Cornea 17(6): 584-589, 1998.
`
`© 1998 Lippincott Williams & Wilkins, Philadelphia
`
`The Pathology of Dry Eye: The Interaction Between
`the Ocular Surface and Lacrimal Glands
`
`Michael E. Stern, Ph.D., Roger W. Beuerman, Ph.D.,
`Robert I. Fox, M.D., Ph.D., Jianping Gao, M.S., Austin K. Mircheff, Ph.D.,
`and Stephen C. Pflugfelder, M.D.
`
`Background. Most dry-eye symptoms result from an abnor-
`mal, nonlubricative ocular surface that increases shear forces
`under the eyelids and diminishes the ability of the ocular sur-
`face to respond to environmental challenges. This ocular-
`surface dysfunction may result from immunocompromise due
`to systemic autoimmune disease or may occur locally from a
`' decrease in systemic androgen support to the lacrimal gland as
`seen in aging, most frequently in the menopausal female. Hy-
`pothesis. Components of the ocular surface (cornea, conjunc-
`tiva, accessory lacrimal glands, and meibomian glands), the
`main lacrimal gland, and interconnecting innervation act as a
`functional unit. When one portion is compromised, normal lac-
`rimal support of the ocular surface is impaired. Resulting im-
`mune-based inflammation can lead to lacrimal gland and neural
`dysfunction. This progression yields the OS symptoms associ-
`ated with dry eye. Therapy. Restoration of lacrimal function
`involves resolution of lymphocytic activation and inflamma-
`tion. This has been demonstrated in the MRL/lpr mouse using
`systemic androgens or cyclosporine and in the dry-eye dog
`using topical cyclosporine. The efficacy of cyclosporine may
`be due to its immunomodulatory and antiinflammatory (phos-
`phatase inhibitory capability) functions on the ocular surface,
`resulting in a normalization of nerve traffic. Conclusion. Al-
`though the etiologies of dry eye are varied, common to all
`ocular-surface disease is an underlying cytokine/receptor-
`mediated inflammatory process. By treating this process, it may
`be possible to normalize the ocular surface/lacrimal neural re-
`flex and facilitate ocular surface healing.
`Key Words: Dry eye—Keratoconjunctivitis sicca—Sjogren’s
`syndrome Ocular surface—Lacrimal gland—Tear film—
`Animal model—Lymphocytic infiltration—Inflammation—
`Autoimmunity—-Neural
`traffic—Apoptosis—Cytokine—
`Neural
`transmitter—Neural peptide—Cyclosporine—
`Androgen.
`
`Submitted January 16, 1998. Revision received May 29, 1998. Ac-
`cepted June 3, 1998.
`From Allergan, Irvine, California (M.E.S., J.G.), LSU Eye Center,
`New Orleans, Louisiana (R.W.B.), Scripps Research Foundation, La
`Jolla, California (R.I.F.), University of Southern California, Los An-
`geles, California (A.K.M.), University of Miami, Miami, Florida
`(S.C.P.), U.S.A.
`Address correspondence and reprint requests to Dr. M.E. Stern,
`Department of Biological Sciences, Allergan,
`lnc., 2525 Dupont
`Drive, P.O. Box 19534, Irvine. CA 92713-9534, USA. E—mail:
`stern_michael @allergan.com
`
`Dry-eye symptoms arise from a series of etiologies
`and are manifest with varying severity in different pa-
`tients, making accurate diagnosis and disease—specific
`treatment difficult. The use of artificial tears is palliative
`at best, resulting in a reduction of ocular surface eyelid
`shear forces and some transient symptomatic relief. As
`recently as 1995,
`the National Eye Institute/Industry
`Workshop on Clinical Trials in Dry Eyes, under the
`chairmanship of Dr. Michael A. Lemp, defined specific
`subtypes of dry eye to standardize clinical tests used in
`the diagnosis and design of clinical studies (1). As re-
`search in this area proceeds, the key question remains:
`What causative factor(s) initiates the sequence of events
`resulting in the clinical symptoms experienced by the
`patient?
`This review organizes observations that the ocular sur-
`face (cornea, conjunctiva, accessory lacrimal glands, and
`meibomian glands),
`the main lacrimal gland, and the
`interconnecting neural reflex loops comprise a functional
`unit (Fig. 1) whose parts act together and not in isolation.
`In the normal individual, when afferent nerves of the
`ocular surface are stimulated, a reflex results in imme-
`diate blinking, withdrawal of the head, and secretion of
`copious amounts of reflex tears from the main lacrimal
`gland. This aqueous secretion contains proteins as well
`as water. Similarly, ocular-surface irritation due to envi-
`ronmental factors (contact lens, low humidity, wind, etc.)
