The role of the lacrimal functional unit in the pathophysiology of dry eye

doi:10.1016/j.exer.2003.09.003

Experimental Eye Research

Volume 78, Issue 3, March 2004, Pages 409-416

https://doi.org/10.1016/j.exer.2003.09.003 Get rights and content

Abstract

The majority of dry eye symptoms are due to a chronic inflammation of the lacrimal functional unit resulting in a loss of tear film integrity and normal function. This leads to a reduction in the ability of the ocular surface to respond to environmental challenges. The underlying cause of tear film dysfunction is the alteration of tear aqueous, mucin, and lipid components. This may result from a systemic autoimmune disease or a local autoimmune event. A lack of systemic androgen support to the lacrimal gland has been shown to be a facilitative factor in the initiation of this type of pathophysiology. Tear secretion is controlled by the lacrimal functional unit consisting of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland and the interconnecting innervation. If any portion of this functional unit is compromised, lacrimal gland support to the ocular surface is impeded. Factors such as neurogenic imflammation and T cell involvement in the disease pathogenesis as well as newly developed animal models of ocular surface inflammation are discussed.

Section snippets

Lacrimal functional unit

The lacrimal functional unit is composed of the lacrimal glands (both main and accessory), the ocular surface and the interconnecting innervation (Fig. 1). Subconscious stimulation of the free nerve endings richly populating the cornea results in the generation of afferent nerve impulses through the ophthalmic branch of the Trigeminal Nerve (V). These impulses travel within these cells through the trigeminal ganglion and on to the mid-brain (pons) where they synapse and the signal is integrated

Environmental challenge

Dry eye is defined as a tear film disorder caused by tear deficiency or extreme tear evaporation which leads to injury on the ocular surface (Lemp, 1995). The normal tear quantity and its anti-inflammatory constituents repair and prevent damage during exposure of the ocular surface in a normal individual to environmental stresses such as wind, low humidity, blinking, or exposure of the surface to bacteria or viruses (Stern et al., 1998). Goblet cells and conjunctival epithelial cells also

Hormonal involvement – breach of androgen threshold

Alterations in the hormonal environment surrounding the ocular surface and lacrimal gland is one of the key factors involved in the etiology of KCS. The normal function of the lacrimal gland and meibomian gland depends on support from circulating hormones. Non-Sjögren's KCS is found predominantly in post-menopausal females and in women who are pregnant or taking birth control pills. Since the vast majority of KCS patients are women, it was initially suspected that estrogen was the key hormone.

Neurogenic inflammation

Stimulation of the lacrimal functional unit in the absence of a protective tear film can result in neurogenic inflammation. In addition, when circulating androgen levels drop below a certain threshold, the main lacrimal gland and ocular tissues will lose their androgen-dependent ‘anti-inflammatory environment’. This will facilitate the initiation of inflammation by several cell types within tissues of the functional unit. Secretion of inflammatory cytokines by these cells (epithelial cells

Pathological apoptosis

Apoptosis is a series of physiological events in the cell which ensure the balance between cell division and loss, therefore playing a pivotal role in the regulation of tissue development and homeostasis. An abnormal increase and/or decrease in the rate of apoptotic cell death in target tissues is considered pathological apoptosis, which is demonstrated in various types of diseases including dry eye. The role of pathological apoptosis in the pathogenesis of KCS has been established based on a

Induction of diapedesis – ‘homing of T cells’

As seen in other mucosal tissues, lymphoid cells are normally present as scattered cells or formed into MALT (mucosa associated lymphoid tissues), patrolling through the ocular tissues as part of immunologic surveillance (Hingorani et al., 1997). Under non-pathological conditions, these trafficking lymphocytes eventually undergo apoptosis and exit via local lymphatic channels. In contrast, progressive and massive lymphocytic infiltration consisting primarily of CD4+ T cells in the lacrimal

Effects of inflammation on the regulation of tear flow

The normal tear film is engendered when stimulation of the ocular surface generates nerve impulses to the central nervous system where the afferent signals are integrated and efferent secretomotor impulse is yielded to the main and accessory lacrimal glands (Stern et al., 1998). Although the exact mechanism(s) for the decreased tear production in KCS is unknown, secretion of inflammatory cytokines by epithelial cells and/or infiltrating lymphocytes in the lacrimal gland and/or ocular tissues

