The core protein and link proteins of proteoglycans are degraded by proteoglycanases. The fragments are further degraded in the pericellular area by other proteinases, such as cathepsin B. GAG peptides are phagocytosed and further degraded in the lysosomes by proteinases, such as cathepsin D. Subsequent attacks by different exoenzymes result in monosaccharide residues and free sulfate [103]. Fibronectin can be degraded by a wide variety of glycoproteinases, including trypsin, chymotrypsin, pepsin, elastases, and cathepsin G and D [104].

to the posterior pole by the 12th week. There are no more differences between the inner and outer portions of the sclera by the beginning of week 10.9, and between the anterior and posterior portions of the sclera by week 13. The fetal sclera has the same ultrastructural characteristics as the adult sclera by week 24.

Human fetal and adult sclera is formed by the collagen types I, III, IV, V, VI, and VIII, by the GAGs dermatan sulfate, chondroitin sulfate, hyaluronic acid, and heparan sulfate, and by the glycoproteins Þbronectin, vitronectin, and laminin. Collagen types I and VI increase steadily from fetus to adult, collagen type III shows little

Human Þbroblasts require growth factors for DNA synthesis. Fibroblast growth factors can be classiÞed either as ÒcompetenceÓ factors or ÒprogressionÓ factors [105]. The competence factors, including platelet-derived growth factor (PDGF) and Þbroblast growth factor, render cells in Go or G1 phase ready for DNA synthesis stimulation [105, 106]. The progression factors, including somatomedins A and C and insulin growth factor, stimulate DNA synthesis in competent cells [105Ð107]. Other known Þbroblast growth factors, including interleukin-1 (IL-1), and T-cell- derived Þbroblast growth factor cannot be considered as either competence or progression factors and remain unclassiÞed [108Ð111]. SpeciÞc receptors on Þbroblasts for PDGF and IL-1 have been identiÞed [105, 106, 108, 109]. Recombinant interferon g may stimulate or suppress Þbroblast growth, depending on culture conditions [112, 113].

1.8Summary

Almost all of the sclera is of neural crest origin, except a small temporal portion formed from mesoderm. The developmental process of the sclera is directed from anterior to posterior and from inside to outside. Scleral differentiation has already started in the region destined to become the limbus by the sixth week, and progresses backward to the equator by the eighth week and

lagen type IV decreases steadily through 16, 19, and 22 weeks, revealing only subtle positivity in adult sclera, except for its dramatic presence in the vessels; the staining pattern of collagen type V is diffuse in fetal sclera but is granular along the edges of the collagen bundles in adult sclera; collagen type VIII staining is intense in posterior fetal and adult sclera and anterior adult sclera but is negative in anterior fetal sclera. Dermatan sulfate and chondroitin sulfate are present in moderate and large amounts, respectively, through the different gestational periods; in contrast, hyaluronic acid changes from a moderate staining at 13 weeks to a subtle positivity in adult sclera; heparan sulfate is present in human fetal and adult sclera in small amounts. Fibronectin, vitronectin, and laminin are present at 13 weeks but steadily disappear onward, except for their presence in the vessels. Fibronectin and laminin may play a major role in directing developmental events.

The postnatal sclera is relatively distensible, thin, and somewhat translucent, allowing the blue color of the underlying uvea to show through. The sclera thickens gradually, becoming opaque and more rigid. In elderly individuals, the sclera shows a decrease in scleral distensibility, water content, and amount of proteoglycans, and an increase in the amount of lipids and calcium phosphate.

Gross anatomical studies show that the scleral shell is an incomplete sphere averaging 22 mm in diameter that terminates anteriorly at the anterior

scleral foramen surrounding the cornea and posteriorly at the posterior scleral foramen surrounding the optic nerve canal. Its thickness varies from 0.3 mm immediately behind the insertion of the rectus muscles to 1.0 mm near the optic nerve. The sclera may be divided into three layers: the episclera, the scleral stroma, and the lamina fusca. It is a relatively avascular structure but is supplied by the episcleral and, to a lesser degree, choroidal vascular networks. The episcleral blood supply is derived mainly from the anterior ciliary arteries anterior to the insertions of the rectus muscles and from the long and short posterior ciliary arteries posterior to these insertions. The sclera receives a profuse sensory innervation; the short, posterior ciliary nerves supply the posterior region of the sclera, whereas the two long, posterior ciliary nerves supply the anterior portion.

Microscopic and ultramicroscopic anatomical studies show that the sclera is composed of dense bundles of collagen, few elastic Þbers, few Þbroblasts, and a moderate amount of amorphous ground substance (proteoglycans and glycoproteins). Episcleral vessels, as capillaries and postcapillary venules, are continuous and have simple walls consisting of endothelial cells attached to an underlying basement membrane secreted by them and a discontinuous layer of pericytes.

The cells, Þbroblasts, and degradative enzymes they secrete (collagenases, elastases, proteoglycanases, and glycoproteinases) play a critical role in the synthesis and organization of the matrix elements.

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Scleritis remains an enigmatic disease. Attempts to demonstrate a speciÞc antigen associated with scleral vessel and tissue damage, or to reproduce suggested pathogenic mechanisms in experimental animal models, have not yielded consistent abnormalities [1]. As the sclera is avascular, nutrients come from the choroid and vascular plexi in Tenon«s capsule and episclera, where there is an artery-to-artery anastomosis in which blood oscillates, rather than ßowing rapidly. This predisposes to the development of vasculitis causing a spectrum of inßammatory conditions of varying intensity which, in the most severe form, necrotizing scleritis, may destroy all of the structural and cellular components of the sclera. The prevailing consensus view, however, based on the available evidence, is that disordered immune responses leading to vessel and tissue damage are central to the pathogenesis of scleritis. The histopathological and immunoßuorescence detection of immune complex inßammatory microangiopathy in affected scleral biopsy specimens [2], the frequent association of scleritis with systemic autoimmune diseases associated with circulating immune complexes (rheumatoid arthritis, systemic lupus erythematosus, or polyarteritis nodosa) [2Ð4], the favorable response of scleritis to immunosuppressive agents [3, 4], and the absence of vascular perfusion in severe types of scleritis, as determined by anterior segment ßuorescein angiography [5], all suggest that scleritis

represents an autoimmune process mediated by a localized immune complex microangiopathy or type III hypersensitivity reaction. The histopathological Þnding of a chronic granulomatous inßammation characterized predominantly by macrophages and T lymphocytes in scleritis biopsy specimens suggests that a cellular immunity dysfunction or type IV hypersensitivity reaction also may play a role [2].

The prevailing hypothesis, based on the aforementioned data and autoimmunity investigations, is that development of scleritis entails the interaction of genetically controlled mechanisms with environmental factors, such as infectious agents (e.g., virus) or trauma. Genetic predisposition, coupled with the triggering event, gives rise to an immune process that damages the vessels through immune complex deposition in vessel ÒwallsÓ and subsequent complement activation (type III hypersensitivity). Persistent immunologic injury leads to granuloma formation (type IV hypersensitivity). In certain systemic vasculitic diseases, circulating immune complexes may deposit in episcleral and scleral perforating vessels, particularly if they have suffered a previous insult (mild infection, trauma), as well as in other vessels or tissues of the body.

This chapter reviews the immunological considerations of the sclera, emphasizing the issues of relevance regarding the pathogenic mechanisms of scleritis.