`results in chronic stimulation of the nerves of the ocular
`
`surface and increased secretory activity in the main and
`accessory lacrimal glands. In individuals suffering from
`dysfunction of any part of this functional unit, the tear
`production is no longer adequate to provide the volume
`and composition of normal tears necessary for homeo-
`stasis and repair.
`The remainder of this article discusses this functional
`
`unit as part of homeostatic maintenance of the normal
`ocular-surface physiology and how it is altered in dry
`eye. Overall, this system has probably developed through
`evolution to maintain the optical properties of the cornea.
`
`584
`
`1
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`ALL 2018
`MYLAN PHARMACEUTICALS V. ALLERGAN
`|PR2016-01128
`
`1
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`ALL 2018
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
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`

`

`PATHOLOGY OF DRY EYE
`
`585
`
`Secretomotor nerv
`impulses /
`
`CNS
`integration
`
`
`
`
`Sensory nerve
`impulses
`
`FIG. 1. Schematic illustration of Iacrimal gland/ocular sur-
`face servomechanism. The ocular surface (cornea, con-
`junctiva, accessory Iacrimal glands, and meibomian
`glands), the main lacrimal gland, and the interconnecting
`neural reflex loops comprise a functional unit whose parts
`act together and not in isolation.
`
`PHYSIOLOGY OF THE NORMAL
`FUNCTIONAL UNIT
`
`The ocular surface is continuously challenged by the
`shear forces of blinking across its surface (2), as well as
`several environmental factors including air currents, low
`humidity—induced desiccation, and foreign bodies (in-
`cluding contact lenses). Shear forces over the ocular sur-
`face applied during blinking (12-15 per minute) can
`
`WATER TRANSPORT
`
`corneal and/or conjunctival
`epithelium
`sensory nerve endings
`
`ll
`
`Iacrimal
`nerve
`(joins V1)
`
`omatic
`z
`nzgve
`
`\
`superior cervical
`sympathetic
`ganglion
`
`'
`‘
`
`*
`mgeminalganglion
`(15, dim of Vm)
`
`ptyregopalaline
`A
`*
`ganglion
`I
`(joins V2) nucleus trigeminal nerve
`pre-ganglionic
`medulla
`sympathetic
`neurons
`(spinal cord)
`
`vidian
`nerve
`
`Afferent and Eflerent
`Paths of Lacrimal Gland
`Innervation forstimulation
`of tear Naw
`
`geniculale
`gangllus
`(sep. from VII]
`
`Iacrimal
`nucleus
`(pans)
`
`salivatory
`nucleus
`lP°"5)
`emu route:
`(or "emotion: I lean"
`
`cause significant trauma to a nonlubricated ocular sur-
`face (2). Additionally, the ocular surface is constantly
`confronted with organisms including bacteria and vi-
`ruses. In normal individuals, the ocular surface remains
`
`intact and is able to repair the damage from these insults.
`Rapid repair of a normal ocular surface has been dem-
`onstrated with rose bengal staining. Staining that results
`from the superficial trauma induced by contact with an
`impression cytology membrane will no longer be ob-
`sewed after 24 h,
`indicating that there is a reparative
`process that actively restores the normal surface barrier
`(3). This healing is possibly due to the presence of a
`trophic surface environment driven by constituents of a
`normal noninflammatory tear film. The presence of tear
`proteins including IgA,
`lactoferrin,
`lysozyme, and
`growth factors such as epidermal growth factor and
`transforming growth factor B (TGF—B) at the appropriate
`concentrations are important for normal ocular—surface
`maintenance. Mucins produced by corneal epithelial
`cells and goblet cells in the conjunctiva] epithelium rep-
`resent a main defense mechanism against various micro-
`trauma. The wing and basal cells of the corneal epithelium
`have been shown to express mucins after wounding (4).
`Stimulation of the ocular surface initiates neural sig-
`nals resulting in aqueous tear secretion and possibly
`stimulation of mucin and lipid secretion. The ocular sur-
`face is exquisitely innervated, with the cornea having a
`density of free nerve endings ~20—4O times that of tooth
`pulp (5). Corneal sensation is very acute, centrally pro-
`cessed, and interpreted solely as pain (5,6). We believe
`that so-called basal tearing (7) results from continuous
`
`C
`
`FIG. 2. Afferent (solid red lines) and efferent (solid blue lines, parasympathetic; dotted blue
`lines, sympathetic) pathways of lacrimal gland innovation for stimulation of tear flow.
