Mucins and TFF peptides of the tear film and lacrimal apparatus

https://doi.org/10.1016/j.proghi.2006.03.001Get rights and content

Abstract

The three-dimensional organization of the tear film, which is produced and drained by the different structures of the ocular adnexa, is essential for maintainance and protection of the ocular surface. This is facilitated by a class of large, highly glycosylated, hydrophilic glycoproteins, the mucins, which are usually expressed in association with a class of peptides having a well-defined, structurally conserved trefoil domain, the mammalian trefoil factor family (TFF) peptides. In this review, the latest information regarding mucin and TFF peptide function and regulation in the human lacrimal system, the tear film and the ocular surface is summarized with regard to mucous epithelia integrity, rheological and antimicrobial properties of the tear film and tear outflow, age-related changes and certain disease states such as dry eye, dacryostenosis and dacryolith formation.

Introduction

The unique composition of tear film enables it to maintain a smooth surface for light refraction, lubricate the eyelids, lubricate the cornea and the conjunctiva, supply the cornea with nutrients and provide white blood cells with access to the cornea and conjunctiva, remove foreign materials from the cornea and conjunctiva, and defend the ocular surface against pathogens by means of both specific and nonspecific antibacterial substances.

The epithelial surface of the eye and its specialized glandular infoldings produce the components of the tear film, which include water, protective antimicrobials, cytokines, lipids as well as mucins and trefoil factor family (TFF) peptides.

Mucins and TFF peptides perform a number of essential functions which, collectively, provide protection of the ocular surface. Mucins are present both in the epithelial glycocalyx and in the tear fluid. They are hydrophilic and play a role in maintenance of water on the surface of the eye. Membrane-anchored mucins are part of the glycocalyx, together with a variety of other glycoconjugates, providing a continuous barrier across the surface of the eye that prevents pathogen penetration. The membrane spanning molecules have signalling capabilities that influence epithelial activity. The high molecular secreted mucins and TFF peptides are responsible for the rheological properties of the tear film, enabling movement over the ocular surface by simultaneous attachment of the tear film. TFF peptides have many other physiological functions in addition to their rheological properties, such as promotion of epithelial cell migration, antiapoptotic properties, induction of cell scattering, epithelial restitution and neuropeptide functions (for a review, see Hoffmann et al., 2001; Hoffmann and Jagla, 2001).

Reduced production of ocular mucins and TFF peptides with altered rheological properties is an important factor in the pathogenesis of dry eyes that are characterized by an inadequate ocular lubrication as a result of impaired lacrimal function, failure in the transfer of lacrimal fluid to the ocular surface epithelia and/or excessive tear evaporation. Moreover, dry eye syndromes also include ocular surface epitheliopathy, tear hyperosmolality, an unstable preocular tear film, varying degrees of inflammation, and symptoms of ocular irritation (Lemp, 1995).

A variety of factors have been found to regulate mucin and TFF peptide gene expression and production at the ocular surface, but the biochemical characteristics of preocular mucins and TFF peptides that determine their physiological roles in the eye have yet to be identified. It should also be pointed out that other molecules such as lipids, proteoglycans and DNA may contribute to the physical properties of ocular surface mucus, and perhaps more so in pathological conditions.

Great strides have been made in identifying and characterizing the major oligomeric mucins and TFF peptides present in tears, the ocular surface and the lacrimal system over the past decade. In this, the collective physical properties of mucins (i.e., length, charge density, macromolecular architecture, interaction and mutual influences) have been related to a specific set of rheological parameters for the mucus gel present in tears and at the ocular surface (Ellingham et al., 1999; Berry et al., 2001, Berry et al., 2004a; Round et al., 2002, Round et al., 2004; Brayshow et al., 2003, Brayshow et al., 2004). For this article, we were given the task of reviewing our own contributions to this area. We have also suggested further avenues to investigation that will prove necessary to gain a better understanding of the biology and pathobiology of mucins and TFF peptides of the ocular surface and lacrimal apparatus.

