VIPergic receptors [7]. Norepinephrine, a sympathetic neurotransmitter, binds to α1-adrenergic and β-adrenergic receptors. A neural innervation of the accessory lacrimal glands has been reported [8Ð10]. Fibers found to be positive for calcitonin gene-related peptide (CGRP) and substance P were associated with secretory tubules, interlobular and excretory ducts, and blood vessels. However, the degree of neural inßuence over accessory lacrimal glands has not been as clearly proven as it has for orbital lacrimal glands.

13.5.2 Goblet Cells

Sensory, sympathetic, and parasympathetic neuropeptides are present in the conjunctiva [11]. Conjunctival goblet cells have a secretory response to the parasympathetic cholinergic muscarinic output from the pterygopalatine ganglion. Goblet cells express M3-muscarinic receptors on their membranes. M1 and M2 receptors are located all through the conjunctiva [12]. α(alpha)1A-adrenergic and β(beta)3-adrenergic receptors are found on conjunctival goblet cells, suggesting the presence of sympathetic nerves.

13.5.3 Meibomian Glands

Transmission electron microscopy of meibomian glands has demonstrated the presence of unmyelinated axons with granular and agranular vesicles. Substance P-positive and CGRPpositive axons have been identiÞed [13, 14], but their functions are uncertain because these neurological peptides would be expected to conduct information to the CNS. It is likely that parasympathetic Þbers innervating the meibomian glands are present at higher levels. Parasympathetic neurotransmitters, neuropeptide Y and VIP, have been found around the meibomian glands, as well as tyrosine hydroxylase in sympathetic axons, implicating that both types of autonomic nerves may play a role in stimulating lipid secretion onto the ocular surface.

Patients with lacrimal keratoconjunctivitis commonly complain of constant corneal sensations, normally described as gritty, sandy, or itchy. These complaints are usually accompanied by pathophysiological changes including a chronic inßammation and a dysfunctional tear Þlm composition. InÞltrating inßammatory cells onto the ocular surface have been reported in dry eye [15Ð17]. These inßammatory cells, in addition to antibodies to gangliosides and other neural proteins, could result in regional degeneration of small diameter axons and their terminals. Chronic dysfunction of the lacrimal functional unit results in a shift toward inßammation and more persistent psychological distress.

13.6Maintenance of the Lacrimal Functional Unit

13.6.1 Hormonal

The LFU is maintained through the activities of the endocrine and immune systems. Initial data indicated that the presence of androgen hormones provided an anti-inßammatory environment over the ocular surface essentially acting as physiological steroids. Androgenic hormones provide an immunosuppressive umbrella to help protect the secretory immune function of the lacrimal glands and the meibomian glands [18Ð 20]. Perimenopausal and postmenopausal women have relative androgen deÞciency, which may be a cause for the higher prevalence of dry eye in women. Interestingly, SjšgrenÕs syndrome keratoconjunctivitis sicca (KCS) arises almost exclusively in women [21]. There is also a body of data that indicates that estrogens can be antiinßammatory and help protect the ocular surface. In most probability, the balance between the two is the key hormonal factor, and it is currently well known that there is a redundant series of cells, both circulating and resident in the ocular surface, which provides a strong immunosuppressive environment in order to prevent the formation of chronic inßammatory disease.

13.6.2 Immunological

Several types of immunoregulatory cells are present at the ocular surface to restrain activation and inÞltration of autoreactive lymphocytes to the ocular surface in an acute inßammatory event. The ocular surface is constantly being surveyed by immunovigilant T cells. These immunovigilant T cells undergo apoptosis if no threat is detected. CD4+CD25+FoxP3+ regulatory T cells have recently been shown to modulate dry eye disease in an experimental mouse model of dry eye [16, 22]. The exact mechanisms by which CD4+CD25+FoxP3+ regulatory T cells and resident intraepithelial lymphocytes (including γδ(gamma/delta)-T cells, natural killer cells, and CD8+ T cells) contribute to the anti-inßammatory environment remain to be determined. CD8+ Tregs in secondary lymphoid organs are crucial for ablating Th1 and Th2-mediated phlogistic responses and have been extensively studied using models of anterior chamber-associated immune deviation (ACAID) [23, 24]. The role of efferent CD8+ Tregs following direct ocular surface injury has not been elucidated.

13.7Conjunctival-Associated Lymphoid Tissue (CALT)

Exogenous antigen comes into contact with mucosal surfaces, such as the conjunctiva, and encounters both the innate and adaptive defensive immune systems. In the conjunctiva, the adaptive immune system includes the conjunctival-associated lymphoid tissue (CALT) [25, 26]. The CALT contains lymphoid cells within and beneath the conjunctival epithelium. This mucosal defensive system is also present in the tear drainage system and the lacrimal glands [27]. Knop and Knop [146] have proposed that the mucosal-associated lymphoid tissue of the ocular surface exists as a whole defense unit, the eye-associated lymphoid tissue.

13.8The Normal Ocular Surface Environment

The ocular surface environment is regulated in large part by tears. The tear Þlm serves four important functions: maintenance of a smooth high-quality optical surface, maintenance of ocular surface comfort, protection from environmental and infectious insults, and maintenance of epithelial cell health.

First, the tear Þlm is a critical component of the eyeÕs optical system. It and the anterior surface of the cornea combine to provide approximately 80% of the refractive power for the eyeÕs focusing mechanism [28]. Even a small change in tear Þlm stability and volume will signiÞcantly change the quality of vision (primarily contrast sensitivity) [29, 30]. The lens and its controlling anatomy ÒÞne-tuneÓ this refractive power. Tear Þlm breakup causes optical aberrations that can degrade the quality of images focused on the retina [31]. Accordingly, the irregular preocular tear Þlm of patients with SjšgrenÕs syndrome lacrimal keratoconjunctivitis may be responsible for symptoms of visual fatigue and photophobia [32Ð34].

Second, the tear Þlm helps maintain ocular surface comfort by continuously lubricating the ocular surface. The normal tear Þlm is subjected to a shear force of about 150 dynes/cm2 by the superior lid margin traversing the ocular surface during a normal blink cycle [28, 35]. Non-Newtonian properties of the tear ÞlmÕs mucin layer decrease this shear force, which would otherwise be exerted on the ocular surface epithelium, to a negligible level [36]. In lacrimal keratoconjunctivitis, alterations of the mucin layer render the ocular surface epithelial cell membranes more susceptible to this shear force, resulting in increased epithelial desquamation and induction of pathological apoptosis [37].

Third, the tear Þlm protects the ocular surface from environmental and infective intrusions. The ocular surface is the most environmentally exposed mucosal surface of the body. It continually encounters temperature extremes, low