`
`Cornea, Vol. /7, No. 6, 1998
`
`2
`
`

`

`586
`
`M.E. STERN ET AL.
`
`'
`
`stimulation of the corneal surface by environmental fac-
`tors, even though these signals occur below the level of
`perception in normal individuals. The conjunctiva does
`not transmit sensations as acutely as the cornea but is
`known to convey sensations of itch as well as some
`temperature fluctuations. The neural pathway for corneal
`stimulatory reflex has been partially elucidated (Fig. 2).
`Sensory (afferent) traffic from the cornea and conjunc-
`tiva travels along the ophthalmic branch (1) of the tri-
`geminal nerve (V) through the trigeminal ganglion into
`the spinal trigerninal nucleus located in the brainstem.
`The initial synapse occurs and neurons then course up to
`the midbrain (pons) where central processing (integra-
`tion) occurs. Other neural traffic travels down to the
`preganglionic sympathetic neurons in the spinal cord and
`then to the superior cervical ganglion,
`located in the
`paravertebral sympathetic chain. Efferent fibers from the
`pons extend, via the facial nerve (VII), to the pterygo-
`palatine ganglion located adjacent to the orbit where they
`again synapse and these neurons send fibers to the lac-
`rimal gland where they release secretagogues that modu-
`late water and protein transport. Sympathetic fibers from
`the superior cervical ganglion also enter the lacrimal
`gland. It is important to note that the neural control of
`accessory lacrimal glandular secretion as well as con-
`junctival goblet cell secretion is only now being inves-
`tigated. Work by Seiffert and Spitznas (8) demonstrated
`that the accessory glands are innervated, and Dartt et al.
`(9) also showed that the conjunctival goblet cells are
`innervated and respond to the presence of vasoactive
`intestinal peptide (VIP), a parasympathetic transmitterl
`neuropeptide.
`The lacrimal glands are at the distal end of the neural
`reflex. The main lacrimal gland resides just superior and
`temporal to the ocular globe within the orbit. The acces-
`sory glands of Wolfring and Krauss reside within the
`superior bulbar conjunctiva and the upper lid, respec-
`tively.
`It is now known that lacrimal gland function is sig-
`nificantly influenced by sex hormones (10,11). Among
`the actions elucidated during the past decade, androgens
`were shown to exert essential and specific effects on
`maintaining normal glandular functions and to suppress
`inflammation in normal and autoimmune animal models
`
`(12-16).
`
`ALTERATIONS IN THE FUNCTIONAL UNIT
`
`The etiology of dry eye is believed to be multifactorial
`and can be related to deficiencies in any one of the three
`components of the tear film. Disruption of the functional
`unit will result in alterations of the quantity and compo-
`sition of tear output leading to symptomatology. The
`major cause for dry eye in Sjogrens syndrome was re-
`ported to be a deficiency in aqueous tear production from
`
`Cornea, Vol. 17, No. 6, 1998
`
`the main and accessory lacrimal glands ( 1,17). Progres-
`sive lymphocytic infiltration has been found in the lac-
`rimal glands of Sjogren’s patients, and immunohisto—
`chemical studies demonstrated that these infiltrates pri-
`marily consist of CD4+ T and B cells (18,19). In the
`conjunctiva of dogs with spontaneous chronic idiopathic
`keratoconjunctivitis sicca (KCS), massive CD3+ T cells
`were also detected (Fig. 3) (20). Prior to this lymphocytic
`infiltration, it appears that a chronic alteration in nerve
`stimulation of the lacrimal gland may initiate glandular
`dysfunction. A recent study conducted in the NZB/NZW
`F1 (NZB) mouse demonstrated the disappearance of the
`varicose synaptophysin-like fibers among the lacrimal
`acini by age of 6-8 months, before the infiltrating lym-
`phocytes are observed (21). This initial inflammation
`may result from the activation of vigilant T cells that are
`normally migrating through the lacrimal gland. Proin-
`flammatory cytokines secreted by these activated lym-
`phocytes may be a causative factor in the disruption of
`nerve cell function associated with operation of the func-
`tional unit. The presence of activated T cells and proin-
`flammatory cytokines was also demonstrated in non-
`Sjogren’s KCS patients, indicating that follicular infil-
`trates, associated with systemic autoimmunity, are not
`necessary to evoke glandular functional disruption. Lac-
`rimal dysfunction therefore appears to be a mechanistic
`result of T-cell activation. Interruption of the neural sig-
`nal at this juncture may be part of the same mechanism
`that initiates the immune responsive migration and pro-
`liferation of lymphocytes in the lacrimal gland and con-
`junctiva. However,
`if the sensory innervation to the
`gland is affected, the resulting release of substance P
`could also be stimulatory to lymphocytes. Schafer et al.
