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 Service, Paulista School of Medicine, Federal University of São Paulo.)
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
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 cytokine transforming growth factor $ \beta $ (TGF- $ \beta $), IL-1 receptor antagonist (IL-1RA, which dampens the
C
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 through the recruitment of regulatory T cells, which return to the ocular surface to modu late and suppress the local immune response.
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 $ \mathrm{I I}^{+} $ Langerhans cells in the limbus of the uninflamed eye. (Courtesy of the laboratory of M. Reza Dana, MD.)
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.
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