Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

Prognosis and complications

Complications from the decrease in lacrimal gland secretion in aqueous-deficient dry eye are infections, blepharitis, and conjunctivitis.8 Dry-eye patients who wear contact lens are particularly susceptible to these complications.17 Keratinization is a second complication that comes from a loss of conjunctival goblet cells that produce the gel-forming mucins in the mucous layer of the tear film. Other complications that can be the result of severe aqueous deficiency such as occurs in Sjögren syndrome dry eye are band keratopathy, limbal stem cell deficiency, sterile stromal ulcers and corneal perforation, and keratoconus-like changes.8 Lacrimal gland deficiency is not the only contributor to these complications. Finally chronic aqueous tear-deficient dry eye, especially Sjögren syndrome, can have debilitating psychological effects, because of the lack of definitive treatments and cures, and can have substantial implications for quality of life.8

Pathology

The difficulty in removing biopsy samples from the human lacrimal gland makes pathological studies of the lacrimal gland difficult, although postmortem samples can be obtained. Available evidence indicates that there is an age-dependent lymphocytic infiltration of the lacrimal gland in dry eye similar to that which occurs in Sjögren syndrome.18–20 The indirect effects of aqueous deficiency on the conjunctiva can be measured by impression cytology and conjunctival biopsy

and include loss of goblet cells, squamous cell metaplasia, increased desquamation, and eventually keratinization.

Etiology

The etiology of aqueous deficiency dry eye can be divided into Sjögren and non-Sjögren dry eye (Figure 14.2). NonSjögren dry eye can result from a variety of causes that include alteration of tear secretion, destruction of the lacrimal gland, or closure of the lacrimal gland secretory ducts (Figure 14.3).8 Obstruction of the tear drainage system or an alteration in its drainage properties can also affect the amount of tears in the tear film.21 Two important mechanisms for the alteration or loss of lacrimal gland secretion are changes in the sensory nerves in the cornea that drive lacrimal gland secretion and systemic medications. Laser in situ keratomileusis (LASIK) surgery and contact lens wear cause dry eye from the alteration in corneal activity. For a complete listing of etiology of aqueous-deficiency dry eye, see Gulati and Dana.8

Pathophysiology

Mechanisms of aqueous-deficiency dry eye

As proposed by the 2007 International Dry Eye Workshop10 and the Cullen Symposium,22 the core mechanisms of dry eye can be divided into tear hyperosmolarity and tear film

Box 14.1  Multiple signaling pathways control

lacrimal gland secretion

Neuronal

•Cholinergic agonists stimulate secretion using the phospholipase C/Ca2+/protein kinase C pathways, but attenuate secretion using phospholipase D and p44/p42 mitogen-activated protein kinase (MAPK) pathways

•α1D-Adrenergic agonists stimulate secretion using the nitric oxide/cyclic guanosine monophosphate and Ca2+/protein kinase C pathways, but attenuate secretion using the endothelial growth factor (EGF)/EGF receptor/ p44/p42 MAPK pathway

•Vasoactive intestinal peptide stimulates secretion using the cyclic adenosine monophosphate and Ca2+ pathways

Hormonal

•Androgens regulate secretory immunoglobulin A production

•Prolactins regulate cellular trafficking of secretory proteins

Figure 14.3  Schematic of the neural regulation of lacrimal gland electrolyte, water, and protein secretion illustrating the components that can be affected causing aqueous-deficient dry-eye disease. A decrease in lacrimal gland secretion (lacrimal gland deficiency) contributes to tear hyperosmolarity and dry eye by four major mechanisms: (1) interruption in the activation of (a) sensory nerves in the cornea or conjunctiva and (b) efferent parasympathetic and sympathetic nerves that innervate the lacrimal gland; (2) destruction of the lacrimal gland by apoptosis; (3) mechanical damage to the lacrimal gland excretory ducts; and (4) alteration in the lacrimal drainage system. CNS, central nervous system.

instability. Lacrimal gland deficiency primarily contributes to tear hyperosmolarity resulting from a decrease in fluid secretion. The causes of lacrimal gland deficiency can be divided into three categories: (1) alteration in stimulation of secretion; (2) destruction of the lacrimal gland; and (3) occlusion of lacrimal secretory ducts (Figure 14.3 and Box 14.1).8

