The inner most layer of the cornea is the endothelium that forms a uniform monolayer of hexagonal cells (5 μ thick) with a cell density of around 2500 cells/mm². The endothelium functions as both a barrier to fluid movement into the cornea and an active pump to move the fluid out of the cornea, ensuring corneal transparency. The barrier function was first demonstrated in the nineteenth century by Leber (Stocker and Reichle 1974). The function, as metabolic pump, discovered almost a century later in 1972, when Maurice DM (Freeman 1972) demonstrated that the endothelium possessed active, energy-dependent fluid pump that moved water from the corneal stroma into the anterior chamber. This ensures corneal transparency. The number of endothelial cells is therefore critical (at least around 400–500/mm²) for the optimal pump activity. Steady-state hydration occurs when the endothelial pump rate equals the GAG-driven leak (Maurice et al. 1981). A “pump-leak” mechanism where the active transport properties of the endothelium represent the “pump” and the stromal swelling pressure represents the “leak” was established (Riley 1969a, b). For the pump to function, Na⁺/K⁺-ATPase activity and the presence of HCO₃ ⁻, Cl⁻, and carbonic anhydrase activities are required. The pump requires Na⁺/K⁺-ATPase activity that actively transports Na⁺ from the stroma to the anterior chamber and forms a diffusing gradient for water, thereby maintaining a constant stromal hydration. Several basolateral (stromal side) anion transporters, apical (facing the aqueous humor) ion channels, and water channels have been identified. Numerous anion transport mechanisms have been identified in the endothelium, namely, basolateral Na(+)/2HCO(3)(−) cotransport, Na(+)/K(+)/2Cl(−) cotransport, Cl(−)/HCO(3)(−) exchange, and apical anion channels permeable to both Cl(−) and HCO(3)(−), apart from the carbonic anhydrase-mediated CO₂-diffusive mode of apical HCO₃ ⁻ flux and apical Ca²⁺-sensitive chloride channel (Bonanno 2003, 2012). The barrier function of the endothelium is in a dynamic regulation where the tight junctions and the adherent junctions play an integral role in addition to the Pumps and the channels (Srinivas, 2010).

Cellular glucose uptake is promoted by the glucose transporters present on both the apical and basolateral endothelial cell membranes (Kumagai et al. 1994). Eighty-five percent of glucose consumed in the cornea is converted to lactic acid (Riley 1969a). Epithelium is impermeable to lactate, and therefore in the cornea, it is about twice the concentration (~13 mM) to that in the aqueous humor (~7 mM), resulting in a large gradient for lactate flux from cornea to anterior chamber across the endothelium. Lactate: H(+) cotransport was demonstrated in the endothelium (Giasson and Bonanno 1994) (Fig. 5.2).

Corneal endothelium has a high density of aquaporin (AQP1) located on both apical and basolateral membranes (Kuang et al. 2004). AQP1 is present for the passive movement of the water for faster stromal hydration as in physiological situations such as eye closure (which swells the cornea by ~4 %) or exposure to hypo-osmotic conditions as in swimming (Bonanno 2012).

There is no mitotic activity of the corneal endothelial cells as these are inhibited in the G1 phase. There is 0.3–0.6 % loss of endothelial cells per year which is compensated by the migration of the neighboring cells or spreading to a pleomorphic shape. Cell loss is critical for the pump activity and can result in corneal edema, bullous keratopathy, and the loss of visual acuity. Cell loss occurs in trauma, refractive surgeries, penetrating keratoplasty, corneal dystrophies, diabetes, and glaucoma. Corneal endothelial dystrophy is a chronic progressive endogenous degeneration of the corneal endothelium, partly due to genetic predisposition (Joyce 2012). Therefore, current researches explore the proliferative capacity of these corneal endothelial cells.