`(22) indicated that parasympathetic neural transmission
`in peripheral nerves can be inhibited by cytokines.
`Therefore, the proinflammatory cytokines such as inter-
`leukin (IL) 1B, IL-2, interferon (INF-'y), and tumor ne-
`crosis factor or, found in lacrimal and salivary gland bi-
`opsies of patients with autoimmune dry—eye syndrome,
`may inhibit neural stimulation of these target tissues and,
`if left unchecked, would result in glandular destruction
`by activated lymphocytes (23-25). In nonautoimmune
`dry eye, loss of neural tone results in gland atrophy and
`further immune activation. The result of this immune-
`
`based inflammation is an abnormal ocular surface epi-
`thelium (26).
`Increased levels of inflammatory cytokines (mRNA
`and protein), such as IL—1|3, IL-6, and IL-8 have been
`found in Sjogren’s syndrome patients (27-29). These pa-
`tients also demonstrated expression of immune activa-
`tion markers HLA-DR and ICAM-1 in the conjunctival
`epithelium (27). Accumulated evidence indicates that the
`epithelial cells in the lacrimal and salivary tissues have
`the potential to be antigen—presenting cells. In vitro, lac-
`rimal acinar cells have shown the ability to express major
`
`3
`
`

`

`PATHOLOGY OF DRY EYE
`
`587
`
`
`
`FIG. 3. The immunoreactivity of CD8 T cells was detected
`in the conjunctival biopsy of KCS dogs. Specific mem-
`brane stainings were found in both the epithelium and
`stroma.
`
`histocompatibility complex (MHC) II after carbachol in-
`duction (30,31). In vivo, acinar cells in both the salivary
`gland of patients and the lacrimal gland of the MRL/lpr
`lymphoproliferative mouse model strongly express class
`II antigens (27,32,33). Additionally, a recent study using
`polymerase chain reaction (PCR), single—strand confor-
`mation polymorphism (SSCP) showed that some infil-
`trating T cells in both lacrimal and salivary glands rec-
`
`ognize the shared epitopes on autoantigens, suggesting
`the importance of restricted epitopes of common autoan—
`tigens in the initiation of Sjogrens’ syndrome (34).
`Therefore, it is reasonable to propose that the epithelial
`cells in inflamed lacrimal or salivary tissues are able to
`present autoantigens to the cell surface receptors such as
`T-cell antigen receptors. This mode of T-cell activation
`can occur locally in the absence of systemic autoimmu-
`nity.
`The question then becomes, what conditions result in
`the inability of the ocular surface and the lacrimal glands
`to respond normally to chronic environmental chal-
`lenges? Although still under investigation, several stud-
`ies indicate that the loss in systemic androgens known to
`occur in pre- and postmenopausal females results in a
`loss of support for lacrimal secretory function and facili-
`tation of an inflammatory environment (l5,35,36).
`The unique effects of androgens are presumably initi-
`ated through specific binding to receptors in the acinar
`nuclei of the lacrimal gland, which in turn lead to an
`altered expression of various cytokines and proto-
`oncogenes (17,34). The activity of androgens in lacrimal
`gland is proposed to be attributed to its ability to induce
`the accumulation of antiinflammatory cytokines such as
`TGF—[3 (17). Given the trophic role that androgens play
`in the lacrimal gland,
`it has been hypothesized that a
`
`FIG. 4. The normal lacrimal (A) and conjunctival (B) epithelial cells exhibited a low level of
`apoptosis. In KCS dogs, apoptosis was increased in the lacrimal (C) and conjunctival (D)
`epithelial cells but decreased in the infiltrating lymphocytes. Note a large number of apop-
`totic cells were stained brown by TUNEL assay.
`
`Cornea, V01. 17, N0. 6, 1998
`
`4
`
`

`

`588
`
`M.E. STERN ET AL.
`
`decrease in androgen level below a certain threshold may
`result in lacrimal atrophy (35). Apoptosis of the intersti-
`tial cells of the lacrimal gland was detected 4 h after
`withdrawal of androgen in ovariectomized rabbits with
`atrophic and necrotic changes in the acinar cells occur-
`ring over the ensuing several days (16). The resulting
`apoptotic fragments represent a source of potential auto-
`antigens that could be subsequently presented either by
`interstitial antigen—presenting cells or acinar cells to CD4
`cell antigen receptors and trigger the autoimmune re-
`sponse.