Alteration in stimulation of secretion

Lacrimal gland secretion is predominantly under neural control. Stimuli from the external environment activate sensory nerves in the cornea and conjunctiva. By a neural reflex these nerves activate the parasympathetic and sympathetic nerves that surround the lacrimal gland secretory cells, the acinar and ductal cells (Figure 14.3 and Box 14.2). In humans it is well known that lacrimal gland secretion of both protein and electrolytes/water is stimulated by acetylcholine released from the parasympathetic nerves interacting with M3 cholinergic receptors (M3AChR) on the secretory cells (Figure 14.4).23 The signaling pathways activated by these receptors have been investigated in the rat lacrimal gland and include activation of phospholipase C (PLC) to produce 1,3,4-inositol trisphosphate. This compound releases Ca2+ from intracellular stores to increase the intracellular [Ca2+] and causes an increase in Ca2+ influx to maintain

Box 14.2  Mechanisms responsible for aqueous-

deficiency dry eye

Alterations in stimulation of lacrimal gland secretion

•Blockage of afferent sensory nerves from the ocular surface

•Blockage of efferent parasympathetic and sympathetic nerves in the lacrimal gland

•Inhibition of lacrimal gland cellular signaling pathways

Destruction of the lacrimal gland

•Congenital absence or functional alteration

•Injured by trauma

•Injured by disease

Occlusion of lacrimal gland secretory ducts by disease

elevated Ca2+ levels. An increase in PLC activity also produces diacylglycerol that activates protein kinase C isoforms. Both an increase in intracellular Ca2+ and activation of protein kinase C stimulate lacrimal gland secretion. Parasympathetic nerves also release the neuropeptide vasoactive intestinal peptide (VIP) that stimulates secretion of both protein and electrolytes/water (Figure 14.5).23 That this is an important mechanism in humans was demonstrated in a patient with a VIP-secreting tumor in whom the tear volume was increased and the osmolarity decreased compared to normal ageand sex-matched controls.24 In the rat and rabbit lacrimal gland VIP stimulates protein and fluid secretion by binding to its receptors (VPAC and II) that activate adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP). Increased cellular levels of cAMP activate protein kinase A (PKA) to induce secretion. β-Adrenergic agonists released from sympathetic nerves are minor stimuli of the cAMP-dependent pathway (Figure 14.5). The third signaling pathway that, in the rat, has been shown to activate protein secretion, is an α1D-adrenergic pathway activated by release of norepinephrine from the sympathetic nerves

Parasympathetic

nerve

Proteinsecretion

H2Oelectrolytes

Figure 14.4  Schematic of the parasympathetic, cholinergic signaling pathway used to stimulate lacrimal gland protein, electrolyte, and water secretion. Stimulation of parasympathetic nerves releases their neurotransmitter acetylcholine (ACh) that binds to and activates muscarinic type 3 ACh receptors (M3AChR) in the cell membrane. This interaction induces a stimulatory pathway involving phospholipase Cβ (PLCβ), Ca2+, and the protein kinase C (PKC) isoforms α, δ, and ε. ACh also induces an inhibitory pathway through the nonreceptor tyrosine kinases Pyk2 and Src that activate the p44/p42 mitogen-activated protein kinasae (MAPK) cascade (Ras, Raf, and MEK). Activation of the inhibitory pathway attenuates stimulated secretion. Gαq, a stimulatory subtype of guanine nucleotidebinding protein; IP3, 1,4,5-inositol trisphosphate. (Reproduced with permission from Dartt DA. Exp Eye Res 2001;73:741–752.)

Pathophysiology

Sympathetic Parasympathetic nerve

nerve

Figure 14.5  Schematic of cyclic adenosine monophosphate (cAMP)- dependent signaling pathways leading to production of lacrimal gland proteins, electrolytes, and water. Stimulation of the parasympathetic and sympathetic nerves releases their neurotransmitters vasoactive intestinal peptide (VIP) and norepinephrine, respectively. Both neurotransmitters bind to their receptors, VIP receptors I and II for VIP and β-adrenegic receptors for norepinephrine and increase the cellular levels of cAMP. cAMP is synthesized from adenosine triphosphate (ATP) by activating the guaninebinding proteins Gas to stimulate adenylyl cyclase (AC). The cAMP produced activates protein kinase A (PKA). cAMP is broken down by cAMP phosphodiesterases (PDE) to produce 5’adenosine monophosphate (AMP). VIP also increases intracellular Ca2+. (Modified with permission from Dartt DA. Regulation of lacrimal gland secretion by neurotransmitters and the EGF family of growth factors. Exp Eye Res 2001;73:741–752.)