The corneal endothelial dystrophies are congenital hereditary endothelial dystrophy 1 (CHED1), congenital hereditary endothelial dystrophy 2 (CHED2), posterior polymorphous corneal dystrophy (PPCD), and Fuchs endothelial corneal dystrophy (FECD) (Weiss et al. 2008). However, the molecular pathologies remain largely unknown. Genetic factors, chronic oxidative stress, mitochondrial damage, extracellular matix changes, endoplasmic reticulum (ER) stress changes, and apoptosis contribute to the pathology of FECD. Early- and late-onset FECD are distinct corneal conditions with the similar clinical and phenotypic characteristics but different genetic risk factors (Schmedt et al. 2012). Two types of congenital hereditary endothelial dystrophy (CHED) have been described: CHED1, which is autosomal dominant, and CHED2, which is autosomal recessive. The major differences between CHED1 and CHED2 lie on the onset, mode of inheritance, genetic mutations, and associated conditions. Mutations of 25 types in different locations of the SLC4A11 gene that codes for BTR1 (bicarbonate transport-related protein) or NaBC1 are known (Schmedt et al. 2012). Genetic defects in SLC4A11 disrupt the fluid flux across corneal endothelium necessary for maintenance of healthy corneal hydration. However, the mechanism by which the mutation leads specifically to atrophy of corneal endothelium is still not clear (Hemadevi et al. 2008; Vithana et al. 2006). Posterior polymorphous corneal dystrophy (PPCD) is a rare nonprogressive disorder that affects corneal endothelium and the DM (Henriquez et al. 1984). Mutations in the genes, VSX1 (visual system homebox 1), TCF8, and CO8A2 seem to have genetic heterogeneity (Schmedt et al. 2012).

Between the cornea and the sclera is the limbus, a zone of approximately 1 mm that surrounds the cornea and is the site for surgical incisions for cataract and glaucoma. In the limbus, the stem cells for the epithelium as well as vascular elements reside in providing nutrients to the avascular cornea. The vasculature of the limbus derives in primates primarily from the anterior ciliary arteries (Van Buskirk 1989). The limbus has two important functions in maintaining a healthy corneal epithelium. It is the source of stem cells for the corneal epithelium; it also acts as a barrier separating the clear avascular corneal epithelium from the surrounding vascular conjunctival tissue. This microenvironment can be altered due to disease leading to limbal stem cell deficiency, when the corneal surface becomes replaced by hazy conjunctival tissue. The causes of limbal stem cell deficiency include, chemical injuries to the eye, inflammatory diseases, and hereditary diseases (Ahmad 2012).

Basement membranes are specialized acellular matrix that not only plays a role in separating the cellular layers but also connect them through the molecular matrix. Corneal epithelial basement membrane modulates the epithelial-to-stroma and stroma-to-epithelial interactions by regulating cytokines and growth factor movement from one cell layer to the other. In cornea, the basement membrane is present between epithelial cells and stroma. After 8 weeks of gestation, the epithelium is separated out from stroma by basement membrane which is avascular. The lamina lucida and lamina densa are the adjacent layers. The basement membrane is chiefly composed of the laminin, apart from collagen, heparan sulfate proteoglycans (HSPG), and nidogens. The composition varies from the limbal region to the central cornea. Laminins are heterotrimeric glycoproteins that are most abundant with different isoforms playing distinct roles. The gene defect has been associated with corneal diseases such as keratoconus, Fuchs dystrophy, and bullous keratopathy. Fibronectin, thrombospondin, matrilin, tenascin C, and nidogens 1 and 2 are the other major basement membrane matrix proteins that act as link proteins to laminin. The anchored proteoglycans such as perlecan, a complex multi-domain HSPG, can bind to various but discrete molecules. It regulates the availability of fibroblast growth factors (FGF), bone morphogenic proteins (BMP), platelet-derived growth factor (PDGF), vascular endothelial growth factors (VEGF), transforming growth factor β-1 (TGF-β1), and insulin-like growth factors (IGF) to bind to their receptors thereby mediates the cell signaling for migration, proliferation, and differentiation of a variety of cells. Perlecan is crucial for corneal epithelium formation and differentiation. Perlecan-deficient mice show epithelial defects. Mutations are reported in integrin, keratins, collagen subtypes, laminin, and many of the basement membrane proteins (Alarcon et al. 2009; Torricelli et al. 2013).