Section snippets

Anatomy and embryology of the lacrimal apparatus and ocular surface

The ocular surface and its adnexa comprise the cornea, the conjunctiva with the bulbar, fornical and palpebral segments (Fig. 1), the main lacrimal gland, the glands of the eye lids, i.e. the Meibomian, Moll and accessory lacrimal glands, and the nasolacrimal system (also termed nasolacrimal ducts or efferent tear ducts) with the upper and lower puncta, paired lacrimal canaliculi, lacrimal sac and nasolacrimal duct. The nasolacrimal ducts collect the tear fluid from the ocular surface and

The preocular tear film

Today it is generally accepted that the preocular fluid is a complex secretion with structure on all scales: lipids, an aqueous component dissolving a great variety of chemical entities, and mucins contribute to a stable and continuous layer covering the external ocular epithelia and anchored onto their apical surfaces (Fig. 8). The lipid component is secreted by the Meibomian glands in the eyelid. The aqueous component is secreted by the main lacrimal gland and the accessory lacrimal glands

Mucins

An evolutionarily ancient protective molecular type, the defining and unifying feature of mucins is the presence of a large number of oligosaccharide chains in which N-acetylgalactosamine (GalNAc) is O-linked to a hydroxylated amino-acid (Ser or Thr) in the peptide core. Oligosaccharides are not evenly distributed along the linear molecule, but concentrated in discrete regions, encoded by repeat sequences in the mucin gene (tandem repeats). These features, preserved in all the wet epithelia

Mucins of the tear film

The ocular surface and tears are rich in diverse mucins adapted to maintaining a transparent and well hydrated gel. The properties of the gel are derived from the characteristics of the backbone polymers, their glycosylation and interactions with other chemical entities in the preocular fluid.

Lacrimal gland mucins

Supported by older studies (Jensen et al., 1969; Ito and Shibasaki, 1964; Kühnel, 1968; Allen et al., 1972; Millar et al., 1996) and the finding that rat lacrimal glands synthesize rMuc4 (Arango et al., 2001), recent studies have demonstrated mucin expression and protein synthesis of a spectrum of mucins (Jumblatt et al., 2003; Paulsen et al., 2004a; Table 2).

Age-related dry eye

The term “dry eye” or dry eye syndrome refers to a common but highly heterogeneous group of ocular surface disorders (Dana and Hamrah, 2002; Schaumberg et al., 2002). Dry eye accounts for the largest group of patients seeking ophthalmic treatment. Most of the cases result from changes associated with aging of the glands and ocular surface epithelia, although the condition can occur at any age. An estimated 20% of people over the age of 45 will experience dry eyes.

In view of the high prevalence

Interaction of mucins with TFF peptides

The localization of TFF1 and TFF3 to the human conjunctival goblet cells matches that of the secretory mucin MUC5AC. Conjunctival TFF1 and TFF3 must therefore be considered typical mucin-associated peptides. It is postulated that TFF peptides function as link peptides interacting noncovalently with mucins and influencing the rheological properties of mucous gels (Hauser et al., 1993). This hypothesis has been confirmed by in vitro studies demonstrating that TFF peptides increase the viscosity

Efferent tear duct mucins

The physiology of lacrimal drainage has been under study for more than a century, but the forces that cause tear flow are not completely understood. Various mechanisms have been proposed to explain tear drainage. These include an active lacrimal pump mechanism that functions by contraction of the orbicularis eye muscle (Jones, 1958; Amrith et al., 2005; Pavlidis et al., 2005; Kakizaki et al., 2005); a “wringing-out mechanism” involving a system of helically arranged fibrillar structures (Thale

Concluding remarks

The human lacrimal gland, the epithelia of the ocular surface (conjunctiva and cornea) and the epithelial structures of the nasolacrimal ducts each synthesize a specific spectrum of mucins and TFF peptides. The diversity of mucins and TFF peptides can be linked to cell signalling, tear film rheology, antimicrobial defences and anti-apoptosis; the production of mucins and TFF peptides in the healthy lacrimal sac and nasolacrimal duct is associated with enhanced tear transport and antimicrobial

Acknowledgments

We acknowledge support by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Bonn, Germany (Program Grants No.: PA738/1-2, PA 738/1-3, PA 738/1-4, PA 738/1-5), the National Eye Research Center (Grant 2000/013), Bristol, UK, the Wilhelm Roux program, Halle, Germany (FKZ 9/18 and 12/08), and the Sicca Forschungsförderung (Dry Eye Research Foundation of Association of German Ophthalmologists), Berlin, Germany.

