Chapter 1 BCSC PDF

CHAPTER 1 Structure and Function of the External Eye and Cornea This chapter includes a related video. Go to www.aao.org/bcscvideo_section08 or scan the QR code in the text to access this content. This chapter includes a related activity. Go to www.aao.org/bcscactivit...

CHAPTER 1 Structure and Function of the External Eye and Cornea This chapter includes a related video. Go to www.aao.org/bcscvideo_section08 or scan the QR code in the text to access this content. This chapter includes a related activity. Go to www.aao.org/bcscactivity_section08 or scan the QR code in the text to access this content. Indicates selected key points within the chapter. Highlights The external eye has both anatomical and immunologic defense mechanisms for protection against infection and other ocular conditions. Knowledge of corneal anatomy is vital for an understanding of corneal disease clas- sifications and mastery of evolving keratoplasty techniques. The cornea is a transparent and avascular tissue. Transparency results from the organization of keratocytes, fibers, and the extracellular matrix within the corneal stroma as well as the delicate balance of forces controlling stromal water content. Eyelids The functions of the eyelid include eye protection, tear distribution, ocular surface cleaning, regulation of light exposure, and contribution to the tear film. Except for fine vellus hairs, the eyelashes (cilia) are the only hairs of the eyelid. Eyelashes catch small particles and work as sensors to stimulate reflex eyelid closure. Blinking stimulates the lacrimal pump to release tears, which are then spread across the cornea, flushing away foreign material. Most indi- viduals blink an average of 10–15 times per minute at rest, 20 times per minute or more dur- ing a conversation, and as few as 5 times per minute when concentrating (eg, reading). Blink frequency also changes in different positions of gaze. The orbicularis oculi muscle, which is innervated by cranial nerve (CN) VII, closes the upper and lower eyelids (Fig 1-1). The leva- tor palpebrae muscle, innervated by CN III, inserts into the tarsal plate and skin and elevates the upper eyelid. The Müller muscle, innervated by sympathetic nerves, also contributes to the elevation of the upper eyelid. The inferior tarsal muscle helps retract the lower eyelid. 3 4 External Disease and Cornea Preaponeurotic orbital fat Orbicularis oculi muscle (orbital portion) Levator palpebrae Orbital septum muscle Orbicularis oculi muscle Peripheral arterial arcade (preseptal portion) Eyelid crease Müller muscle (non-Asian) Gland of Wolfring Levator aponeurosis Conjunctiva Orbicularis oculi muscle (pretarsal portion) Tarsus Meibomian gland Eyelid crease (Asian) Marginal arterial arcade Gland of Zeis Gland of Moll Cilium A Figure 1-1 The eyelid. A, Illustration of a cross section of the upper eyelid. (Continued) The epidermis of the eyelids abruptly changes from keratinized to nonkeratinized stratified squamous epithelium at the mucocutaneous junction of the eyelid margin, along the row of meibomian gland orifices. Holocrine sebaceous glands and eccrine sweat glands are present in the eyelid skin. Near the eyelid margin are apocrine sweat glands (the glands of Moll) and numerous modified sebaceous glands (the glands of Zeis). For additional discussion of eyelid anatomy, see BCSC Section 2, Fundamentals and Principles of Ophthalmology, and Section 7, Oculofacial Plastic and Orbital Surgery. Argilés M, Cardona G, Pérez-Cabré E, Rodríguez M. Blink rate and incomplete blinks in six different controlled hard-copy and electronic reading conditions. Invest Ophthalmol Vis Sci. 2015;56(11):6679–6685. Lin LK, Gokoffski KK. Eyelids and the corneal surface. In: Mannis MJ, Holland EJ, eds. Cornea. Vol 1. 4th ed. Elsevier; 2017:40–45.  