The hemidesmosome (HD) link is a complex of extracellular transmembrane and cytoplasmic molecules that form structural link between the intracellular keratin intermediate filament of cytoskeleton of the basal epithelial cell and the underlying basement membrane. The basement membrane zone has the hemidesmosome and the lamina lucida and lamina densa, which is the uppermost region of the stroma (Borradori and Sonnenberg 1999). Basement membrane normally functions as a barrier to the penetration of epithelial TGF-β1 and PDGF into the stroma. Loss of basement membrane leads to penetration of these factors that promote myofibroblasts development. Thus, basement membrane functions as the regulating barrier, limiting the fibrotic responses in injury, by regulating molecular interaction between the epithelium and the stroma. It plays a role in maintaining homeostasis of the matrix by downregulating wound healing signaling, modulation of epithelial cell growth proliferation and differentiation (Singh et al. 2011). Basement membrane also acts as a barrier to the bacterial penetration (Alarcon et al. 2009).

Descemet’s membrane is a thick basement membrane (5–10 μm). Descemet’s membrane like other basement membranes consists of two distinct layers, a posterior layer adjacent to the endothelium and an anterior layer formed by collagen lamellae and proteoglycans (Kabosova et al. 2007).

An important characteristic of the cornea is its heavy innervations, with around 300 times the number of nerve endings per square mm of the skin. These are sensory nerves derived from the ciliary nerves of the trigeminal ganglion ophthalmic branch. The nerves penetrate the cornea through the peripheral stroma in a radial pattern and shed their myelin sheet, surrounded only by Schwann cell sheaths. They subdivide several times into smaller side branch and then advance to the epithelium to form the basal epithelial nerve plexes. The absence of a myelin sheath on central corneal axons is necessary to maintain corneal transparency. Corneal nerves exert a trophic effect on the epithelium and maintain the health of corneal epithelium. Dysfunction of the nerve causes degenerative neurotrophic keratitis resulting in decreased mitotic activity of the basal epithelial cells, decreased epithelial thickness, increased epithelial permeability, loss of cellular glycogen stores, decreased oxygen uptake rates, and altered hypoxic swelling responses. Table 5.1 shows the various trophic factors released by the corneal nerve endings and their response (Muller et al. 2003).

Though the cornea is avascular, during injury there is an inflammatory response characterized by stromal cell infiltration of polymorphonuclear neutrophils (PMNs) that come from the limbal vessels followed by a cascade of events involving anti-inflammatory mediators. If inflammation is not resolved, then corneal fibrosis, pigmentation, and neovascularization take place, resulting in corneal scarring and disruption of the blood ocular barrier, resulting in chronic immune-mediated uveitis (Grahn and Cullen 2000).

Ocular immune system protects the eye from infection and regulates healing processes following injuries. The eye is an immune-privileged site and is endowed with remarkable properties that permit the long-term survival of foreign tumor and tissue grafts due to multiple anatomical, physiological, and immunoregulatory processes. Innate immune responses provide an inherent barrier against corneal infection while also serving as a primary mode of defense that is present from birth. The most evident is the tear film that coats the cornea and conjunctiva and serves several important functions such as lubrication, supply of oxygen, and protection against a range of potential pathogens. Ocular tissues and fluids express a wide variety of anti-inflammatory and immunosuppressive molecules, including lysozyme, lactoferrin, lipocalin, calcitonin gene-related peptide, somatostatin, and complement regulatory proteins. Table 5.2 lists the various antimicrobial proteins and peptides in the tear.

Toll-like receptors present at the ocular surface render additional immune barrier by triggering the earliest immune response to the invading pathogens. The TLRs act by modulating the adaptive immune response which is mediated by MyD88 (myeloid differentiation factor 88). Additionally, certain TLRs can also induce TRIF {TIR [Toll/IL (interleukin)-1 receptor] domain-containing adaptor protein which induces IFN (interferon) β}-dependent signaling (Kenny and O’Neill 2008). The activation of these intracellular signaling pathways induces the expression of cytokines, chemokines, and adhesion molecules.