Activation of T cells

Ocular surface inflammation is associated with the activation of CD4+ T cells. The role of T cells in KCS has been clearly demonstrated in both humans and animal models in disease pathogenesis (Gao et al., 1998, Stern et al., 2002). Naı̈ve CD4+ T cells require two signals for activation and differentiation into effector cells. Naı̈ve CD4+ T cells recognize antigenic peptide in the context of MHC class II on an antigen presenting cell (APC) via their antigen-specific T cell receptor. A second

Models of ocular surface inflammation

The development of animal models of KCS that affect the functional unit in a similar manner to the effect seen in human dry eye disease is beneficial for determining the multiple mechanisms occurring in the pathogenesis of dry eye. SS, which causes dry eye and dry mouth, is characterized by a large female prevalence, lymphocytic infiltration of CD4+ T cells and B cells into the lacrimal and submandibular glands, and autoantibodies against the nuclear antigens Ro/SS-A and La/SS-B, fodrin, a

Summary

The lacrimal functional unit acts as an integrated servo-mechanism. If one or more parts of the lacrimal functional unit are compromised, possibly due to loss of androgen support, both the ocular surface and lacrimal gland can become inflamed. In this inflamed state, the release of inflammatory cytokines from lymphocytes and ocular resident cells can obstruct the tearing reflex by interfering with neurotransmitter release and the response of the lacrimal gland to neurotransmitters. Inflammation

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ReviewThe role of the lacrimal functional unit in the pathophysiology of dry eye

Abstract

Section snippets

Lacrimal functional unit

Environmental challenge

Hormonal involvement – breach of androgen threshold

Neurogenic inflammation

Pathological apoptosis

Induction of diapedesis – ‘homing of T cells’

Effects of inflammation on the regulation of tear flow

Activation of T cells

Models of ocular surface inflammation

Summary

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Exp. Eye Res.

Semin. Immunol.

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Neurosci. Lett.

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Exp. Eye Res.

Am. J. Ophthalmol.

Exp. Eye Res.

Serum soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin) and neopterin in patients with Sjögren's syndrome

Acta Medica (Hradec Kralove)

Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjögren's syndrome

Invest. Ophthalmol. Vis. Sci.

Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eyes

Invest. Ophthalmol. Vis. Sci.

Lymphocyte homing and homeostasis

Science

Presence of nerves and their receptors in mouse and human conjunctival goblet cells

Invest. Ophthalmol. Vis. Sci.

A mouse model of keratoconjunctivitis sicca

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Experimentally induced dry eye produces ocular surface inflammation and epithelial disease

Adv. Exp. Med. Biol.

Expression of T lymphocyte chemoattractants and activation markers in vernal keratoconjunctivitis

Br. J. Ophthalmol.

Sjögren's syndrome: mechanisms of pathogenesis involve interaction of immune and neurosecretory systems

Scand. J. Rheumatol.

The role of apoptosis in the pathogenesis of canine keratoconjunctivitis sicca: the effect of topical Cyclosporin A therapy

Cornea

ICAM-1: its role in the pathophysiology of immune activation in the MRL/LPR mouse

Adv. Exp. Med. Biol.

Transforming growth factor beta-1 and beta-2 in human tear fluid

Curr. Eye Res.

Identification of α-Fodrin as a candidate autoantigen in primary Sjögren's syndrome

Science

Aqueous tear production in patients with neurotrophic keratitis

Cornea

Sjögren's syndrome in MRL/l and MRL/n mice

Arthritis Rheum.

Utilization of the NOD mouse as an animal model for the study of Sjögren's syndrome

Adv. Exp. Med. Biol.

Murine models of Sjögren's syndrome: immunohistological analysis of different strains

Invest. Opthalmol. Vis. Sci.

Th1 versus Th2 immune responses in autoimmune lacrimal gland disease in MRL/Mp mice

Invest. Ophthalmol. Vis. Sci.

Cytokines in autoimmune lacrimal gland disease in MRL/MpJ mice

Invest. Opthalmol. Vis. Sci.

Sjögren's syndrome: cytokine and Epstein-Barr viral gene expression within the conjunctival epithelium

Invest. Ophthalmol. Vis. Sci.

Effect of androgen deficiency on the human meibomian gland and ocular surface

J. Clin. Endocrinol. Metab.

Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes

Arch. Ophthalmol.

Parasympathetic innervation of the meibomian glands in rats

Invest. Ophthalmol. Vis. Sci.

Report of the national eye institute/industry workshop on clinical trials in dry eyes

CLAO J.

The neuropeptide substance P activated transcription factor NF-kB and kB-dependent gene expression in human astrocytoma cells

J. Immunol.

Review
The role of the lacrimal functional unit in the pathophysiology of dry eye