(Figure 14.6). Activation of α1D-adrenergic receptors stimulates protein secretion by inducing endothelial nitric oxide synthase to produce nitric oxide. Nitric oxide activates guanylyl cyclase to produce cGMP that in turn activates protein kinase G to stimulate protein secretion.25 Electrophysiology experiments in rats and mice suggest that this pathway could also cause electrolyte and water secretion.

Surprisingly, in rat lacrimal gland, cholinergic and α1D- adrenergic agonists also activate inhibitory pathways that can attenuate stimulated secretion. Cholinergic agonists activate the nonreceptor tyrosine kinases Pyk2 and Src to stimulate p44/p42 mitogen-activated protein kinase (MAPK) or ERK1/2 that decreases secretion (Figure 14.4).26 α1D-Adrenergic agonists activate the matrix metalloproteinase ADAM 17 that releases the active site of membranespanning epidermal growth factor (EGF). The active site interacts with the EGF receptor, causing it to be phosphorylated (Figure 14.6).27 The phosphorylated receptor attracts adapter proteins that stimulate a cascade of kinases to activate MAPK that decreases secretion.

Neurotransmitters released from activated nerves stimulate acinar and duct cells to secrete proteins. A list of pro-

teins secreted by the lacrimal gland has been compiled.23,28 Multiple secretory proteins are antibacterial as the tears function in the innate defense system. Other proteins are growth factors that sustain and maintain the health of the ocular surface. At least three different secretory processes are used for protein secretion, exocytosis, ectodomain shedding, and transcytotic secretion (secretory IgA). Additionally, electrolytes and water are secreted transcellularly and paracellularly. All these secretory processes are under neural control, with additional hormonal control of secretory IgA production.

Fluid (electrolytes and water) secretion occurs by activation of ion channels, Na/K-ATPase, and other ion transport mechanisms described in detail elsewhere.23 The net result is the secretion of a plasma-like primary fluid containing Na+, K+, and Cl– into the lumen. The primary fluid is modified by secretion of proteins, electrolytes, and water by the duct cells. In particular the duct cells secrete K+ so that the final lacrimal gland fluid is higher in potassium than plasma. The mechanism of ductal electrolyte secretion is described by Ubels et al.29 With low flow rates lacrimal gland fluid is hypertonic, but with stimulation causing higher flow rates, lacrimal gland fluid is isotonic.30

While nerves acutely stimulate protein and fluid secretion, systemic hormones can regulate expression of key components of these processes. Androgens stimulate the synthesis of secretory component and hence the production of secretory IgA, a slower process than mediated by nerves. In addition androgens can influence the synthesis of Na/K-ATPase, the driving force for neurally mediated fluid secretion.31 The peptide hormone prolactin can also function as a systemic hormone and a paracrine mediator of secretion by altering the cellular trafficking of the enzymes used in synthesis and storage of secretory proteins.32,33

Neural and hormonal stimulation of secretion can be interrupted at several points by different processes (Figure 14.3).

1.Activation of sensory nerves in the cornea and conjunctiva can be blocked. This can be the result of overuse of topical anesthetics, contact lens wear, refractive surgery, infection, neurotrophic keratitis, herpetic keratitis, diabetes mellitus, and aging.8 If ocular surface sensory nerves are blocked, secretion is either decreased or completely prevented. In either case tear

110

osmolarity increases (becoming hyperosmolar) from decreased lacrimal gland flow rate and the amount of lacrimal gland secretory proteins released by exocytosis is decreased.

2.Activation of efferent nerves to the lacrimal gland can be blocked (Figure 14.3). In familial dysautonomia, there is dysfunction of the sensory nerves of the cornea as well as the sympathetic and parasympathetic nerves to the lacrimal gland.10 This defect blocks both afferent and efferent innervation to the gland and prevents secretion of protein, electrolytes, and water. Defects in both afferent and efferent nerves can lead to agedependent lacrimal gland hyposecretion. Finally, dysfunction of the efferent nerves has been suggested to play a role in the pathology of Sjögren syndrome based on an animal model, the MRL/Mp-Faslpr mouse. In Sjögren syndrome T lymphocytes (CD4+ and smaller amount of CD8+ cells) infiltrate the lacrimal gland,

forming foci and producing inflammatory cytokines such as interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α).34–37 Androgens play a role here as well, as androgens normally produce

anti-inflammatory cytokines such as transforming growth factor β (TGF-β). In androgen deficiency anti-inflammatory cytokine production is decreased, leading to production of proinflammatory cytokines from lymphocytes.38 Production of proinflammatory cytokines by the lymphocytes, in a positive-feedforward mechanism, stimulates the lacrimal gland acinar cells to produce these destructive cytokines.39 IL-1β can prevent release of neurotransmitters from efferent nerve endings, blocking stimulation of lacrimal gland secretion in both Sjögren syndrome and aging.34,39–41