Around, 10 TLRs (TLR1–TLR10) have been shown to be present in humans (Akira et al. 2001; Yu and Hazlett 2006). Different TLRs play a key role in the regulation of the response to infectious agents in the cornea: TLR4 and TLR5 are involved in Gram-negative; TLR2 in Gram-positive bacterial infections, TLR2 and TLR4 are activated in fungal keratitis; TLR3, TLR7, and TLR8 are involved in viral infections. Both the bacterial and viral genomes are able to activate a TLR9 response. Lambiase et al. have reviewed the scope of toll-like receptors at ocular surface (Lambiase et al. 2011).

Reports suggest that TLRs may become therapeutic targets in inflammatory ocular diseases, associated with the possibility to use extracellular TLR agonists. Pharmacological modulation of TLR intracellular signaling pathways may allow novel therapeutic strategies for avoiding the detrimental effects of prolonged inflammation at the ocular surface. The evaluation of TLR-modulating molecules in human diseases has already started with several ongoing clinical trials (Hennessy et al. 2010). There is a rapidly growing literature on TLRs in the cornea and conjunctiva, opening the possibility of targeting these molecules in the management of ocular surface diseases.

The neutral lipids form the major composition in human cornea, which is 34 %. This includes cholesterol, cholesterol esters, and triglycerides followed by the sphingolipids (24 %) and the gangliosides (10 %) (Feldman 1967). The phospholipids in cornea include phosphatidyl choline, phosphatidyl ethanolamine, and sphingomyelins (Rodrigues et al. 1983). The fatty acids predominantly seen are oleic acid, palmitic acid, and stearic acid (Tschetter 1966).

The tear film lipid layer consists of a mixture of nonpolar lipids (wax esters, cholesterol, and cholesterol esters), which is 60–70 % of the layer; the rest is composed of phospholipids, glycolipids, and a small amount of free fatty acids, including omega fatty acids and mono- and diglycerides (Andrews 1970; Tiffany 1987). Tear lipids arrive from meibomian glands and the accessory sebaceous gland of Zeis. The phospholipids secreted by the meibomian gland act as amphiphilic molecules to form an interphase between the outer nonpolar lipid layer and the inner aqueous layer (Pucker and Haworth 2015). Dietary intake of omega fatty acids and its topical application is shown to be effective against dry eye (Roncone et al. 2010).

Corneal arcus results from lipid infiltration into the peripheral cornea in humans. These lipids are cholesterol-rich lipid particles deficient in apolipoprotein (apo)-B (Cogan and Kuwabara 1959). Lipid keratopathy is another condition common in women, often associated with hypercholesterolemia with cholesterol esters as droplets deposited in the stroma by lipid-overloaded fibroblasts (Gaynor et al. 1996). Corneal neovascularization can pave way for lipid access to the cornea; herpetic keratitis and chemical injuries produce severe lipid keratopathy (Forsius 1961). Another disease, granular corneal dystrophy, an autosomal dominant heritable condition, is characterized by granular deposits in the cornea and shows an increase in phospholipids with no changes in cholesterol (Rodrigues et al. 1983). Lipids are known to be involved in the pathology of dry eye with the loss of the lipid layer thickness being associated with the severity of the dry eye (Foulks 2007).

Injury to the cornea stimulates the release of platelet activation factor (PAF), a bioactive lipid that activates phospholipoase A2 (PLA2). This results in the release of arachidonic acid (AA) as well as its conversion to prostaglandins (PGD), thromboxanes (TX), and lipoxygenase (LOX) derivatives (Bazan 1987; Bazan et al. 1985a, b) in all the three layers of the cornea. Cycloxygenase-1 (COX-1) is expressed throughout the cornea, whereas COX-2 is predominantly expressed close to the wound (Amico et al. 2004). Laser in situ keratomileusis (LASIK), which damages the stroma, induces expression of COX-2 in the central epithelium and in the keratocytes adjacent to the wound (Miyamoto et al. 2004). COX-2 metabolites contribute to tissue damage and neovascularization. LOX derivatives from arachidonic acid, 12- and 15-hydroxy/hydroperoxy eicosatetraenoic acids, and lipoxin A4 resolvins (RvE1) from eicosapentaenoic acid (EPA) and neuroprotectin D1 (NPD1) from docosahexaenoic acid (DHA) potentiate repair and regeneration. Stimulation of the cornea with pigment epithelial-derived factor in the presence of DHA gives rise to the synthesis of NPD1, a derivative of LOX activity, and increases regeneration of corneal nerves (Kenchegowda and Bazan 2010).