`
`THERAPIES FOR DRY-EYE DISEASE
`
`The immunomodulatory drug cyclosporine (37), as
`well as steroids (38), has been found to reduce ocular-
`surface rose bengal staining. Cyclosporine is most well
`known as an immunomodulating drug used to prevent T
`cell—dIiven rejection after organ transplantation (39) and
`to treat a variety of autoimmune diseases (40-42). The
`proposed mechanism of its action is its binding to a
`specific cytosolic protein, cyclophilin, which is required
`for the initiation of the inhibition of T-cell activities, thus
`
`'
`
`preventing the production of inflammatory cytokines
`such as IL-2 and IFN-y (43). Studies in the chronic id-
`iopathic dry-eye dog demonstrated that topical ophthal-
`mic cyclosporin A eliminates both the conjunctival and
`lacrimal gland lymphocytic infiltrates (20,44).
`Previous studies suggested that epithelial cell (lacri-
`mal acinar, conjunctival epithelial cells) apoptosis, as
`well as lymphocytic apoptosis, may both be involved in
`the pathogenesis of autoimmune dry eye. In the MRL/lpr
`mouse,
`lymphoproliferative disorder was found to be
`partly due to defects in the gene controling Fas antigen
`that mediates apoptosis (45). In vitro, the cultured human
`salivary gland acinar cells underwent apoptosis after ex-
`posure to IFN—y (46). Our recent finding indicates that
`apoptosis plays an important role in dry-eye mechanisms
`(47). In the chronic idiopathic KCS dog, we evaluated
`the level of apoptosis in both acinar epithelial cells and
`lymphocytes in the lacrimal and conjunctival
`tissues
`(Gao et al.,
`this issue). Normally stable lacrimal and
`conjunctival epithelial cells were found to exhibit in-
`creased levels of apoptosis, whereas apoptosis in the in-
`filtrating lymphocytes appeared suppressed compared
`with those in the normal tissues (Fig. 4). However, after
`topical cyclosporine treatment, the apoptotic level was
`decreased in the epithelial cells and increased in the lym-
`phocytes, allowing elimination of the previously ob-
`served follicular infiltrates. We also found that there was
`
`a positive correlation between the levels of apoptosis and
`the expression of p53 protein, a product of a tumor sup-
`pressor gene that was shown to be critical in both dif-
`ferentiation and apoptosis in certain cell types (48). The
`inhibitory activity of cyclosporine on both apoptosis and
`p53 expression in the epithelial cells, as demonstrated in
`
`Cornea, Vol. 17, N0. 6, I998
`
`canine KCS, implies that the apoptotic process in the
`lacrimal gland may be mediated by a p53-dependent
`mechanism.
`
`Androgens may also serve as important therapeutics
`for dry eye. Systemic androgens have been shown to
`reduce the extent of lymphocytic infiltration in the lac-
`rimal gland of the MRL/lpr mouse and appear to reverse
`the inflammation-induced disruption of acinar and ductal
`epithelium (49). Additionally, androgens applied to the
`ocular surface of dry-eye dogs also demonstrated an in-
`hibitory effect on apoptotic level in the lacrimal gland
`and resolved lymphocytic infiltrates in the lacrimal aci-
`nar lobules (Stern, unpublished data).
`
`SUMMARY
`
`We propose that the pathology of dry eye occurs when
`systemic androgen levels fall below the threshold neces-
`sary to support secretory function and mainten an anti-
`inflammatory environment. Under these conditions, in-
`flammation of the lacrimal glands and ocular surface can
`occur. Secretion of proinflammatory cytokines subse-
`quently interfere with the normal neural connections that
`drive the tearing reflex. The lacrimal gland is thus effec-
`tively isolated, perhaps exacerbating atrophic alterations
`of the glandular tissue. These changes promote antigen
`presentation at the surface of the lacrimal acinar cells and
`increase lymphocytic infiltration of the gland. A similar
`series of events may be occurring on the ocular surface.
`From this hypothesis we conclude:
`
`l. The ocular surface, lacrimal gland, and interconnect-
`ing innervation act as an integrated functional unit.
`2. Once the lacrimal gland loses its androgen support, it
`is subject to immune-based inflammation leading to
`neurally mediated dysfunction.
`3. Antiinflamrnatory therapeutic agents may be capable of
`normalizing the ocular surface/lacrimal neural reflex,
`improving the quality and quantity of the tear film.
`4. The ocular surface is an appropriate target for dry-eye
`therapeutics.
`
`Acknowledgment: The authors express their gratitude to Dr.
`Brenda Reis, David Power, and Kevin Burnett for their help in
`the preparation of this manuscript.
`
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