris, ciliary body (infectious or non-infectious) and clinical phenotype and choroid. Although all three tissues are highly (diffuse (Figure 8), nodular or necrotising (Figure 9)). vascularised, they do not contain lymph vessels and possess no draining lymph nodes. The low permeability of iris blood vessels and tight junctions between non- pigmented ciliary epithelial cells, maintain the blood- aqueous barrier. Similarly, tight junctions between retinal pigment epithelial cells (RPE) and between endothelial cells of retinal blood vessels, form the blood- retinal barrier. Under normal conditions these barriers ensure that the anterior chamber, vitreous and retina, are relatively isolated both from exogenous antigens (toxic and microbacterial) and from the systemic immune system. In pathologic circumstances e.g. uveitis, inflammation causes alteration of the blood- ocular barriers leading to leukocyte migration and increased vascular permeability. The most common type of uveitis is acute anterior uveitis in which there is an influx of PMNs and T cells into the anterior chamber. This is seen clinically as a red eye with cells in the anterior chamber (Figure 11) and in extreme cases, hypopyon may form. About 60% of patients presenting in this way are HLA B27 positive, but those who are B27 negative can also have a similar type of inflammation. Topical corticosteroids are the Some patients have an underlying systemic vasculitis or mainstay of treatment, but occasionally more intense connective tissue disorder, including rheumatoid inflammation may require peri-ocular or even systemic arthritis, systemic lupus erythematosus (SLE), therapy. Acute uveitis is defined as that lasting less Wegener’s granulomatosis, and poly-arteritis nodosum than three months and in some patients, chronic (PAN). In others, it can be associated with infection inflammation occurs for many years. These patients including acanthamoeba. The inflammatory cells may present with a red or white eye, the latter being a infiltrating the episcleral and scleral tissue are mainly T problem as the inflammation may have been present for 5 Ocular Immune System cells, which produce a variety of cytokines, activated macrophages and HLA DR upregulation. Some CD8+ T cells and B cells are seen, but there is little evidence to support immune complex deposition as a major cause of the inflammation. The nature of the antigens involved is not known, although an immune response to retinal proteins, such as retinal s-antigen and interphotoreceptor binding protein, are seen in animal models of uveitis, but these are not specific to any disease process. In contrast, in patients with choroidal inflammation associated with the Vogt-Koyanagi-Halada disease, the immune response appears to be directed to melanin associated antigens. In sympathetic ophthalmia, penetrating trauma (which includes intraocular surgery) in one eye incites an immune response, which results in inflammation of both eyes. Exactly how this occurs is not known and fortunately, it is uncommon. The predominant infiltrating cell is the CD4+ T cell with some CD8+ cells. some time before the patient notices the sequelae. Immunology of the neuroretina and RPE Such cases are not usually HLA B27+ and other The retina and RPE contain many antigens that disorders e.g. sarcoidosis can also be present. The potentially can provoke an immune response: e.g. inflammatory process can cause posterior synechiae retinal s-antigen, interphotoreceptor retinol binding formation (Figure 12), cataract and glaucoma. Many protein (IRBP), and rhodopsin. However, it is unclear different types of cytokines are found in the aqueous whether these proteins act as primary immunological humour but increased levels of IL-10, which is an targets in human disease. The retina may also be inflammation down-regulatory cytokine, may be seen in involved in immune responses to systemic less aggressive forms of inflammation such as Fuch’s malignancies, for example melanoma-associated heterochromic cyclitis (FHC). retinopathy (MAR) and carcinoma-associated retinopathy (CAR). These conditions are characterised As the uvea is in close contact with the retinal and by circulating antibodies to tumour antigens that cross- scleral tissue, inflammation within it (uveitis) may also react with retinal proteins, leading to visual dysfunction. involve these structures. There are many different causes of posterior uveitis, some of which are In patients with retinitis pigmentosa, an inflammatory associated with systemic diseases such as sarcoidosis response may be seen due to retinal antigen and Behçet’s disease and others which are not. In all sensitisation. A similar response can occur following cases, the immunopathology within the choroid and laser photocoagulation of ischaemic retina where anti- retinal tissues is similar with a predominance of CD4+ T retinal antibodies have been detected. However, it is unusual for these to affect retinal function as they do in CAR and MAR. Recently, a hypothesis has been put forward implicating immune mechanisms in the pathogenesis of age-related macular degeneration (AMD). It is suggested that dendritic cells are intimately associated with drusen development (Figure 13) and complement activation occurs, both within drusen and along the RPE-choroid interface. Oxidative stress and free radical formation, as well as antioxidants are also thought to be important. Choroidal neovascular membranes are a sight threatening sequela of AMD (Figure 14) and large amounts of IgG, IgA and IgE, as well the complement components C1q, C3c and C3d, have been found to be diffusely distributed in the surrounding connective tissue and within the new blood vessel walls. In addition, numerous isolated HLA-DR- and -DQ-expressing cells, including glial, RPE and vascular endothelial cells have been found, whereas B cells, natural killer cells or T cells are uncommon. 