15-hydroxy/hydroperoxyeicosatetraenoic acid [15(S)-HETE] formed from arachidonic acid (AA) by LOX action has a protecting effect from the dry eye (Gamache et al. 2002) and promotes mucin secretion (Jackson et al. 2001). While LOX derivatives are protective agents in the cornea, PAF plays a central role in mediating corneal inflammation, cell death, and neovascularization.

Corneal injury causes altered levels of growth factors that activate 12/15-LOX. Prostaglandins show a variety of effects in cornea through the eicosanoids (Table 5.3). A balance of pro- and anti-inflammatory levels of bioactive lipids decides the fate of corneal injury.

The tear film is considered a vital structure whose main role is to protect the ocular surface from external environment, infectious agents, and desiccation. The multiple functions of tear fluids include: lubrication of the eyelids, formation of a smooth and even layer over the cornea and conjunctiva, providing antibacterial systems for the ocular surface and nutrients for the epithelium, act as a vehicle for the entry of polymorphonuclear leukocytes in case of injury, and washing away the toxic irritants (Lemp and Blackman 1981; Braun et al. 2015).

Tear film is a trilaminar structure consisting of: (1) a thin anterior lipid layer (0.1 μ) originating from the meibomian glands which contains both polar and nonpolar lipids; (2) an intermediate aqueous layer (7 μ) originating from the lacrimal glands, which contains water soluble substances, including electrolytes, proteins, retinol, immunoglobulins, and enzymes- and (3) innermost mucous layer (0.02–0.04 μ) – secreted by conjunctival goblet cells and lacrimal gland acinar cells and containing components loosely bound to glycocalyx of the corneal and conjunctival epithelial cells.

Tear is composed of 98 % water and 2 % solids, like proteins, lipids, carbohydrates, and salts. The total tear volume produced is around 6.2 μl, ranging from 3.4 to 10.7 μl. The thickness of tear film is 6–7 μm; the pH slightly basic, i.e., 7.5; and the osmolarity is 300–334 milli osmolar (Jordan and Baum 1980). Sodium, potassium, chloride, bicarbonate, magnesium, and calcium salts are found in the tear. The chloride concentration is more in tears compared to the serum (Van Haeringen 1981). Tear has metabolites such as glucose, urea, lactate, pyruvate, ascorbate, retinol, free amino acids, uric acid and bilirubin.

The tear film is thus a complex mixture of proteins, lipids, mucus, salts, enzymes, and other metabolites produced from multiple sources such as the lacrimal gland, meibomian gland, goblet cells, and accessory lacrimal glands of the ocular surface. Glands of Krause located in the lamina propria of the conjunctival fornices (superior and inferior), Moll glands at the base of the lashes anterior to the meibomian glands and Wolfring located above the superior border of the upper lid tarsus contributes to the secretion of components into the lacrimal fluid (Lamberts et al. 1994). The lacrimal gland is a paired, almond-shaped gland, one for each eye that secretes the aqueous layer of the tear film. They are situated in the upper, outer portion of each orbit, in the lacrimal fossa of the orbit formed by the frontal bone (Walcott 1998). The lacrimal glands secrete lacrimal fluid as a result of neuronal stimuli, which flows through the main excretory ducts into the space between the eyeball and lids and during blinking of eyes. The lacrimal fluid is spread across the surface of the eye accumulating in the lacrimal lake and is drawn into the puncta by capillary action, flowing through the lacrimal canaliculi to the inner corner of the eyelids entering the lacrimal sac, then to the nasolacrimal duct, and then finally into the nasal cavity. Lacrimal functional unit (LFU) is an integrated system including lacrimal gland, ocular surface, lids, and sensory and motor nerves, to carry out its function. The lacrimal glands consist of a tubular secretory epithelium organized into lobes that drain into ducts. It is a multilobular tissue composed of acinar, ductal, and myoepithelial cells. The acinar cells account for 80 % of the cells present in the lacrimal gland and are the sites for synthesis, storage, and secretion of proteins. Several tear proteins like lysozyme, lactoferrin, growth factors such as epidermal growth factor and transforming growth factor are crucial to the homeostasis of the ocular surface.

