Chapter 7

Ocular Involvement

Stephen C. Pflugfelder, Karyn Siemasko, and Michael E. Stern

Contents

7.1Sjögren’s Syndrome: A Disease of the Lacrimal Functional Unit

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by diminished production and secretion of tears by the lacrimal glands and saliva by the salivary glands resulting in keratoconjunctivitis sicca and stomatitis sicca, respectively. The estimated prevalence of primary SS (pSS) in the USA is 1.3 million individuals

S.C. Pflugfelder (*) • M.E. Stern

Department of Ophthalmology¸ Ocular Surface Center, Cullen Eye Institute, Baylor College of Medicine, Houston, TX, USA

K. Siemasko

Biological Sciences, Allergan, Inc, Irvine, CA, USA

and the prevalence is 10–20 greater in women [1–4]. Primary SS is an autoimmune inflammation to self-antigens in the lacrimal and salivary glands in the absence of a defined systemic autoimmune disease. Multiple factors, including defective immunoregulation, genetic background, and environmental insults (e.g., desiccating stress and viral infection) have been proposed in the pathogenesis of glandular and mucosal autoimmunity in pSS [5–7]. In secondary SS, salivary and lacrimal gland inflammation develops in the presence of an existing autoimmune disease, such as rheumatoid arthritis, systemic lupus erythematosus, or scleroderma [8, 9].

The main and accessory lacrimal glands, along with the conjunctiva, cornea, meibomian glands, and their interconnecting neural network comprise the lacrimal functional unit (LFU) [10]. SS causes profound dysfunction of multiple components of the LFU, resulting in severe chronic dry eye [11].

7.2Components of the Lacrimal Functional Unit

The LFU is essential in maintaining a homeostasis on the ocular surface by maintaining a stable tear film of normal composition. Factors in healthy tears support and protect the conjunctiva and cornea. The tear fluid contains numerous proteins, including enzymes, growth factors (e.g., epidermal growth factors) and antimicrobial factors such as secretory IgA, cystatins, and defensins. The tear film is currently considered to be a hydrated mucin gel [12]. It is composed of three major components, including mucins secreted by the stratified ocular surface epithelial and conjunctival goblet cells, aqueous produced by the lacrimal glands, and lipids secreted by the meibomian glands [13].The conjunctiva and corneal epithelia express membrane-tethered mucins 1, 2, and 16 that make up the glycocalyx that lubricates the ocular surface and binds the tear mucin layer to the hydrophobic epithelial cell surface [14].

MUC5AC is a soluble mucin secreted by conjunctival goblet cells, and the lacrimal glands contribute MUC-7 to the tear film [15–17]. Mucins are thought to clear pathogens, provide ocular surface lubrication, and serve as a barrier function to microbial invasion and inflammatory cellular infiltration of the ocular surface [18, 19]. The aqueous component secreted by the lacrimal glands contains trophic and protective factors including growth factors, immunoglobulin A, lactoferrin, lysozyme, defensins, interleukin-1 receptor antagonist, and electrolytes [13]. Finally, the meibomian glands secrete the lipid layer that functions to decrease tear film evaporation. A stable tear film keeps the cornea surface smooth, continuously lubricates the ocular surface, protects it from microbial infections and environmental insults, and delivers factors to maintain well-being of the epithelial surface. As the primary refracting surface of the eye, a healthy and stable tear film is essential for high quality vision. Tear film instability and the corneal epithelial disease that develops in dry eye can decrease functional vision and contrast sensitivity [20–22]. Consequently, many SS patients experience blurred and fluctuating vision, visual fatigue, and severe photophobia [22, 23]. Even small alterations in tear composition resulting from disease of the LFU in SS can produce deleterious consequences for the ocular surface.

7.3Lacrimal Gland

The lacrimal gland secretes tears produced by acinar and ductal epithelia on demand. The main lacrimal gland, consisting of the palpebral and orbital lobes, is located in the superior temporal orbit. The accessory lacrimal glands consist of the glands of Krause that are located in the upper fornix and glands of Wolfring in the superior conjunctiva just above the upper edge of the tarsus. The majority of tear secretion by the lacrimal glands is reflexive, in response to neural stimulation [24]. Innervating parasympathetic cholinergic nerves release acetylcholine that binds to the muscarinic 3 acetylcholine receptor (M3R) located on the basolateral cell membranes of lacrimal gland secretory epithelia [25, 26]. In addition, the cholinergic neurotransmitter VIP interacts with the type I and type II VIP receptors on these cells [27]. Binding of acetylcholine and VIP to their respective receptors activates signaling pathways, leading to the fusion of secretory granules with the apical membrane, membrane ion transporter activation, and ion pump insertion to coordinate electrolyte secretion and regulate tear osmolarity. Sympathetic nerves also innervate the lacrimal gland. The binding of norepinephrine to a1- and b-adrenergic receptors increases Ca+ flux into the cytosol [28]. Finally, the neurotransmitters substance P and calcitonin gene-related peptide (CGRP) are released by sensory nerves in the lacrimal glands [25].

Proteins secreted by the lacrimal gland are synthesized and mannosylated in the endoplasmic reticulum. As the proteins move through the Golgi complex, the carbohydrate groups are modified. While in the trans-Golgi apparatus, proteins are assembled into transport vesicles and packaged into secretory vesicles. The lacrimal gland contains T and B lymphoid follicles and IgA-producing plasma cells that surround the acini. These lymphocytes make up what has been referred to as the mucosal-associated lymphoid tissue (MALT).

7.4Conjunctiva

The conjunctiva covers the majority of the ocular surface and functions as the major support system for the cornea by producing tear components and supplying immune and inflammatory cells [29]. The conjunctiva has three topographic zones: bulbar, palpebral, and forniceal. The conjunctiva forms a continuous mucosal surface over these three zones. The bulbar conjunctiva covers the anterior surface of the globe, the palpebral conjunctiva lines the inner surface of the eyelids, and the forniceal conjunctiva connects the palpebral and bulbar conjunctiva. The conjunctiva consists of two components, the stratified nonkeratinized secretory epithelium and the underlying stroma. Goblet cells comprise approximately 5–20% of conjunctival epithelial cells. These specialized cells secrete MUC5AC mucin and TGF-b2 into the tears [30]. The conjunctiva is also a source of the sIgA found in tears [31]. The lamina propria of the conjunctiva is vascularized and contains numerous bone marrow-derived cells, including macrophages, mast cells, lymphocytes, plasma cells, and dendritic cells [31].