3.Alteration in signaling pathways: systemic medications can induce aqueous-deficiency dry eye by altering the signaling pathways that induce lacrimal gland secretion

(Figure 14.3). Antimuscarinics block the M3AChR that is necessary for the stimulation of secretion. Antihistamines, as a side-effect, can also block the

M3AChR.42 Multiple other systemic medications have antimuscarinic effects that would cause aqueousdeficiency dry eye. Beta-adrenergic blockers can cause vasoconstriction and would decrease lacrimal gland fluid secretion stimulated by parasympathetic nerve release of acetylchline and VIP.43 Diuretics such as furosemide can decrease lacrimal gland secretion by blocking the ion transport processes that are vital for electrolyte and water secretion.41 The signaling pathways are also altered in aging when not only does the release of neurotransmitters with age fail to stimulate secretion, the neurotransmitter agonists fail as well.40

Destruction of the lacrimal gland

The lacrimal gland can be absent in congenital alacrima, injured by trauma, or injured by disease (Figure 14.3). Diseases that injure the lacrimal gland include aging, graft- versus-host-disease, and Sjögren syndrome. In rat and mouse models of aging there are increased numbers of mast cells and lymphocyte foci along with increased lipofuscin accumulation, fibrosis, and acinar atrophy in the lacrimal gland.40,44,45 In graft-versus-host disease there is uncontrolled fibrosis and excessive accumulation of extracellular matrix proteins in the lacrimal gland of patients with this disease.46 Another hypothesis for lacrimal gland deficiency is that acinar cells are lost due to apoptosis. In mouse lacrimal gland injection of IL-1β can induce massive apoptosis that is reversed within days, suggesting that the proinflammatory cytokines can destroy the acinar cells.47 The evidence that apoptotic cell death leads to lacrimal gland hyposecretion in Sjögren syndrome or other dry-eye diseases has not yet been substantiated.

Occlusion of lacrimal secretory ducts

Lacrimal gland fluid stimulated by nerves is secreted on to the ocular surface through a number of ducts (Figure 14.3). Dry eye occurs when this duct system is blocked by diseases such as trachoma, cicatricial pemphigoid, erythema multiforme, and chemical and thermal burns.8,10 The dry eye that occurs is a mechanical consequence of secreted lacrimal gland fluid failing to reach the ocular surface.

Conclusion

Suggested mechanism of role of lacrimal gland deficiency in dry-eye disease

The following hypothetical mechanism for the role of the lacrimal gland in dry-eye disease has been suggested.1,22,48 Under normal conditions, stimuli from the external environment activate sensory nerves in the cornea and conjunctiva that in turn stimulate efferent parasympathetic and sympathetic nerves to cause secretion of proteins, electrolytes, and water from the lacrimal gland on to the ocular surface in an isotonic fluid (Figure 14.3). Lacrimal gland secretions, combined with those of the other glands and epithelia that secrete tears, nourish and maintain a healthy, painfree ocular surface and a transparent cornea. As shown in Figure 14.7, dry eye can be caused by blocking: (1) afferent sensory nerves in the ocular surface by refractive surgery, contact lens wear, neurotrophic keratitis, or topical anesthesia; (2) efferent parasympathetic and sympathetic nerves that innervate the lacrimal gland that occurs in Sjögren syndrome and aging; (3) lacrimal gland cellular signaling pathways by systemic drugs, aging, androgen deficiency, and Sjögren syndrome, some of which produce inflammatory damage to the lacrimal gland; and (4) release of lacrimal gland fluid due to mechanical damage to the ducts occurring in scarring diseases of the ocular surface. The decreased lacrimal gland flow leads to tear hyperosmolarity that induces inflammation in the cornea and conjunctiva. This inflammation is a vicious circle that produces proinflammatory cytokines in the ocular surface epithelial cells. The cytokines can irritate the sensory nerves in the ocular surface and cause: (5) increased reflex drive to the lacrimal gland (not illustrated) or (6) neurogenic inflammation and the release of sensory neurotransmitters from the ocular surface sensory nerves. The released sensory neurotransmitters further exacerbate the disease by affecting the mucins of the goblet cells and stratified squamous cells of the cornea and conjunctiva. The meibomian gland also enters the picture as its dysfunction causes tear instability and increased evaporation, further exacerbating the dry eye. The role of ocular surface inflammation, mucins, and meibomian glands in dry eye will be presented in detail in Chapter 15.