Ductal cells: These cells modify the primary fluid secreted by the acinar cells to secrete water and electrolytes. Myoepithelial cells contain multiple processes, which surround the basal area of the acinar and ductal cells. They contain a smooth muscle actin that helps to contract and force the fluid out of the ducts and onto the ocular surface similar to salivary and mammary glands. Other cell types present in the lacrimal gland includes plasma cells, B and T cells, dendritic cells, macrophages, bone marrow-derived monocytes, and mast cells. Immunoglobulin A (IgA)-positive plasma cells are the majority of the mononuclear cells in the lacrimal gland (Dua et al. 1994; Wieczorek et al. 1988). These cells synthesize and secrete IgA, which is then transported into acinar and ductal cells and are secreted by these epithelial cells as secretory IgA.

Glycoproteins are abundantly expressed, especially in the conjunctival cells and are abundantly found in tears. 424 glycogenes have been identified by the gene chip array of the conjunctival epithelium. Mucins are high-molecular-weight glycoproteins, and the carbohydrate-binding proteins form the major component of the tear glycoproteins (Mantelli and Argueso 2008). They have a characteristic property of tandem repeats of amino acids rich in serine and threonine to which O-glycan is attached (Gendler and Spicer 1995). Apical cell layers of the corneal epithelium produce mucin. MUC5AC is the major secreted mucin of the conjunctival goblet cells. The transmembrane mucins, MUC1, MUC4, and MUC16, are produced by the epithelium (Guzman-Aranguez et al. 2010).

Mucins along with galectin-3 promote barrier integrity and prevent bacterial adhesion. Galectin-3 is the most abundantly expressed carbohydrate-binding protein in human conjunctival epithelium, while galectin-8 and galectin-9 are found in much lower concentrations (Mantelli and Argueso 2008). Oligomerization of galectin-3 results in lattices that resist lateral movement of membrane components on the glycocalyx (Pablo Argüeso et al. 2013). Human tear mucins consist primarily of α2-6 sialyl core 1 (Galβ1-3GalNAcα1-Ser/Thr) (Guzman-Aranguez et al. 2009). However, in the conjunctiva, α2-3 sialyl core 1 is seen. The glycosylated mucins are hydrophilic and are responsible for the water-binding capacity that prevents ocular surface drying. In addition to mucins, glycosyltransferases, proteoglycans, glycan degradation proteins, and Notch signaling molecules are expressed on the ocular surface. They act as receptors for the pathogens, thereby trapping and removing pathogens from the epithelial surfaces. They prevent barrier function by preventing endocytosis (Guzman-Aranguez et al. 2012). Thus, lubrication and clearance of pathogens and debris are the major functions of the mucins and other glycoproteins in the tear.

The lens of the vertebrate eye is a unique organ in that it is nonvascularized and noninnervated (Bloemendal 1981). The entire organ is composed of cells of surface ectodermal origin at various stages of differentiation surrounded by a basal lamina, the lens capsule (Duncan 1981; Bloemendal 1981). The epithelial cells ranging from 9 to 17 mm in diameter (Brown and Bron 1987) remain quiescent in the central epithelium (nondividing phase), surrounded by a germinative dividing zone of cells which divide toward the equatorial area (dividing phase) and terminally differentiate (differentiating phase) into long, transparent fiber cells in the equatorial region (Papaconstantinou 1967; Piatigorsky 1981). The transition of lens cortex into fiber cells during the developmental stages is characterized by biochemical changes which includes the synthesis of fiber-specific proteins, α- and β-crystallins, and arid morphologic changes such as cell elongation, loss of cellular organelles, and disintegration of the nucleus (Worgul et al. 1989). The single monolayer of anterior epithelial cells in the mature lens represents a very static population and is essential for maintaining the metabolic homeostasis and transparency of the entire lens (Spector et al. 1995). Anteriorly, they form an epithelial monolayer, while internally they are represented by shells of concentrically arranged fully differentiated fiber cells, which form the bulk of the lens (Winkler and Riley 1991). Thus, the lens continually grows throughout life and maintains its distinct polarity with the monolayer of epithelial cells covering only the anterior half of the fibers (McAvoy and Chamberlain 1989).