CHAPTER 1: Structure and Function of the External Eye and Cornea 5 Goblet cells Tarsus Tarsal conjunctiva Muscle of Riolan “Grey line” Substantia propria Meibomian glands Orbicularis Cilia Glands of Moll oculi muscle Zeis glands Epidermis B Goblet cell Figure 1-1 (continued) B, Hematoxylin-eosin (H&E) stained section of the normal eyelid. (Part A illustration by Christine Gralapp, part B © American Academy of Ophthalmology 2020.) Lacrimal Functional Unit The lacrimal functional unit (LFU) comprises the lacrimal glands, ocular surface, and eyelids, as well as the sensory and motor nerves that connect these components (Video 1-1; Fig 1-2). The LFU is responsible for the following: regulation, production, health, and integrity of the tear film (carrying out lubricat- ing, antimicrobial, and nutritional roles) health of the ocular surface (maintaining corneal transparency and the surface stem cell population) quality of the image projected onto the retina VIDEO 1-1 Perception of touch and innervation of the lacrimal functional unit. Modified with permission from Pflugfelder SC, Beuerman RW, Stern ME, eds. Dry Eye and Ocular Surface Disorders. Published by CRC Press. © Marcel Dekker; 2004, reproduced by arrangement with Taylor & Francis Books UK. 6 External Disease and Cornea Nasociliary nerve Lacrimal nerve Frontal nerve Ciliary Long ciliary ganglion nerve Carotid artery CN V nucleus Superior CN V1 salivatory nucleus CN V2 CN V3 CN VII motor nucleus Conjunctival afferents Infraorbital nerve Geniculate Sphenopalatine ganglion ganglion Afferent sensory fibers Efferent parasympathetic fibers Efferent sympathetic fibers Figure 1-2 The sensory and motor nerves connecting the components of the lacrimal func- tional unit. CN = cranial nerve. (Modified with permission from Pflugfelder SC, Beuerman RW, Stern ME, eds. Dry Eye and Ocular Surface Disorders. Published by CRC Press. © Marcel Dekker; 2004, reproduced by arrangement with Taylor & Francis Books UK.) The LFU responds to environmental, endocrinologic, and cortical influences. The afferent component of the LFU is mediated through ocular surface and trigeminal no- ciceptors, which synapse with the efferent nerves (autonomic and motor nerves) in the brainstem. The autonomic nerve fibers innervate the meibomian glands, conjunctival gob- let cells, and lacrimal glands. The motor nerve fibers innervate the orbicularis muscle to initiate blinking. During blinking, the meibomian glands express lipid, and the tears are replenished from the inferior tear meniscus and spread across the cornea while excess tears are directed into the lacrimal puncta. Pflugfelder SC, Beuerman RW, Stern ME, eds. Dry Eye and Ocular Surface Disorders. CRC Press/Taylor & Francis; 2004. Tear Film The tear film is currently thought to be a mixed gel consisting of soluble mucus, fluids, and proteins that are contributed by the lacrimal gland, conjunctival goblet cells, and surface epithelium (Fig 1-3). This hydrophilic gel moves over the glycocalyx of the superficial corneal epithelial cells and is topped by a lipid layer produced by the meibomian glands. A healthy tear film is critical for both good vision and a healthy eye. Functions of the tear film include maintaining a smooth optical surface between blinks contributing to refractive power of the eye through the air–tear film interface removing irritants, pathogens, toxins, allergens, and debris  CHAPTER 1: Structure and Function of the External Eye and Cornea 7 Conjunctiva Goblet cells Lacrimal gland Lipid Mucin gel Glycocalyx Corneal Corneal epithelium nerve Membrane-associated mucins (MUC 1, 4, and 16) Lactoferrin Cleaved membrane mucins Defensins Goblet cell mucin, MUC5AC MMP-9 EGF TGF-β IL-1RA IgA TIMP1 Figure 1-3 The tear film consists of a mixed mucin/aqueous layer produced by the lacrimal glands, conjunctival goblet cells, and surface epithelium. It is topped by a lipid layer produced by the meibomian glands. Its functions include lubrication (mucins), healing (epidermal growth factor [EGF]), and protection of the cornea against infection (lactoferrin, defensins, immunoglobu- lin A [IgA]). When the tear film is inflamed, it produces interleukin 1 receptor antagonist (IL-1RA), transforming growth factor β (TGF-β), and tissue inhibitor of matrix metalloproteinase 1 (TIMP 1). MMP-9 = matrix metalloproteinase 9. (Modified with permission from Pflugfelder SC. Tear dysfunction and the cornea: LXVIII Edward Jackson Memorial Lecture. Am J Ophthalmol. 2011;152(6):902, with permission from Elsevier.) facilitating the diffusion of oxygen and other nutrients to the cornea and conjunctiva maintaining homeostasis of the normal ocular flora contributing to the antimicrobial defense of the ocular surface Maintenance of the tear film is thus critical to normal corneal function. Pflugfelder SC. Tear dysfunction and the cornea: LXVIII Edward Jackson Memorial Lecture. Am J Ophthalmol. 2011;152(6):900–909. Conjunctiva The conjunctiva can be broadly divided into 3 geographic zones as follows: palpebral, or tarsal: starts at the mucocutaneous junction of the upper and lower eyelids and covers the inner eyelid; it is tightly adherent to the underlying tarsus bulbar: covers the ocular surface and is loosely attached to the Tenon capsule; it inserts into the limbus forniceal: covers the superior and inferior fornices The plica semilunaris is a crescent-shaped vertical fold of conjunctiva, located at the medial angle of the eye. The caruncle—a fleshy, ovoid mass approximately 5 mm high and 3 mm wide—is attached to the inferomedial side of the plica semilunaris and contains 8 External Disease and Cornea goblet cells and lacrimal tissue, as well as hairs, sebaceous glands, and sweat glands. This area also contains the lacus lacrimalis (lacrimal lake), a small triangular space where tears accumulate after bathing the ocular surface. The cell morphology of the conjunctival epithelium varies from stratified cuboidal over the tarsus and columnar in the fornices to squamous on the globe. Goblet cells account for up to 10% of basal cells of the conjunctival epithelium and are most numerous in the palpe- bral conjunctiva, the inferonasal bulbar conjunctiva, and the area of the plica semilunaris. The substantia propria of the conjunctiva consists of loose connective tissue. Conjunctiva- associated lymphoid tissue (CALT), which consists of lymphocytes and other leukocytes, is present, especially in the fornices. Lymphocytes interact with mucosal epithelial cells through reciprocal regulatory signals mediated by growth factors, cytokines, and neuropeptides. The palpebral conjunctiva shares its blood supply with the eyelids. The bulbar con- junctiva is supplied by the anterior ciliary arteries, which arise from muscular branches of the ophthalmic artery. These capillaries are fenestrated and leak fluid, producing chemo- sis (conjunctival swelling), as a response to allergies or other inflammatory events. Sclera The sclera is the opaque, white, fibrous tissue that extends from the corneal limbus to the optic nerve, where it merges to form the dural sheath of the optic nerve. It is divided into 3 layers (from outermost inward): episclera, stroma, and lamina fusca. The scleral stroma is composed of collagen fibers, which have varied orientation, separation, and diameter, resulting in the sclera’s opaque appearance in contrast to the cornea. The sclera receives its vascular supply from the anterior and posterior ciliary arteries and drains through the vortex veins. The thickness of the sclera ranges from 0.3 mm to 1 mm; it is thinnest behind the insertions of the rectus muscles. It is innervated by the ciliary nerves of cranial nerve V1. For additional discussion of the sclera, see BCSC Section 2, Fundamentals and Princi- ples of Ophthalmology, and Section 4, Ophthalmic Pathology and Intraocular Tumors. Cornea The cornea is a transparent, avascular tissue that consists of 5 layers (Activity 1-1; Fig 1-4): epithelium, Bowman layer, stroma, Descemet membrane, and endothelium; these are dis- cussed in the subsections that follow. In adults, the cornea measures approximately 11–12 mm horizontally and 10–11 mm vertically. It is 500–600 µm thick at its center, gradually increasing in thickness toward the periphery. ACTIVITY 1-1 Corneal layers and corresponding confocal images. Confocal images courtesy of Danielle