Conclusion

The lacrimal gland is the major producer of the aqueous layer of the tear film and the primary target of aqueous deficiency, in contrast to evaporative, dry-eye disease. Diagnosing aqueous-deficiency dry-eye disease and distinguishing this form from other types of dry-eye disease is problematic because: (1) there is no gold-standard sign or symptom for aqueous-deficiency dry eye; and (2) many individuals have overlapping types of dry-eye disease. These problems lead to inaccuracy in diagnosing the disease, calculating incidence and prevalence, and treating the disease. In spite of this inadequacy, research has elucidated substantial information on the normal regulation and mechanism of lacrimal gland electrolyte, water, and protein secretion. This research can be used to describe the pathophysiology of the lacrimal gland in dry eye, identify potential targets for drug treatments of aqueous-deficiency dry eye, and unravel potential sites of disease vulnerability in the regulation and mechanism of lacrimal gland secretion.

+

–Mechanical –

Blepharitis, Lid flora Lipases esterases

detergents

Ocular injury Preservatives CL wear?

+

Tear film instability

Goblet cell glycocalyx mucin loss epithelial damage - apoptosis

IL-1

TNFα +

MMPs

Refractive surgery

Contact lens wear

Topical anesthesia

Aging

Two important questions about the pathophysiology of the lacrimal gland in dry-eye disease remain unanswered. First, what initiates age-related and non-Sjögren dry eye? Second, which cellular mechanisms are altered in these types of dry eye to cause the decrease in lacrimal gland secretion and damage to the ocular surface?

Acknowledgment

The author thanks Robin Hodges for her contributions to the manuscript and NIH EY06177 for funding.

1.The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:75–92.

3.Mircheff AK, Wang Y, Jean M de S, et al. Mucosal immunity and self-tolerance in the ocular surface system. Ocul Surf 2005;3:182–192.

4.Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:179–193.

7.Gulati A, Sullivan R, Buring JE, et al. Validation and repeatability of a short questionnaire for dry eye syndrome. Am J Ophthalmol 2006;142:125–131.

8.Gulati A, Dana M. Keratoconjunctivitis sicca: clinical aspects. In: Foster C, Azar D, Dohlman C (eds) Smolin and Thoft’s The Cornea. Philadelphia: Lippincott Williams & Wilkins, 2005:603–627.

12.Schaumberg DA, Sullivan DA, Buring JE, et al. Prevalence of dry eye syndrome

among US women. Am J Ophthalmol 2003;136:318–326.

15.Management and therapy of dry eye disease: report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:163–178.

21.Paulsen FP, Schaudig U, Thale AB. Drainage of tears: impact on the ocular surface and lacrimal system. Ocul Surf 2003;1:180–191.

22.McDermott AM, Perez V, Huang AJ, et al. Pathways of corneal and ocular surface inflammation: a perspective from the Cullen Symposium. Ocul Surf 2005; 3(Suppl.):S131–S138.

23.Hodges RR, Dartt DA. Regulatory pathways in lacrimal gland epithelium. Int Rev Cytol 2003;231:129–196.

25.Hodges RR, Shatos MA, Tarko RS, et al. Nitric oxide and cGMP mediate alpha1D-adrenergic receptor-stimulated protein secretion and p42/p44 MAPK activation in rat lacrimal gland. Invest

Ophthalmol Vis Sci 2005;46:2781– 2789.

27.Chen L, Hodges RR, Funaki C, et al. Effects of alpha1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells. Am J Physiol Cell Physiol 2006; 291:C946–C956.

29.Ubels JL, Hoffman HM, Srikanth S, et al. Gene expression in rat lacrimal gland

duct cells collected using laser capture microdissection: evidence for K+ secretion by duct cells. Invest Ophthalmol Vis Sci 2006;47:1876–1885.