The uvea is otherwise called as uveal coat/tract or vascular tunic and is comprised of the iris, ciliary body, and choroid, of which the iris and ciliary body lie in the anterior segment, while the choroid spans the entire eye ball between the retina and sclera. The uveal vasculature functions for the nutrition and gas exchange by direct perfusion into the iris and ciliary body and indirectly to the lens, sclera, and retina. Moreover, the uvea helps in reducing the light reflection within the eye, by light absorption, and hence improves the image quality. The most important function of the uvea includes the secretion of aqueous humor by the ciliary process.

The inner surface of the ciliary body which has two layers of epithelium forms the aqueous humor. This epithelium has an inner nonpigmented layer and outer pigmented layer. The ciliary capillaries are highly fenestrated, and the ultrafiltrate of the blood fills the stroma which is formed by the active transport of ions. From the stroma, selective transport of solutes occurs producing osmotic flux producing the AH.

Uveitis is a group of intraocular disorders involving inflammation of the uvea and, in few cases, other related ocular structures that cause about 10 % of blindness (Agrawal et al. 2010), of which about 50 % have bilateral vision impairment (Durrani et al. 2004). Uveitis can be classified as anterior, intermediary, and posterior uveitis; iridocyclitis is the inflammation at the anterior uvea (iris and ciliary body). In case of inflammation of the iris alone, it is referred to as iritis. Inflammation at ciliary body is cyclitis, which is intermediate uveitis. Acute anterior uveitis starts with an intense inflammation around the cornea. The case of posterior uveitis may be bilateral, associated with painless loss of vision. When an inflammation in the vitreous is involved, floaters may be present that are aggregates of inflammatory cells suspended in the vitreous. Loss of vision may be generally due to cataract, opacity in the vitreous, chorioretinal scarring, cystoid macular edema, secondary glaucoma, retinal vascular occlusions, inflammatory optic neuropathy, and retinal detachment (Guly and Forrester 2010; Lowder and Char 1984). Posterior uveitis refers to inflammation in the choroid called as choroiditis, and when the adjacent layer to the uvea is also involved, the condition is termed as retinochoroiditis/uveoretinitis. When the retina is involved, in case of retinal blood vessels, it is called retinal vasculitis, vitritis (vitreous), and when the optic nerve is involved, it is papillitis (Char and Schlaegel 1982).

Various causes have been attributed to the onset of uveitis as drug induced, traumatic, infection induced, and autoimmunity. Uveitis in some cases is found to be generally coupled with many systemic diseases, namely, Behcet’s syndrome, juvenile idiopathic arthritis, sarcoidosis, masquerade syndrome, and infectious diseases like tuberculosis. In about half the cases, it is considered to be idiopathic, and no systemic association is found. In such cases uveitis is presumed to be autoimmune (Rothova et al. 1992). The management of uveitis is determined by the presence or absence of infection or is noninfective and by the likelihood of a threat to sight (Guly and Forrester 2010). The immune response elicited to the infection is considered in part to be responsible for the inflammation and thus the consequent ocular damage and visual loss. Hence topical and systemic steroids are often used in addition to suppress inflammation in patients with infection-related uveitis.

The sclera is the white, fibrous, opaque protective external tunic of the eye rich in elastin and collagen fibers. It extends from the anterior to posterior chambers, i.e., limbus (corneoscleral junction) to the cribriform plate (optic nerve head). The type I collagen irregularity contributes to the opaqueness of the sclera (Keeley et al. 1984). The layers of sclera are episclera, stroma, lamina fusca, and endothelium. The sclera is continuous with the dura mater and cornea. It contributes to the maximal connective tissue layer of the eye, providing resistance against the internal and external stresses and acts as a support harboring extraocular muscular insertions. A healthy sclera appears normal and white, while one with inflammation has the scleral blood vessels engorged. While the episclera is vasculairsed, the scleral stroma is avascular receiving the nutrients from the episcleral and he underlying choroidal vasculatures. The sclera is richly supplied with nerves. The posterior ciliary nerves enters the sclera near the optic nerve.