References (275)

  • T.L. Gururaja et al.

    Candidacidal activitiy prompted by N-terminus histatin-like domain of human salivary mucin (MUC7)

    Biochim Biophys Acta

    (1999)
  • A. Herrmann et al.

    Studies on the “insoluble” glycoprotein complex from human colon Identification of reduction-insensitive MUC2 oligomers and C-terminal cleavage

    J Biol Chem

    (1999)
  • M. Hingorani et al.

    Characterisation of the normal conjunctival leukocyte population

    Exp Eye Res

    (1997)
  • S.A. Hodson

    Corneal stromal swelling

    Prog Ret Eye Res

    (1997)
  • J.A. Hutch

    The role of urethral mucus in the bladder defense mechanism

    J Urol

    (1970)
  • J. Aarbiou et al.

    Neutrophil defensins enhance lung epithelial wound closure and mucin gene expression in vitro

    Am J Respir Cell Mol Biol

    (2004)
  • S.N. Abraham et al.

    Host defenses against adhesion of bacteria to mucosal surfaces

  • M.C. Acosta et al.

    Tear secretion induced by selective stimulation of corneal and conjunctival sensory nerve fibers

    Invest Ophthalmol Vis Sci

    (2004)
  • M.-L.R. Aknin et al.

    Normal but not altered mucins activate neutrophils

    Cell Tissue Res

    (2004)
  • M. Allen et al.

    The human lacrimal gland A histochemical and organ culture study of the secretory cells

    Arch Ophthalmol

    (1972)
  • S. Amrith et al.

    Tear flow dynamics in the human nasolacrimal ducts – a pilot study using dynamic magnetic resonance imaging

    Graefe's Arch Clin Exp Ophthalmol

    (2005)
  • M.E. Arango et al.

    Production and localization of Muc4/sialomucin complex and its receptor tyrosine kinase erbB2 in the rat lacrimal gland

    Invest Ophthalmol Vis Sci

    (2001)
  • P. Argüeso et al.

    Analysis of human ocular mucus: effects of neuraminidase and chitinase enzymes

    Cornea

    (1998)
  • P. Argüeso et al.

    Decreased levels of the goblet cell mucin MUC5AC in tears of patients with Sjogren syndrome

    Invest Ophthalmol Vis Sci

    (2002)
  • P. Argüeso et al.

    MUC16 mucin is expressed by the human ocular surface epithelia and carries the H185 carbohydrate epitope

    Invest Ophthalmol Vis Sci

    (2003)
  • M. Ayub et al.

    The cavernous body of the human efferent tear ducts functions in regulation of tear outflow

    Invest Ophthalmol Vis Sci

    (2003)
  • S. Bacman et al.

    Muscarinic acetylcholine receptor antibodies as a new marker of dry eye Sjögren's syndrom

    Invest Ophthalmol Vis Sci

    (2001)
  • C. Basbaum et al.

    Control of mucin transcription by diverse injury-induced signaling pathways

    Am J Respir Crit Care Med

    (1999)
  • R.C. Bast et al.

    Reactivity of a monoclonal antibody with human ovarian carcinoma

    J Clin Invest

    (1981)
  • L.W. Baughan et al.

    Salivary mucin as related to oral Streptococcus mutans in elderly people

    Oral Microbiol Immunol

    (2000)
  • M. Baus-Loncar et al.

    Trefoil factors multiple regulatory pathways for trefoil factor (TFF) genes cell

    Mol Life Sci

    (2005)
  • M. Baus-Loncar et al.

    Trefoil factor family 2 deficiency and immune response

    Cell Mol Life Sci

    (2005)
  • C. Belmonte et al.

    Excitation by irritant chemical substances of sensory afferent units in the cat's cornea

    J Physiol

    (1991)
  • M. Berry et al.

    Polydispersity of normal human conjunctival mucins

    Invest Ophthalmol Vis Sci

    (1996)
  • M. Berry et al.

    Membrane-associated mucins in normal human conjunctiva

    Invest Ophthalmol Vis Sci

    (2000)
  • M. Berry et al.

    Exploring the molecular adhesion of ocular mucins

    Biomacromolecules

    (2001)
  • M. Berry et al.