38.Sullivan DA. Tearful relationships? Sex, hormones, the lacrimal gland, and aqueous-deficient dry eye. Ocul Surf 2004;2:92–123.

39.Zoukhri D, Hodges RR, Byon D, et al. Role of proinflammatory cytokines in the impaired lacrimation associated with autoimmune xerophthalmia. Invest Ophthalmol Vis Sci 2002;43: 1429–1436.

Clinical background

Key symptoms and signs

The symptoms of dry-eye disease are discussed in detail in Chapter 14. A point that bears emphasis is that patient presentation is extremely variable. Patients may experience troublesome symptoms but present none of the standard clinical signs and even have increased fluid production; may report symptoms and show ocular surface pathology but have normal fluid production; or may show decreased fluid production but deny symptoms.

Historical development

Papers describing fibrotic and atrophic changes in the lacrimal glands of aged subjects began appearing in the late nineteenth century. In 1903 Schirmer noted that fluid production varied widely among normal individuals but tended to decrease with increasing age and to decrease more severely in women. Later investigators1 substantiated Schirmer’s conclusions. In the 1930s, Sjögren introduced the terms “keratoconjunctivitis sicca” (KCS) and “sicca complex,” and reported findings from patients with the sicca complex and arthritis, including documentation of inflammatory changes in glands obtained from several of the affected individuals.

The concept of autoimmune diseases emerged in the subsequent decade, along with the discovery that patients’ sera frequently contained antibodies directed against certain tissues or intracellular structures. Bloch and Bunim2 showed that the sicca complex and glandular histopathology occurred in patients with other autoimmune diseases in addition to rheumatoid arthritis. Bloch et al3 reported that the sicca complex and autoantibody titers also occurred in patients with no sign of autoimmune disease affecting other tissues. The distinction between primary Sjögren’s syndrome and secondary Sjögren’s syndrome was established by the mid-1970s.

The nature of lacrimal gland atrophy and dysfunction outside the setting of Sjögren’s syndrome and other inflammatory diseases has been somewhat controversial. Examining lacrimal gland and salivary gland histology in autopsy

Austin K Mircheff and Joel E Schechter

subjects, Waterhouse4 found at least slight adenitis in the lacrimal glands of between 8% and 22% of men in different age groups, with no indication of an age-associated increase. In contrast, the frequency of adenitis, which he interpreted as an autoimmune phenomenon, increased in women, from 22% in women younger than 44 years to 65% in women 75 and older. Whaley et al5 determined the frequency of decreased Schirmer test scores and increased rose Bengal staining in inpatients hospitalized for various indications but explicitly excluding autoimmune diseases. Because they found no correlation between the ocular surface findings and various autoantibodies, they concluded that dry-eye disease in their subjects was due to atrophic changes, rather than autoimmune phenomena. Subsequent postmortem and biopsy studies, discussed in detail in the section on pathology below, documented the frequency of ageassociated fibrosis and parenchymal atrophy, and they generally also demonstrated associations with increased lymphocytic infiltration.

A development in oral pathology is of interest in this context. Daniels and Whitcher6 described histopathological features of labial salivary glands from patients who could and could not be diagnosed as having Sjögren’s syndrome on the basis of serum autoantibodies and clinical diagnoses of xerostomia and dry eye. Their conclusion might seem paradoxical to those who have been taught that the pathophysiology of Sjögren’s syndrome is autoimmune-mediated destruction of the secretory parenchyma: While parenchyma was replaced by lymphocyte aggregates, Sjögren’s syndrome cases were distinguished by an absence of acinar atrophy or ductal dilatation, even in parenchymal areas immediately adjacent to large aggregates.

Epidemiology

This topic is reviewed in Chapter 14.

Genetics and risk factors

There is a significant genetic influence on the incidence of Sjögren’s syndrome, since having a first-degree relative with an autoimmune disease increases the risk sevenfold.7 An association between human leukocyte antigen (HLA) DR

Box 15.1  Gender-related lacrimal gland

dimorphisms

The rodent lacrimal gland is subject to gender-related dimorphisms. Androgens support10:

•Larger population of dimeric immunoglobulin A (dIgA)- producing plasmacytes

•Greater parenchymal expression of the polymeric immunoglobulin receptor (pIgR)

•Greater secretion of secretory IgA (sIgA) and secretory component (SC)

•Lower basal rate of fluid production

alleles and autoantibodies is recognized,8 but other reported genetic associations have been controversial.9 Having delivered a baby doubles the risk for developing Sjögren’s syndrome 2.1-fold.7

There appear to be no reports of genetic factors influencing dry-eye disease not associated with autoimmune diseases. Other risk factors are discussed in Chapter 14.