The metabolic requirement of the sclera is low and has low turnover of the collagen. Scleral matrix is made up of scaffold of protein fibrils, collagen and elastin, and interfibrillar proteoglycans and glycoproteins, which surround a diffuse population of cells. The human sclera contains predominantly collagen which is about 50–75 % depending upon the different techniques done for estimating (Keeley et al. 1984).

The Tenon’s capsule fibroblasts synthesize the collagen (Gross 1999). These include the different types of collagen such as I, II ,V, and VI with type I followed by type III as the predominant ones, and are restricted to the outermost sclera (Heathcote 1994). The collagen fibrils of the sclera range from 25 to 300 nm as observed by electron microscopy (Komai and Ushiki 1991). There are thinner fibrils in the lamina cribrosa, trabecular meshwork, and corneoscleral angle (Albon et al. 1995). This is attributed to adaptation and the required elasticity (Parry and Craig 1984). Type XII is associated with type I fibrils in human sclera as a different isoform (Anderson et al. 2000). The elastin component of the sclera aids as additional supporting system for the collagen network. Elastin contains amino acids like alanine, valine, isoleucine, and leucine. It contains little hydroxyproline and hydroxylysine unlike collagen. It contains cross-links, namely, desmosine and isodesmosine. The elastin fibers are abundant in the inner stromal region near the extraocular muscles. There are four times more elastin in the lamina cribrosa and peripapillary sclera compared to the equatorial region (Quigley et al. 1991). The sclera matrix consists of proteoglycans. The main proteoglycans mostly belong to small leucine-rich repeat family members, namely, Decorin and Biglycan (Friedman et al. 2000). Decorin has been found to play an important role in development and wound healing, and reduced synthesis is found and seen in the development of myopia (Rada et al. 2000). Lumican found in the sclera by immunohistochemical studies is involved in regulating collagen fibrillogenesis and has been linked with high myopia in humans. Lumican deficiency causes scleral anomalies (Austin et al. 2002). Recent studies have revealed the presence of perlecan, agrin, prolargin, versican, aggregan, mimecan, and fibromodulin in scleral layers as revealed by immunofluoresence staining (Keenan, et al. 2012). These studies reveal that electron dense filaments of the decorin distribute along the collagen fibrils with a periodic pattern (Kimura et al. 1995). The C-terminal region of collagen type I binds to decorin and is also associated with type VI collagen (Keene et al. 1987).

Sclera exhibits low cellularity compared to most vascularized tissues, and the only cell is the scleral fibrocyte. Sclerocytes can undergo rapid transformation into active fibroblasts following insult like trauma, surgery, postoperative scarring and topical application of drugs, and neoplasia to the sclera. Histiocytes, blast cells, granulocytes, lymphocytes, and plasma cells can also be seen in the sclera occasionally. In inflammatory stimulus, these cells enter from blood vessels of the choroid and episclera and arrive to the site of insult. Scleral cells respond to growth factors like platelet-derived growth factor (PDGF), transforming growth factor, fibroblast growth factor, thymocyte-derived growth factors, IL-1 and interferon gamma.

Scleritis is a chronic ocular inflammatory condition of the sclera. Scleritis is marked with redness in the sclera that is diffuse or localized in a pie-shaped area. The etiology of this condition varies from idiopathic, confined to the eye to systemic autoimmune diseases and in rare cases due to infection or drug reaction as well as due to a tumor or surgical complications. Infectious scleritis can be primary or secondary to keratitis or endophthalmitis. Surgery, trauma, and the use of corticosteroids are considered as major predisposing factors (Ramenaden and Raiji 2013; Smith et al. 2007). With non-necrotizing scleritis, there is no much threat to vision unless there is presence of uveitis or keratitis. In case of necrotizing scleritis, much visible necrosis of sclera can be viewed along with the exposure of the underlying uvea, which is more often coupled with rheumatoid arthritis or systemic vasculitis (Smith et al. 2007; Sainz de la Maza and Foster 1994). Watson and Hayray (Watson and Hayreh 1976) defined five distinct classifications of scleritis, namely: