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 various features of the innate and adaptive arms of the immune system, see BCSC Section 9, Uveitis and Ocular Inflammation. BCSC Section 2, Fundamentals and Principles of Ophthalmology, discusses the biochemistry and metabolism of the tear film and cornea in detail.
Components of the ocular adnexa—periorbital area, eyelids and lashes, lacrimal and meibomian glands—play different but important roles in the production, spread, and drainage of the tear film. 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 1-7). The normal tear 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 significantly upregulated in a variety of corneal inflammatory diseases, such as corneal graft rejection and dry eye disease. Similarly, increased expression of growth factors, prostaglandins, neuropeptides, and proteases has been observed in a wide array of immune disorders of the ocular surface.
Figure 1-7 Immunoregulation of the ocular surface. A, Immunoregulation of the ocular surface: The ocular surface tissues contain a variety of soluble and cellular factors to reduce inflammation-induced pathology in the lacrimal functional unit. Those implicated in immunoregulation within the ocular surface tissues include the following: (1) Natural regulatory T cells (nTreg cells) (eg, CD4+, CD8+, and natural killer T cells), which include many of the conjunctival intraepithelial lymphocytes, are thought to dampen or inhibit the inflammatory/ autoimmune response on the ocular surface. (2) The anti-inflammatory cytokine transforming growth factor β (TGF-β) is present on the ocular surface and has profound suppressive effects on resident dendritic cell (DC) maturation in the cornea; proliferation, differentiation, and survival of autoreactive T cells; and Treg cell differentiation and maintenance. The activity of the potent acute-response, proinflammatory cytokine interleukin-1 (IL-1) is modulated by the IL-1 receptor antagonist (IL-1RA), which is expressed and secreted by corneal and conjunctival epithelial cells. Vasoactive intestinal peptide (VIP) also seems to be protective; VIP secreted by sensory nerve endings in the cornea increases production of TGF-β and IL-10 and inhibits expression of the proinflammatory cytokines and chemokines, IL-1β, tumor necrosis factor α, interferon-γ, and chemokine (C-X-C motif) ligand 2. Hormones are also implicated in curbing inflammation and maintaining homeostasis. In addition, the corneal epithelium expresses vascular endothelial growth factor (VEGF) receptor-1 to sequester VEGF and reduce neovascularization. (3) Antigen-presenting cells (APCs) bearing self-antigen derived at the ocular surface may migrate to the regional lymph nodes to induce antigen-specific Treg cells (iTreg cells). B, Immunoregulation in the lymphoid organs: nTreg cells may exert their immunosuppressive function through (1) release of soluble factors (eg, TGF-β, IL-10); (2) cell–cell contact, which disables pathogenic effector T cells (Teff cells) and/or APCs; and/or (3) competition for soluble factors (eg, IL-2). (4) iTreg cells may use similar mechanisms to inhibit cells bearing or responding to autoantigens. It is possible that these Treg-dependent mechanisms may also function within the ocular surface tissues. C, Other peripheral immunoregulatory mechanisms: additional mechanisms also limit access and effector function of autoreactive T cells within the ocular surface tissues: (1) TGF-β and (2) nTreg and iTreg cells are thought to suppress infiltrating autoreactive lymphocytes, and (3) low-level expression of integrins in endothelial cells of the healthy ocular surface, coupled with expression of the programmed death ligand-1 (PD-L1), negatively regulates activated T cells within the ocular surface tissues.
(Modified with permission from 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.)
The normal, uninflamed conjunctiva contains polymorphonuclear leukocytes (neutrophils), lymphocytes (including regulatory T cells [Treg cells], which dampen the immune response), macrophages, plasma cells, and mast cells. The conjunctival stroma has an endowment of dendritic antigen-presenting cells (APCs). The conjunctival epithelium contains a special subpopulation of dendritic APCs known as Langerhans cells, which are capable of both uptake of antigens and priming (sensitizing) of naive (antigen-inexperienced) 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 has a plentiful supply of 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 Treg cells, which return to the ocular surface to modulate and suppress the local immune response.
The normal, uninflamed cornea, like the conjunctiva, is also endowed with dendritic cells. Like those in the conjunctiva, the dendritic APCs in the corneal epithelium are Langerhans cells. They are located primarily in the corneal periphery and limbus (Fig 1-8). These APCs are in an activated, 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 peripheral 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 Treg cells in the regional lymph nodes and perhaps at the local level as well. See also Chapter 11 on corneal graft rejection.
Figure 1-8 Langerhans cells. 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.)
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.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.