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Modulation of Inflammation and Immunity in Dry Eye Disease

Dry eye disease, or keratoconjunctivitis sicca (KCS), was traditionally considered to be caused solely by an inadequate quantity or quality of the tear film. The traditional approach to treat dry eye focuses on tear replacement with artificial tears or on conserving the patient’s tears through occlusion of the tear drainage system. These therapies have been demonstrated to decrease symptoms and signs of dry eye1 and to improve the resultant blurred vision,² but they can be considered palliative in that they do not address the immunoinflammatory process that underlies the disease. In fact, even though it is not known what triggers the pathogenic mechanism that leads to dry eye disease, a growing body of evidence suggests that chronic KCS is characterized by an inflammatory process affecting the lacrimal gland-ocular surface functional unit.³ The inflammation is responsible for feeding a vicious cycle of tear insufficiency, leading to ocular surface damage that in turn leads to symptoms and signs of chronic dry eye. Although artificial tears can have an indirect anti-inflammatory effect by lowering tear osmolarity and diluting proinflammatory factors on the ocular surface, they cannot definitively interrupt this vicious cycle of inflammation-ocular surface damage in dry eye.

Recently, topical and systemic anti-inflammatory agents, such as corticosteroids, cyclosporin A (CsA), and tetracyclines have been reported to be effective in treating ocular surface symptoms and signs by reducing the infiltration of inflammatory cells in the lacrimal gland or the inflammatory cascade in the ocular surface. Here we review the immunological aspects of the lacrimal gland and ocular surface in dry eye disease and the mechanism of action of the anti-inflammatory therapies to suggest a rational approach to treat patients with KCS.

♦ Inflammation in Dry Eye Disease

The ocular surface (cornea, conjunctiva, accessory lacrimal glands), meibomian glands, main lacrimal gland, and interconnecting neural reflex loops constitute a functional unit.³ In dry eye disease, inflammation affects all the components of the functional unit, leading to the concept that immunological circuits are an integrated part of the system. Therefore, understanding these mechanisms is the basis for a rational approach to the immunological therapy for dry eye.

Lacrimal Gland Inflammation

The lacrimal gland normally contains small populations of plasma cells and T lymphocytes (with a ratio of 2:1 of CD8 + /CD4+ cells), as well as a limited array of dendritic cells, macrophages, and B cells.⁴ In patients with Sjögren’s syndrome, focal lymphocytic infiltration of the lacrimal gland has been demonstrated.⁵ The periductal and perivascular infiltrates consist primarily of CD4+ T cells and B cells. The activated immune cells in the inflammatory infiltrate release proinflammatory cytokines, such as interleukin (IL)-1p, IL-2, interferon (IFN)-γ and tumor necrosis factor α (TNF-α). These cytokines can cause apoptosis of the glandular epithelial cells,⁶ and may expose epitopes that activate autoreactive lymphocytes,⁷ resulting in a progressive destruction of the parenchyma and in decreased secretion of tears. The direct proof of the role of the CD4+ T-cell infiltration of the lacrimal gland comes from the work of Zhu et al.⁸ They induced an autoimmune disease resembling Sjögren’s syndrome in rabbits by injecting into the lacrimal gland autologous peripheral blood lymphocytes proliferated in culture with epithelial cells obtained from the contralateral excised gland. The histopathological picture of the lacrimal glands so treated was similar to the finding in patients with Sjögren’s syndrome, with predominantly CD4+ T-cell infiltrates. Moreover, a decrease in tear production and an increase in rose bengal staining of the ocular surface were recorded. The cause of CD4+ T-cell infiltrates in the lacrimal gland of Sjögren’s syndrome has been attributed to viral infections, such as Epstein-Barr virus, hepatitis C, or human T-cell leukemia virus type 1, but currently the causative role of these viruses is uncertain.

In non-Sjögren’s dry eye disease, the lacrimal gland dysfunction is attributed to senile atrophy with lobular and periductal fibrosis, resulting in part from loss of hormonal support, particularly low levels of androgens. In a study of lacrimal glands obtained at autopsy, however, lymphocytic infiltration increased with age and was accompanied by fibrosis and acinar atrophy.⁹ Such findings suggest that the tear volume and protein content changes observed with aging^10,11 are due not only to senescent atrophy but also to immune dysfunction of the lacrimal gland.

Ocular Surface Inflammation

Clinically significant dry eye disease is associated with variable degrees of ocular surface inflammation, although the exact pathogenesis of inflammation has not been firmly established. The first step in the generation of inflammation is an inciting stimulus. This might be provided by a desiccating environmental stress and alterations in the tear film compositions secondary to lacrimal gland inflammation. It is thought that the inciting stimulus in turn leads to expression of proinflammatory mediators (cytokines, chemokines, and adhesion factors). There is indirect evidence that the ocular surface is directly involved in this first step of the inflammatory process. For example, an increased concentration of several proinflammatory cytokines (IL-1α and β, IL-6, TGF-β1, and TNF-α) in the conjunctival epithelium has been observed with a concomitant increased concentration of certain cytokines (IL-1α and β, IL-6) in the tear fluid of patients with Sjögren’s syndrome KCS.¹² Epithelial cell proliferation, keratinization, and angiogenesis can result from increased concentration of these proinflammatory cytokines.¹³ Elevated cytokine level within the tear film may create an environment in which terminal differentiation of the ocular surface epithelium is impaired, thereby impairing the epithelial surface production of mature protective surface molecules, including the membrane-spanning mucin, MUC-1.¹⁴ Chemokines such as IL-8, which is chemotactic for neutrophils, are increasingly expressed by the conjunctival epithelium of patients with Sjögren’s syndrome as shown by its increased RNA.¹² Finally, cell adhesion molecules are important proinflammatory mediators in the generation of immunity. The role of intercellular adhesion molecule 1 (ICAM-1) in predisposing ocular tissues to immune-based inflammation in patients with dry eye disease and in mice, has been demonstrated.15 The integrin leukocyte function-associated antigen 1 (LFA-1) binds to ICAM-1, which is upregulated in the lacrimal and conjunctival epithelial cells in patients with dry eye disease⁷ and may mediate leukocyte binding to vascular endothelium during acute inflammation, thus promoting lymphocyte activation and migration to the ocular .¹⁵ ICAM-1 can also provide naïve T cells with the requisite second signal for sensitization.

The next step in the generation of adaptive (antigen-specific) immunity is antigen presentation by the antigen-presenting cells (APCs) to the naïve T cells in association with major histocompatibility complex (MHC) class II molecules, leading to T-cell priming and subsequent proliferation of antigen-specific T cells. Dry eye disease has been related to a delayed-type hypersensitivity reaction (type IV hypersensitivity) mediated by CD4+ T cells. This is supported by the T-cell lymphocytic infiltration observed in conjunctival stroma and epithelium of dry eyes of patients with moderate to severe Sjögren’s syndrome.¹⁶ The T cells are predominantly CD4+, with increased expression of CD11a and CD23, indicating activated phenotype. CD4+ T_H1 cells recognize antigenic peptides in association with MHC class II molecules on the surface of APC and release proinflammatory cytokines that increase vascular permeability and recruit further inflammatory cells to the site of injury. MHC class II molecule overexpression on the surface of the nonprofessional APCs such as the conjunctival epithelial cells has been seen, which is indicative of an active role of resident epithelial cells of the ocular surface in the pathogenesis of dry eye.¹⁷

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