Effect of inflammation on lacrimal gland function

Abstract

The lacrimal gland is the main contributor to the aqueous layer of the tear film. It secretes proteins, electrolytes and water, which helps to nourish and protect the ocular surface. Lacrimal gland secretion is primarily under neural control, which is achieved through a neural reflex arc. Stimuli to the ocular surface activate afferent sensory nerves in the cornea and conjunctiva. This in turn activates efferent parasympathetic and sympathetic nerves in the lacrimal gland to stimulate secretion. Sex steroid hormones are also important regulators of lacrimal gland functions. A decrease or lack of lacrimal gland secretion is the leading cause of aqueous tear deficient dry eye syndrome (DES). It has been suggested that DES is an inflammatory disorder that affects the ocular surface and the lacrimal gland. In several pathological instances, the lacrimal gland can become a target of the immune system and show signs of inflammation. This can result from autoimmune diseases (Sjögren's syndrome), organ transplantation (graft versus host disease), or simply as a result of aging. The hallmarks of lacrimal gland inflammation are the presence of focal lymphocytic infiltrates and increased production of proinflammatory cytokines. The mechanisms leading to lacrimal gland dysfunction are still poorly understood. Apoptosis, production of autoantibodies, hormonal imbalance, alterations in signaling molecules, neural dysfunction, and increased levels of proinflammatory cytokines have been proposed as possible mediators of lacrimal gland insufficiency in disease states.

Figure 1

Schematic of the neural reflex arc that connects the ocular surface to the lacrimal gland. Activation of the afferent sensory nerves in the cornea and conjunctiva leads to activation of efferent parasympathetic and sympathetic nerves that signal the lacrimal gland to secrete proteins, electrolytes and water. Reprinted from The Ocular Surface 2004, 2: 76-91.

Figure 2

Immunolocalization of parasympathetic nerves in normal and inflamed lacrimal glands. Fluorescence micrograph showing the localization of the parasympathetic neurotransmitter, vasoactive intestinal peptide (VIP), in the lacrimal glands of 18-week old female MRL/lpr (diseased) and MRL/+ (control) mice. Upper micrographs show Hematoxylineosin (H&E) staining of the lacrimal gland sections (See also, Zoukhri et al., Clin. Immunol. Immunopathol. 1998; 89(2): 126-133).

Figure 3

Immunolocalization of IL-1β in the lacrimal gland. Lacrimal glands were removed from 13-week old female MRL/lpr (diseased mice, A, B, and D) and 18-week old female MRL/+ (control mice, C and E) mice. A, B, and C, micrographs depict immunofluorescence staining with an antibody against murine IL-1β. D and E, micrographs showing negative controls in which the primary antibody was omitted. An asterisk denotes areas of lymphocytic infiltration. Reprinted from Zoukhri et al., Invest. Ophthalmol. Vis. Sci. 2002; 43: 1429-1436.

Figure 4

Immunodetection of IL-1RI in lacrimal gland homogenates. Lacrimal glands were removed from 16-week old female MRL/lpr (diseased) and MRL/+ (control) mice. Acinar cells were then prepared and lymphocytes removed. Acini were homogenized and proteins separated by SDS-PGAE followed by western blotting. The molecular weight (in KDa) of protein standards is shown in the left. Asterisks denote the migration of IL-1RI. The upper band is a heavily glycosylated and slowly migrating form of the IL-1RI. Each lane represents samples from a different animal (See also, Zoukhri et al., Invest. Ophthalmol. Vis. Sci. 2002; 43: 1429-1436).

Figure 5

Immunolocalization of IL-1RI in the lacrimal gland. Lacrimal glands were removed from 13-week old female MRL/lpr (diseased) and 18-week old female MRL/+ (control) mice. A, B, and C, micrographs depict immunofluorescence staining with an antibody against murine IL-1RI. D and E, micrographs showing negative controls in which the primary antibody was omitted. An asterisk denotes areas of lymphocytic infiltration. Reprinted from Zoukhri et al., Invest. Ophthalmol. Vis. Sci. 2002; 43: 1429-1436.

Figure 6

Schematic showing the effect of proinflammatory cytokines on the neural reflex arc that connects the ocular surface to the lacrimal gland. Inhibition of neurotransmission either of the afferent sensory nerves or the efferent parasympathetic and sympathetic nerves would result in inadequate lacrimal gland secretion. Reprinted from The Ocular Surface 2004, 2: 76-91.