Trief, MD, and David D. Verdier, MD. For nutrition, the cornea depends on diffusion of glucose from the aqueous humor and diffusion of oxygen through the tear film. The peripheral cornea is supplied with oxygen  CHAPTER 1: Structure and Function of the External Eye and Cornea 9 Epithelium Bowman layer Stroma Descemet membrane Endothelium Figure 1-4 The layers of the normal cornea. The epithelium is composed of 4–6 cell layers, but it can increase in thickness to maintain a smooth surface (H&E, x32). from the limbal circulation. The density of nerve endings in the cornea is among the high- est in the body, and the sensitivity of the cornea is 100 times that of the conjunctiva. Sen- sory nerve fibers extend from the long ciliary nerves, penetrating the cornea in the deep peripheral stroma near the limbus and coursing anteriorly to form a subepithelial plexus. Zones of the Cornea The cornea is aspheric, although the central portion of the anterior corneal surface has been described as a spherocylindrical convex mirror. The central cornea is typically 3.00 diopters (D) steeper than the periphery, a positive shape factor (prolate). Clinically, the cornea can be divided into 5 zones (Fig 1-5) as follows: central zone: 1–3 mm in diameter; closely resembles a spherical surface paracentral zone: a 3–4 mm “doughnut” surrounding the central zone; has an outer diameter of 7–8 mm and progressively flattens out from the center apical zone: comprises the paracentral and central zones, used in contact lens fit- ting; is primarily responsible for the refractive power of the cornea peripheral or transitional zone: adjacent to the paracentral zone, has an outer dia- meter of approximately 11 mm; is the area of greatest flattening and asphericity in the normal cornea limbal zone (limbus): where the cornea steepens prior to joining the sclera at the limbal sulcus; outer diameter averages 12 mm 10 External Disease and Cornea Limbal zone Peripheral zone Paracentral zone Central zone Limbus Pupil border Figure 1-5 Topographic zones of the cornea. (Illustration by Christine Gralapp.) Other corneal reference definitions include the following: optical zone: the portion of the cornea that overlies the entrance pupil of the iris corneal apex: the point of maximum curvature, typically temporal to the center of the pupil corneal vertex: the point located at the intersection of the line of fixation and the corneal surface; represented by the corneal light reflex when illuminated coaxially with fixation. It is the center of the keratoscopic image and does not necessarily cor- respond to the point of maximum curvature at the corneal apex (Fig 1-6) Corneal Epithelium The hydrophobic corneal epithelium is composed of 4–6 layers, which include 1–2 layers of superficial squamous cells, 2–3 layers of broad wing cells, and an innermost layer of co- lumnar basal cells. It is 40–50 µm thick (see Fig 1-4; also see the Pachymetry section in Chapter 2). The epithelium and tear film form an optically smooth surface. Tight junctions between superficial epithelial cells prevent penetration of tear fluid into the stroma. Con- tinuous proliferation of limbal stem cells gives rise to the other layers, which subsequently differentiate into superficial cells. With maturation, these differentiated cells become coated with microvilli on their outermost surface (glycocalyx) and then desquamate into the tears. The process of differentiation takes approximately 7–14 days. Basal epithelial cells secrete a continuous, 50-nm-thick basement membrane, which is composed of type IV collagen, laminin, and other proteins. Corneal clarity depends on the tight packing of epithelial cells, which results in a layer with a nearly uniform refractive index and minimal light scattering. Bowman Layer Bowman layer lies anterior to the corneal stroma. Previously considered a membrane, Bowman layer is rather the acellular condensate of irregularly arranged collagen fibrils at  CHAPTER 1: Structure and Function of the External Eye and Cornea 11 Optical axis Line of sight (visual axis) Corneal apex Corneal vertex Temporal Nasal Figure 1-6 Corneal vertex and apex. (Illustration by Christine Gralapp.) the most anterior portion of the stroma (see Fig 1-4). This layer is 15 µm thick and helps maintain the shape of the cornea. If disrupted, it will not regenerate. Corneal Stroma The corneal stroma accounts for roughly 90% of total corneal thickness (see Fig 1-4). It is composed of stromal cells (keratocytes), fibers, and an extracellular matrix. The anterior stroma is denser than the posterior stroma due to an increased number of keratocytes and greater interweaving of collagen lamellae. The anterior 40% of the corneal stroma has twice the tensile strength of the posterior 60%. This difference between the anterior and posterior stroma may play a role in the occurrence of corneal ectasia following deep excimer laser ablation. Keratocytes vary in size and density throughout the stroma and form a 3-dimensional network throughout the cornea. These cells, which are flattened fibroblasts, are located be- tween the stromal collagen lamellae (Fig 1-7) and continually digest and manufacture stromal molecules. Keratocyte density declines with age and also following laser refractive surgery. The extracellular matrix of the corneal stroma is formed from collagens and proteo- glycans. Type I and type V fibrillar collagens are intertwined with filaments of type VI collagen. The major corneal proteoglycans are decorin (associated with dermatan sulfate) and lumican (associated with keratan sulfate). The even distribution of keratocytes, fibers, and the extracellular matrix in the corneal stroma is necessary for a clear cornea. Corneal transparency also depends on maintaining the water content of the corneal stroma at 78%. Corneal hydration is largely controlled by intact epithelial and endothelial barriers and the functioning of the endothelial pump, which is linked to an ion-transport system controlled by temperature-dependent enzymes 12 External Disease and Cornea Stromal Fibroblasts lamellae 10 µm A B Figure 1-7 Keratocytes (A) are flattened fibroblasts (B) that are situated between the stromal collagen lamellae. (Part A courtesy of Nishida T, Yasumoto K, Otori T, Desaki J. The network structure of corneal fibroblasts in the rat as revealed by scanning electron microscopy. Invest Ophthalmol Vis Sci. 1988;29(12):1887–1890. Part B reproduced with permission from Oyster CW. The Human Eye: Structure and Function. Oxford University Press; 1999:331. Reproduced with permission of the Licensor through PLSclear.) such as Na+,K+-ATPase. In addition, negatively charged stromal glycosaminoglycans tend to repel each other, producing a swelling pressure (SP). Because intraocular pressure (IOP) tends to compress the cornea, the overall imbibition pressure of the corneal stroma is calculated as IOP—SP. Corneal hydration varies from anterior to posterior and increases closer to the endothelium. The most posterior aspect of the stroma forms a thin, acellular layer (15-µm thick) that is tightly adherent to Descemet membrane. This novel layer is called pre-Descemet layer, or Dua layer, and is important in deep anterior lamellar keratoplasty (DALK). Dua layer is strong and resists air dissection from Descemet membrane. During DALK, air is injected on the stromal side of Dua layer to create a big-bubble stromal dissection, form- ing a type I bubble. This bubble is sturdier and less likely to tear or burst, in contrast to an air dissection between Dua layer and Descemet membrane (a type II bubble). Dua HS, Faraj LA, Said DG, Gray T, Lowe J. Human corneal anatomy redefined: a novel pre- Descemet’s layer (Dua’s layer). Ophthalmology. 2013;120(9):1778–1785. Randleman JB, Dawson DG, Grossniklaus HE, McCarey BE, Edelhauser HF. Depth- dependent cohesive tensile strength in human donor corneas: implications for refractive surgery. J Refract Surg. 2008;24(1):S85–S89. Schlötzer-Schrehardt U, Bachmann BO, Tourtas T, et al. Ultrastructure of the posterior corneal stroma. Ophthalmology. 