6 Ocular Immune System Immunology of the extra-ocular constituents of the orbit: optic nerve, lacrimal gland, muscles and soft tissue The optic nerve, which is myelinated along its length, is known to be involved in several inflammatory processes, which can involve the vessels in and around the nerve, or the surrounding myelin sheathing. The lymphocytes (Figure 18) which are predominantly T inflammation can be retrobulbar in which case the optic cells. CD4+ and CD8+ T cells are seen and the cytokine nerve looks normal, or the nerve can be swollen (Figure profile reflects both TH1 and TH2 cell activity. In 15). Inflammation of the optic nerve, known as optic addition, there is glycosoaminoglycans production within neuritis, has a variety of causes, one of which is multiple the muscle fibres, which causes them to swell further. sclerosis (MS) where the inflammatory process affects Proptosis of the globe results where there is an the myelin sheathing and reduces the function of the increased volume of the orbital contents and optic nerve. The immunopathology is similar to that compression of the optic nerve can occur. Damage to seen in MS brain plaques and T cells are involved. the extraocular muscle fibres occurs, fibrosis ensues and their function may be permanently impaired In the orbit, the muscles can be affected by several requiring corrective surgery for the resulting strabismus. immune mediated processes. In Grave’s disease, where exophthalmos (Figure 16) is associated with In myasthenia gravis, weakening of the lid muscles and thyrotoxicosis, the extra-ocular muscles and orbital fat extra-ocular muscles can occur particularly when the are enlarged (Figure 17) and are infiltrated by patient is tired, as antibodies (which can be detected in 7 Ocular Immune System to orbital pseudotumours, which may require use of corticosteroids and other immunosuppressive agents to suppress the inflammatory response and prevent further damage to the orbital structures. The main other component of the orbit is the lacrimal gland. An autoimmune reaction located at the level of the lacrimal acinar cells (which secrete the aqueous component of the tears) reduces tear volume and alters the composition of the tears. This can be observed in many dry eye syndromes such as Sjögren’s syndrome and sarcoidosis. T cells, autoantibodies and cytokines have all been implicated in its pathogenesis. In the early stages before too much gland destruction has occurred, improvement of tear production has been achieved using topical cyclosporin suggesting that activated T cells are involved in the destructive process. Conclusion In this the second part of Unit 2 of the Principles of Therapeutics module, the particular immune defence mechanisms and responses of the eye and the role played by the immune system in the pathogenesis of certain ocular abnormalities have been discussed in detail. The actions of the innate immune system and the adaptive system are complex and require a balanced response to attack pathogens and also maintain transparency. The individual defence mechanisms of the ocular surface, sclera, uvea, neuroretina and RPE have each been considered and the role of these mechanisms in disorders such as ocular allergy, pemphigoid, scleritis, uveitis thyroid eye disease, myasthenia gravis and AMD have been explored. Unit 3 will concentrate on microbiology and clinical laboratory testing. Acknowledgements and further reading Akpek, E.K., Thorne, J.E., Qazi, F.A., Do, D.V. and Jabs, D.A. (2004) Evaluation of patients with scleritis for systemic disease. Ophthalmology, 111, 501-6. Algvere, P.V. and Seregard, S. (2002) Age-related maculopathy: pathogenetic features and new treatment modalities. Acta. Ophthalmol. Scand., 80, 136-43. the serum) against the acetylcholine receptor at the Boyd, S.R., Young, S. and Lightman, S. (2001) synapses exhausts nerve-muscle signal transduction. Immunopathology of the noninfectious posterior and Miller Fisher syndrome is characterised by a triad of intermediate uveitides. Surv. Ophthalmol., 46, 209-33. ataxia, ophthalmoplegia, and reduced or absent tendon reflexes, with minimal if any limb weakness. Both Calder, V.L and Lackie, P.M. (2004) Basic science and lymphocytes and macrophages are seen and anti-GQ1b pathophysiology of ocular allergy. Curr. Allergy Asthma IgG antibodies are present in high titers in most Rep., 4, 326-31. patients, but the reason for this is unknown. Hodge, C. and Martin, P. (2003) Thyroid eye disease. Both the muscles in the orbit and the orbital tissue can Eye series-10. Aust. Fam. Physician, 32, 939-40. become infiltrated with cells, particularly lymphocytes and become inflamed. In orbital myositis, one or more Missotten, T. And Lightman, S. (2004) Ocular muscles become involved, with pain on ocular immunology. Optician, 5962 (228) 23-34 movement and swelling on imaging. This may be idiopathic or associated with systemic inflammation or Pappa, A., Lawson, J.M., Calder, V., Fells, P. and infection. Lymphocytic infiltration of the orbit gives rise Lightman, S. (2000) T cells and fibroblasts in affected 8 Ocular Immune System extraocular muscles in early and late thyroid associated ophthalmopathy. Br. J. Ophthalmol., 84, 517-22 Streilein, J.W. (2003) New thoughts on the immunology of corneal transplantation. Eye, 17, 943-8. Thorne, J.E., Anhalt, G.J. and Jabs DA. (2004) Mucous membrane pemphigoid and pseudopemphigoid. Ophthalmology, 111, 45-52. 9