That most dry-eye patients, and the large majority of patients with Sjögren’s syndrome, are women prompted studies of sex steroid actions in animal models (Box 15.1).

Androgens clearly influence immune cell activity in the lacrimal glands and the status of the ocular surface.10–13 Rocha et al14 proposed that androgens exert their influences by controlling expression of immunomodulatory mediators by parenchymal cells; this important concept is discussed at length in the section on pathophysiology, below. However, much remains to be learned about mechanisms underlying the androgens’ influences. Gonadectomizing or hypophysectomizing experimental animals causes significant biochemical and functional changes15,16 but does not cause acinar atrophy or fibrosis on the scale of the changes that occur in the aging human lacrimal gland or normally aging rats17 and mice.18

Other hormones also influence lacrimal gland and ocular surface cytophysiology and immunophysiology. Mathers et al19 found that lacrimal fluid production correlates positively with increasing serum testosterone only in premenopausal women. In contrast, in all groups studied, i.e., premenopausal, postmenopausal without hormone replacement therapy, and postmenopausal with hormone replacement therapy, all measures of lacrimal function correlate negatively with increasing levels of serum prolactin (PRL). Notably, all subjects in this study had PRL values within the normal range.

Findings on the actions of estrogens defy explanations based on a single hormone-regulated process. Women with premature ovarian failure present increased signs and symptoms but produce fluid at normal rates.20 On the other hand, estrogen replacement therapy is associated with exacerbation of dry-eye symptoms in older women.21

Differential diagnosis, treatment, and prognosis

These topics are addressed in Chapter 14. The extent to which dry-eye disease occurs in association with local and systemic inflammatory diseases should be noted.

Pathology

Pathology

Lacrimal gland

Most studies of the histopathology of the human lacrimal gland in normal aging have confirmed the earlier finding that aging is associated with increased fibrosis, ductal pathology, acinar atrophy, and infiltration of immune cells. Damato et al22 and Pepose et al23 described the presence of lymphoid aggregates or foci, and, occasionally secondary follicles, even in individuals without a history of autoimmune disease. Roen et al24 and Obata25 noted the frequent occurrence of ductal dilatation, and Obata also documented the frequency of fatty infiltration. In an analysis of postmortem lacrimal glands, Obata et al26 found that diffuse fibrosis, diffuse acinar atrophy, and periductal fibrosis were more frequent in the orbital lobes of elderly women, and in the palpebral lobes of aging men. They also noted that the frequency of lymphoid foci increased with age and, as Wieczorek et al27 had found, that most foci were located near intralobular or interlobular ducts, i.e., those within, but at the periphery of, a lobule.

Nasu et al28 compared lacrimal glands from subjects with autoimmune diseases and with no history of autoimmune diseases. They concluded that the entire population shared common histopathological features and differed only by degree. Although the incidence of lymphoid foci was highest in patients with Sjögren’s syndrome and other autoimmune diseases, only 36% of lacrimal glands from subjects without autoimmune diseases appeared to be free of infiltrates. In the remainder, the incidence and severity of infiltration were highest among those older than 40 years and the incidence was nearly identical in males (63.9%) and females (62.8%).

The immunohistopathology of the lacrimal glands in patients with Sjögren’s syndrome presents some diversity. Pflugfelder et al29 found that, of 6 patients, lymphocytic infiltration was diffuse in 4 and focal in 2. Tsubota et al30 compared the histopathological features of the lacrimal glands of subjects with Mikulicz’s disease and Sjögren’s syndrome, which share several features, including massive infiltration by essentially identical proportions of CD4+, CD8+, and CD21+ lymphocytes. Whereas fluid production is severely impaired in patients with Sjögren’s syndrome, patients with Mikulicz’s disease retain exocrine function, and their ocular surfaces appear normal.

