Impaired neurotransmitter release from lacrimal and salivary gland nerves of a murine model of Sjögren's syndrome.

Lacrimal and salivary glands are exocrine tissues that have the main function of secreting tears and saliva, respectively.1–3 These glands consist of acini, ducts, nerves, myoepithelial cells, mast cells, and plasma cells. Approximately 80% of each gland is acini, which secrete electrolytes, water, and proteins.1,4 It is well established that lacrimal and salivary gland fluid secretion is under neural control.1,4,5 For example, reflexes from the ocular surface and optic nerve, as well as from higher centers of the brain, stimulate lacrimal gland secretion using parasympathetic and sympathetic efferent pathways.2,3 Parasympathetic and sympathetic nerves innervate the acinar cells, duct cells, and blood vessels of the lacrimal and salivary glands.1,6 – 8 The parasympathetic nerves contain the neurotransmitter acetylcholine, which acts through cholinergic muscarinic receptors, and vasoactive intestinal peptide. Sympathetic nerves contain norepinephrine, which acts through adrenergic receptors. A decrease in lacrimal and salivary gland secretion is a primary cause of dry eye and dry mouth. Sjogren's syndrome is the leading cause of the aqueous tear-deficient type of dry eye.9–11 It is an autoimmune disease that occurs almost exclusively in females (>90%). This syndrome is associated with an extensive lymphocytic infiltration of the lacrimal and salivary glands and destruction of epithelial cells.9–11 To date there is no cure for this disease. Moreover, the exact cause of Sjogren's syndrome is largely unknown but may involve numerous factors including those of viral, endocrine, neural, genetic, and environmental origin.10,12,13 Several strains of mice have been proposed as models of human Sjogren's syndrome.14–17 Each of these strains has its advantages and disadvantages. Nonobese diabetic (NOD) mice were first used as a model for type I diabetes. Subsequently, it was found that in these mice, lesions develop in the salivary and lacrimal glands that resemble human Sjogren's syndrome.18 However, the incidence of the lymphocytic accumulation in lacrimal glands in these mice is more frequent and severe in male than in female mice, which is the opposite of that which occurs in humans.19 The New Zealand black (NZB) and hybrid New Zealand black/New Zealand white (NZB/NZW) mice described by Kessler20 and the MRL/l mice and congenic MRL/Mp-lpr/lpr mice first described by Murphy21 were used as models to study another autoimmune disease, systemic lupus erythematosus. Later, it was found that these animals had coexisting Sjogren's syndrome. NZB/NZW and MRL/lpr mice show spontaneous development of a mononuclear cell infiltration of the salivary and lacrimal glands and other organs. The disease in both animals occurs almost exclusively in females (.90%) and develops in an age-dependent manner.14,15,19 MRL/lpr mice, compared with NZB/NZW mice, have more pronounced and destructive mononuclear infiltrates in the lacrimal and salivary glands.16,19 The precise mechanism(s) responsible for the decrease in tear and saliva secretion in Sjogren's syndrome is unknown.10,11,13 It is believed that the dry eye and dry mouth in this disease are due to a progressive lymphocytic infiltration of the lacrimal and salivary glands, an immune-mediated destruction of the epithelial cells, and a consequent decline in tear and saliva production.10,11,13 However, adjacent to the immuno pathologic lesions in Sjogren's syndrome, the lacrimal and salivary gland tissues appear to contain normal acinar and ductal epithelia that should be able to secrete enough tears and saliva. One hypothesis could be that a decrease in lacrimal gland innervation and/or an alteration of the signaling pathways of the remaining epithelia accounts for the decreased function of the lacrimal and salivary glands associated with Sjogren's syndrome. In previous studies, using the MRL/lpr mice, we found that the lymphocytic infiltration of the lacrimal and salivary glands did not alter the parasympathetic, sympathetic, and sensory innervation of the remaining epithelial cells in these tissues.22 We also found that acinar cells isolated from lacrimal and salivary glands of diseased MRL/lpr animals were hyper-responsive to exogenous cholinergic and adrenergic stimulation when compared with age-matched control MRL/+ animals.23 We hypothesized that the exocrine tissues from diseased animals behave as denervated ones—that is, the remaining nerves are not able to release their neurotransmitters, leading to increased responsiveness of these tissues to exogenous stimulation. Another consequence of the impaired release of neurotransmitters is a loss of tear and saliva secretion from lacrimal and salivary glands that leads to dry eye and dry mouth. The purpose of the present studies was to test for this hypothesis.