2015;122(4):693–699. Sridhar M. Anatomy of the cornea and ocular surface. Indian J Ophthalmol. 2018; 66(2): 190–194. Descemet Membrane Descemet membrane is the basement membrane of the corneal endothelium (see Fig 1-4). Its thickness increases with age; at birth, it is 3 µm, increasing to 10–12 µm by adulthood. It is composed of an anterior banded zone that develops in utero and a posterior amorphous, non- banded zone that is laid down throughout life. The Schwalbe line is a gonioscopic landmark that defines the end of the Descemet membrane and the beginning of the trabecular meshwork.  CHAPTER 1: Structure and Function of the External Eye and Cornea 13 Corneal Endothelium Corneal endothelial cells lie on the posterior surface of the cornea (see Fig 1-4), compos- ing a monolayer of closely interdigitated cells arranged in a mosaic pattern of mostly hex- agonal shapes. If cell loss occurs, especially as a result of trauma or surgery, the defective area is initially covered through a process of cell enlargement and spread of surrounding cells or perhaps peripheral stem cells. These cell findings can be observed by specular or confocal microscopy as polymegethism (variability in cell size) and polymorphism (vari- ability in cell shape). It was previously thought that the corneal endothelial cells were unable to replicate. Scientists are now investigating whether these cells have some mitotic ability, particularly the cells in the corneal periphery. Migration of these cells may be aug- mented by pharmacological agents such as Rho kinase inhibitors. Cell density varies throughout the endothelial surface; the concentration is typically highest in the periphery. Central endothelial cell density decreases with age at an average rate of approximately 0.6% per year, diminishing from a count of about 3400 cells/mm2 at age 15 years to about 2300 cells/mm2 at age 85 years. The normal central endothelial cell count is between 2000 and 3000 cells/mm2. It has been observed that eyes with an endo- thelial cell count below 500 cells/mm2 may be at risk for development of corneal edema. As mentioned earlier, the corneal endothelium helps maintain corneal transpar- ency by controlling corneal hydration and maintaining stromal deturgescence. It does so through its functions as a barrier to the aqueous humor and as a metabolic pump that moves ions, and draws water osmotically, from the stroma into the aqueous humor. The barrier and pump functions of the endothelium can be measured clinically by fluoropho- tometry and pachymetry. The endothelium must also be permeable to nutrients and other molecules from the aqueous humor. Increased permeability and insufficient pump sites occur with reduced endothelial cell density, although the cell density at which clinically evident edema occurs is not an absolute. For more detailed information on the histology and physiology of the cornea, see BCSC Section 2, Fundamentals and Principles of Ophthalmology, Chapter 8. Amann J, Holley GP, Lee SB, Edelhauser HF. Increased endothelial cell density in the paracentral and peripheral regions of the human cornea. Am J Ophthalmol. 2003; 135(5): 584–590. Bourne WM. Biology of the corneal endothelium in health and disease. Eye (Lond). 2003; 17(8): 912–918. DelMonte DW, Kim T. Anatomy and physiology of the cornea. J Cataract Refract Surg. 2011; 37(3):588–598. Gambato C, Longhin E, Catania AG, Lazzarini D, Parrozzani R, Midena E. Aging and corneal layers: an in vivo corneal confocal microscopy study. Graefes Arch Clin Exp Ophthalmol. 2015;253(2):267–275. Koizumi N, Okumura N, Ueno M, Kinoshita S. New therapeutic modality for corneal endothelial disease using Rho-associated kinase inhibitor eye drops. Cornea. 2014;33(11):S25–31. Nishida T, Saika S, Morishige N. Cornea and sclera: anatomy and physiology. In: Mannis MJ, Holland EJ, eds. Cornea. Vol 1. 4th ed. Elsevier; 2017:1–22. Whikehart DR, Parikh CH, Vaughn AV, Mishler K, Edelhauser HF. Evidence suggesting the existence of stem cells for the human corneal endothelium. Mol Vis. 2005;11: 816–824. 