    Commensal ocular bacteria degrade mucins

    Br J Ophthalmol

    (2002)
  • M. Berry et al.

    Functional processing of ocular mucins

    Adv Exp Med Biol

    (2002)
  • M. Berry et al.

    Patterns of mucin adherence to contact lenses

    Invest Ophthalmol Vis Sci

    (2003)
  • M. Berry et al.

    Dynamic molecular resolution imaging of preocular fluid impressions

    Br J Ophthalmol

    (2004)
  • M. Berry et al.

    Human preocular mucins reflect changes in surface physiology

    Br J Ophthalmol

    (2004)
  • D.J. Brayshow et al.

    Optimisation of sample preparation methods for air imaging of ocular mucins by AFM

    Ultramicroscopy

    (2003)
  • D.J. Brayshow et al.

    Molecular adsorption: early stage surface exploration

    Ultramicroscopy

    (2004)
  • A.J. Bron et al.

    Meibomian gland disease

    Classification and grading of lid changes eye

    (1991)
  • H. Busse et al.

    Zur Enstehung der idiopathischen Dakryostenose

    Klin Monatsbl Augenheilkd

    (1977)
  • I. Carlstedt et al.

    The macromolecular structure of human cervical mucus glycoproteins

    J Biochem

    (1983)
  • I. Carlstedt et al.

    Mucous glycoproteins: a gel of a problem

    Essays Biochem

    (1985)
  • I. Carlstedt et al.

    ‘Soluble’ and ‘insoluble’ mucins – identification of distinct populations

    Biochem Soc Trans

    (1995)
  • K.L. Carraway et al.

    Multiple facets of sialomucin complex/MUC4, a membrane mucin and erbb2 ligand, in tumors and tissues (Y2K update)

    Front Biosci

    (2000)
  • J. Celli et al.

    Viscoelastic properties and dynamics of porcine gastric mucin

    Biomacromolecules

    (2005)

    • Cited by (86)

    • Urea and ocular surface: Synthesis, secretion and its role in tear film homeostasis

      2023, Ocular Surface

    • Immunohistochemical detection of urea transporter-A in the tear-producing part of the lacrimal system

      2022, Annals of Anatomy

    • Urea transporter-B expression on the ocular surface and in the lacrimal glands

      2022, Annals of Anatomy

    • Biochemistry of human tear film: A review

      2022, Experimental Eye Research
      Citation Excerpt :

      They are secreted by goblet cells in the conjunctival epithelium, the acinar cells of the lacrimal glands and corneal cells (Cher, 2014; Dartt and Willcox, 2013). Based on their structures, mucins in tears can be divided to soluble mucins (MUC-2, -5AC, -5B, -C6, -7, -9 & -C19) (Jumblatt et al., 2003; McKenzie et al., 2000; Paulsen and Berry, 2006; Yu et al., 2008) and membrane-associated mucins (MUC-C1, -4, -16, & −20) (Hori, 2018; Pflugfelder et al., 2000; Woodward and Argüeso, 2014). Mucins stabilise the aqueous layer by lowering the surface tension (Hodges and Dartt, 2013) and play important roles in the wettability and lubrication of the ocular surface (Gipson and Argüeso, 2003; Gipson et al., 2004).

    • Clinical Implications of Goblet Cells in Dacryoadenosis and Normal Human Lacrimal Glands

      2020, American Journal of Ophthalmology
      Citation Excerpt :

      This diagnosis requires prominent lymphoid aggregates, often with follicular organization; an increased presence of interacinar mononuclear inflammatory cells; progressive interacinar and periductal fibrosis; focal, segmental or diffuse acinar destruction; and, finally, the preferential survival of the preacinar ductules. The normal lining epithelium of the intralobular and interlobular ducts does not display goblet cells, which do appear in the more distal segments of the excretory ducts6,7 along with small pseudoapocrine apical snouts.10 The excretory ducts are formed by the confluence of the interlobular ducts and empty into the superolateral conjunctival fornix.

    • Epithelial dysplasia in pterygium postoperative granuloma

      2018, Experimental Eye Research
    View all citing articles on Scopus
    View full text
    Copyright © 2006 Elsevier GmbH. All rights reserved.