Conjunctiva and cornea

The corneal and conjunctival epithelia undergo marked morphological changes in dry-eye disease. The number of goblet cells in the conjunctival epithelia decreases; cells in the superficial conjunctival epithelial layers flatten, such that the epithelium thins even as the number of strata increases; cells in the most superficial layer lose most of their microvilli and separate from their normally close attachment to the penultimate layer; hyaline bodies, suggested to represent the residua of defunct goblet cells, appear in the epithelium; and vacuoles and other inclusions appear within the cytoplasm.31,32 The lamina propria underlying areas of affected epithelium becomes increasingly populated by lymphocytes and leukocytes.33 Subsequent studies have confirmed that

increased numbers of lymphocytes are present within the conjunctiva of patients with dry-eye disease. Epithelial cells expressing HLA DR (human major histocompatibility complex (MHC) class II) molecules were present in conjunctival impression cytology specimens from 50% of patients34 and in brush cytology specimens from 66% of patients35 with idiopathic dry-eye disease.

Etiology

Explicit concepts are emerging for the mechanisms by which environmental stresses, iatrogenic factors, allergy and infection, and endocrine changes can initiate dry-eye disease. Before presenting these concepts, it is appropriate to review physiological principles and cytophysiological mechanisms that influence disease development.

Pathophysiology

Nexus between the visual system and the mucosal immune system

The normal ocular surface fluid provides a microenvironment for the living epithelial cells exposed in the interpalpebral regions of the cornea and conjunctiva. Figure 15.1 illustrates the general wiring scheme by which perception of irritation or dryness in the cornea or conjunctiva elicits production of lacrimal fluid.

Lacrimal

Parasympathetic nucleus

The epithelia of the lacrimal glands, ocular surface, and lacrimal drainage system form a topological continuum with the mucosae of the respiratory system and the gastrointestinal system. The ocular surface system, like the respiratory and gastrointestinal systems, contains organized inductive sites for adaptive mucosal immunity, and it also performs both innate and adaptive mucosal immune effector functions. Even as the lacrimal epithelia perform the exocrine functions associated with production of the ocular surface fluid, they devote much of their cytophysiology to accomplishing mucosal immune effector functions.

Cytophysiological apparatus

Lacrimal epithelial cells employ ion pumps, symporters, exchangers, and channels that are common to essentially all nucleated cells. They generate vectorial ion fluxes by using transport vesicles to insert specific ion transporters into the basal, lateral and apical domains of their plasma membranes. Figure 15.2 illustrates the disposition of the ion transporters as an apparatus for secreting Cl− ions and K+ ions through the cells and Na+ ions through the paracellular pathway. This apparatus is distinct from the apparatus that secretes proteins.

Figure 15.1  Wiring of a physiological servomechanism. A perception of irritation or dryness by sensory nerve endings in the cornea and conjunctiva elicits afferent signals, which travel through the trigeminal ganglion to reach a lacrimal center in the brainstem. (Note that sensory nerve endings are also present in the lacrimal gland.) Like sensory information from the viscera, signals from the ocular surface are processed and lead to the generation of efferent autonomic secretomotor signals, even when there is no conscious awareness that the status of the ocular surface has deviated from its homeostatic setpoint. The secretomotor signals reach the lacrimal glands by way of both sympathetic and parasympathetic nerves, which release their neurotransmitters in the general vicinity of, but do not form synapses with, parenchymal epithelial cells.

Figure 15.2  The cytophysiological apparatus for exocrine secretion of Cl− ions, Na+ ions, and, in ductal cells, K+ ions. Secretion of the ions creates the osmotic driving force that causes water to move from the interstitial

space to the lumen of the acinus−duct system. Recent studies indicate that the Na+/H+ exchanger (NHE) and the Cl−/HCO3− exchanger (anion exchanger, AE) work in concert36 and in parallel with the Na+K+2Cl− symporters (NKCC)37,38 to drive Cl− ions from the interstitial fluid to the cytosol, against an unfavorable electrochemical potential difference. Secretagoguemediated opening of apical Cl− channels allows Cl− ions to flow into the lumen. Flux of Na+ ions through the paracellular pathway dissipates the lumen-negative transepithelial voltage difference that results from the transcellular flux of Cl− ions. Apical K+ channels and K+-Cl− symporters are primarily found in ductal epithelial cells.38 (Not illustrated is the fact that the transporters spend 90% of their time in the intracellular compartments depicted in Figure 15.3. Secretagogue stimulation recruits more Na,K-ATPase (NKA) pump units to the basal lateral plasma membrane and activates NHE exchangers in the basal lateral membrane.)