14 External Disease and Cornea Limbus The limbus is the transition zone between the transparent cornea and the opaque sclera. This area harbors corneal epithelial stem cells, which are responsible for the normal ho- meostasis and wound repair of the corneal epithelium. The palisades of Vogt, which are concentrated in the superior and inferior limbus, are thought to be the site of the limbal stem cells’ niche and can be observed biomicroscopically as radially oriented fibrovas- cular ridges concentrated along the corneoscleral limbus (Fig 1-8). The posterior limbus appears to be responsible for stem cell maintenance, while the function of the anterior limbus may be to prompt regeneration of corneal epithelium. Stem cells have an unlimited capacity for self-renewal and are slow cycling (ie, they have low mitotic activity). Once stem cell differentiation begins, it is irreversible. Renewal occurs from basal cells, with centripetal migration of stem cells from the periphery. This is known as the XYZ hypothesis, where X represents proliferation and stratification of lim- bal basal cells; Y, centripetal migration of basal cells; and Z, desquamation of superficial cells. The health of the cornea depends on the sum of X and Y being equal to Z. Damage to epithelial stem cells impairs long-term regeneration of corneal epithelial cells. Damage to the limbus leads to loss of the barrier that prevents invasion of the conjunctiva and neovascularization of the ocular surface. Singh V, Shukla S, Ramachandran C, et al. Science and art of cell-based ocular surface regeneration. Int Rev Cell Mol Biol. 2015;319:45–106. Yoon JJ, Ismail S, Sherwin T. Limbal stem cells: central concepts of corneal epithelial homeostasis. World J Stem Cells. 2014;6(4):391–403. Defense Mechanisms of the External Eye and Cornea The external eye and cornea comprise complexly integrated tissues that, along with the tear film, help protect the eye against infection. For an in-depth discussion of the im- mune system, see BCSC Section 9, Uveitis and Ocular Inflammation. BCSC Section 2, Figure 1-8 Slit-lamp photograph showing the corneoscleral limbus with radially oriented fi- brovascular ridges (palisades of Vogt). (Courtesy of Cornea Ser vice, Paulista School of Medicine, Federal University of São Paulo.)  CHAPTER 1: Structure and Function of the External Eye and Cornea 15 Fundamentals and Principles of Ophthalmology, discusses the biochemistry and metabo- lism of the tear film and cornea. As discussed earlier, the tear film serves as a protective layer, washing away irritants and pathogens and diluting toxins and allergens. Each functional blink promotes tear turnover. Tears are secreted from the lacrimal gland and spread across the cornea while excess tears are directed into the lacrimal puncta; all of these actions reduce the contact time of microbes and irritants with the ocular surface. Immunoregulation of the ocular surface occurs through tolerance and regulation of the innate and adaptive arms of the ocular immune response (Fig 1-9). The normal tear C A Immunoregulation VIP TGF-β Androgens iDC TGF-β Teff IL-10 2 1 T8 cell IL-1RA 1 2 TGF-β iTreg nTreg CD8+ TGF-β PD-L1 Treg mDC CD4+ Teff Treg IL-10 TGF-β TGF-β 3 IL-10 To draining LN PD-L1 VCAM1 ICAM 3 Efferent response Afferent response 4 mDC IL-35 iTreg 1 nTreg APC (Ag-specific iTreg) IL-2 IL-10 TGF-β IL-2R nTreg nTreg Teff 3 cAMP, eg, TGF-β, 2 granzyme b APC APC Teff B Figure 1-9 Reducing inflammation on the ocular surface. A, The following soluble and cellular factors on the ocular surface lead to a reduction in inflammation: (1) Natural regulatory T cells (nTreg cells, which include CD4, CD8, and natural killer cells). (2) The anti-inflammatory cyto- kine transforming growth factor β (TGF-β), IL-1 receptor antagonist (IL-1RA, which dampens the (Continued) 16 External Disease and Cornea Figure 1-9 (continued) pro-inflammatory cytokine IL-1), and vasoactive intestinal peptide (VIP). (3) Hormones such as androgen. Together, these factors suppress maturation of the mature dendritic cell (mDC) and survival of autoreactive T cells. B, In the lymphoid organs, nTreg cells continue to suppress inflammation by (1) releasing anti-inflammatory cytokines (TGF-β, IL-10); (2) directly disabling pathogenic effector T cells (Teff cells) through cell contact; (3) competing for soluble factors (eg, IL-2); (4) inhibiting cells bearing or responding to autoantigens. C, Back on the ocular surface, autoreactive lymphocytes (Teff) are suppressed by TGF-β and nTreg and iTreg cells. Activated T cells are also negatively regulated by programmed death ligand-1 (PD-L1), coupled with integrins on endothelial cells. (Modified with permission from Springer Nature. Stern ME, Scha- umburg CS, Dana R, Calonge M, Niederkorn JY, Pflugfelder SC. Autoimmunity at the ocular surface: pathogenesis and regulation. Mucosal Immunol. 2010;3(5):425–442.) film contains components of the complement cascade, proteins, growth factors, and an array of cytokines. Cytokines such as interleukin 1 and tumor necrosis factor α are sig- nificantly upregulated in a variety of corneal inflammatory diseases, such as corneal graft rejection and dry eye disease. Increased expression of growth factors, prostaglandins, neu- ropeptides, and proteases has been observed in a wide array of immune disorders of the ocular surface. The normal, uninflamed conjunctiva contains neutrophils, lymphocytes (including regulatory T cells, which dampen the immune response), macrophages, plasma cells, and mast cells. The conjunctival stroma contains dendritic antigen-presenting cells (APCs). The conjunctival epithelium has a special subpopulation of dendritic APCs known as Langerhans cells, which are capable of both uptake of antigens and sensitizing of antigen- inexperienced (naïve) T lymphocytes. Hence, these dendritic cells serve as the sentinel cells of the immune system of the ocular surface. In addition to containing immune cells, the conjunctiva is supplied with blood vessels and lymphatic vessels, which facilitate the trafficking of immune cells and antigens to the draining lymph nodes, where the adaptive immune response is generated. This occurs Figure 1-10 Langerhans cells. Langerhans cells are a subclass of dendritic antigen present- ing cells (APCs) found on the cornea and conjunctival epithelium. This micrograph shows the predominance of major histocompatibility complex class II+ Langerhans cells in the limbus of the uninflamed eye. (Courtesy of the laboratory of M. Reza Dana, MD.)  CHAPTER 1: Structure and Function of the External Eye and Cornea 17 through the recruitment of regulatory T cells, which return to the ocular surface to modu- late and suppress the local immune response. Like the conjunctiva, the normal, uninflamed cornea is endowed with dendritic cells. These dendritic APCs in the corneal epithelium are also Langerhans cells. They are lo- cated primarily in the corneal periphery and limbus (Fig 1-10). These APCs are in an acti- vated, mature state (expressing class II major histocompatibility complex [MHC] antigens and costimulatory molecules) and hence are capable of efficiently stimulating T cells. In addition to these dendritic cells, small numbers of lymphocytes are present in the periph- eral epithelium and anterior stroma of the cornea. A highly regulated process, mediated by vascular endothelial adhesion molecules and cytokines, controls the recruitment of the various leukocyte subsets from the intravascular compartment into the limbal matrix. Immune responses are also mediated by regulatory T cells in the regional lymph nodes and perhaps at the local level as well. See Chapter 13 for discussion of immune-related disorders and corneal graft rejection. Ecoiffier T, Yuen D, Chen L. Differential distribution of blood and lymphatic vessels in the murine cornea. Invest Ophthalmol Vis Sci. 2010;51(5):2436–2440. Niederkorn JY. Cornea: window to ocular immunology. Curr Immunol Rev. 2011;7(3): 328–335. Stern ME, Schaumburg CS, Dana R, Calonge M, Niederkorn JY, Pflugfelder SC. Autoimmunity at the ocular surface: pathogenesis and regulation. Mucosal Immunol. 2010;3(5):425–442.