Cause Of Dry Eye Research Articles

Impaired neurotransmission in lacrimal and salivary glands of a murine model of Sjögren's syndrome.

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. 1-3 It is an autoimmune disease occurring almost exclusively in females (> 90%) and involves an extensive lymphocytic infiltration of the lacrimal and salivary glands as well as destruction of epithelial cells. 1-3 No cure exists for this disease. Moreover, its exact etiology is largely unknown, but may involve numerous factors including those of viral, endocrine, neural, genetic and environmental origin. 2-4-5

Proinflammatory cytokine inhibition of lacrimal gland secretion.

A decrease in lacrimal and salivary gland secretion is a primary cause of dry eye and dry mouth. Sjögren’s syndrome is the leading cause of the aqueous tear deficient type of dry eye.1-3 It is an autoimmune disease, which occurs almost exclusively in females (>90), and involves an extensive lymphocytic infiltration of the lacrimal and salivary glands and destruction of epithelial cells.4-5 No cure exists for this disease. Moreover, the exact etiology of Sjögren’s syndrome is largely unknown, but may include factors of viral, endocrine, neural, genetic and environmental origin.2-5

The Pathology of Dry Eye

Homeostasis of the tear film involves delicate hormonal and neuronal regulatory mechanisms. The eye appears to be a target organ for sex hormones, particularly the androgens, as they modulate the immune system and trophic functions of the lacrimal glands and the functioning of the meibomian glands. The cornea, lacrimal glands, mucous cells, and meibomian glands are all richly innervated, indicating the importance of nervous regulation in their function. Parasympathetic, sympathetic, and sensory innervation play complex stimulatory or inhibitory roles, and neuronal pathways interact via complex surface results cascades. Abnormalities at any point in these pathways can cause overall dysregulation of lacrimal function. Whatever the initial causes of dry eye, chronic dryness of the ocular surface results in inflammatory reactions and gradual destruction of the lacrimal glands and conjunctival epithelium. Once dry eye disease has developed, inflammation is the key mechanism of ocular surface injury, as both the cause and consequence of cell damage. In practice, dry eye can be associated with Sjögren's syndrome, allergies, infection, blepharitis, and preservative-containing eye drops.

IMPAIRED NEUROTRANSMISSION IN LACRIMAL AND SALIVARY GLANDS OF A MURINE MODEL OF SJÖGREN'S SYNDROME.

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. 1-3 It is an autoimmune disease occurring almost exclusively in females (> 90%) and involves an extensive lymphocytic infiltration of the lacrimal and salivary glands as well as destruction of epithelial cells. 1-3 No cure exists for this disease. Moreover, its exact etiology is largely unknown, but may involve numerous factors including those of viral, endocrine, neural, genetic and environmental origin. 2-4-5

Proliferation of Lacrimal Gland Acinar Cells in Primary Culture. Stimulation by Extracellular Matrix, EGF, and DHT

The study of lacrimal dysfunction and insufficiency, a major cause of dry eye, has been hampered by the inability to induce the proliferation of primary lacrimal acinar cells in vitro. Particularly in light of observations that androgens are able to support the overall size and functional status of the lacrimal glands as well as certain specific lacrimal functions, an in vitro culture system that is permissive for cell proliferation would be most beneficial to study the molecular basis for these processes. Here, we report on the successful establishment of such a system. Using a culture system containing Hepato Stim Medium®and Matrigel®, we were able to induce the efficient proliferation of primary rabbit lacrimal gland acinar cells with epidermal growth factor (EGF) and dihydrotestosterone (DHT). The generation of this in vitro cell culture system should greatly facilitate study of the regulation of acinar cell function at the molecular and cellular levels.

Impact of Gender on Exocrine Gland Inflammation in Mouse Models of Sjögren's Syndrome

Sjögren's syndrome is a complex autoimmune disorder, that occurs almost exclusively in females, induces extensive lymphocyte accumulation in lacrimal and salivary glands, and represents one of the leading causes of dry eye and mouth in the world. The purpose of this study was to determine whether the profound, gender-related differences observed in the magnitude of exocrine gland inflammation in Sjögren's syndrome may also be found in tissues of mouse models of this disorder. Lacrimal and submandibular glands were obtained from adult MRL/lpr, MRL+/+ (MRL+), NZB/NZW F1 (F1), C3H/lpr, C3H/gld (gld), C57BL/6-lpr/lpr [B6/lpr; with (bcl-2+/lpr) or without (bcl-2−/lpr) bcl-2 transgene insertion] and nonobese diabetic (NOD) mice after the onset of autoimmune disease, and processed for microscopy and image analysis. Our results showed that: (1) the extent of inflammation was significantly greater in lacrimal glands of female MRL/lpr, MRL+, F1, C3H/lpr and gld mice, and salivary glands of female MRL+, F1 and gld mice, relative to those of males; (2) the severity of inflammation in NOD mice showed a tissue-specific pattern: inflammation was far worse in lacrimal glands of males, whereas immune pathology was far greater in salivary tissues in females; and (3) no gender-related variations were present in the degree of inflammation in lacrimal glands of bcl-2+/lpr and bcl-2−/lpr mice or in submandibular tissues of MRL/lpr, C3H/lpr, bcl-2+/lpr and bcl-2−/lpr mice. Our findings demonstrate that gender-, strain- and tissue-related differences exist in the extent of inflammation in several mouse models of Sjögren's syndrome.

A clinician looks at the tearfilm.

Today as we open the Second International Conference on the Lacrimal Gland, Tear Film, and Dry Eye Syndromes, I want us to let go of preconceived ideas, long-held dogma, and bias and to look to the future as we pursue basic knowledge about pathophysiology and regulation of the lacrimal and meibomian glands and the ocular surface, the causes of dry eye, and new treatments. Remember, the reason we are pursuing this knowledge is to help those who suffer from dry eye, our patients, and, perhaps, someday offer a cure for each of the different types of dry eye.

Hormonal support of lacrimal function, primary lacrimal deficiency, autoimmunity, and peripheral tolerance in the lacrimal gland

Several causes of lacrimal insufficiency have been recognized, including Sjogren's syndrome and other immune-related processes as well as a disparate group of non-immune related disorders. However, the mechanisms underlying primary lacrimal deficiency (PLD), the most common cause of dry eye, have remained obscure. After summarizing mechanisms of lacrimal secretion and stimulus-secretion coupling, the authors review the thesis that optimal lacrimal gland function depends on a hormonal milieu in which androgens play a crucial role. According to this thesis, simple acquired PLD results when bioavailable androgen levels decrease below critical values. However, it is noted that PLD also may be complicated by local autoimmune processes, and hypothetical pathways leading to such processes are discussed. Cell death following withdrawal of hormonal support may lead to processing and presentation of parenchymal cell antigens. Normal intracellular membrane traffic patterns may cause acinar cells to secrete autoantigens into the interstitium. When acinar cells have been induced to express major histocompatibility complex Class II molecules, their intracellular membrane traffic may allow them to process and present autoantigens, essentially mimicking the functions of professional antigen presenting cells. The possibility is discussed that perturbations of the spectra of released and presented autoantigens upset the equilibria of idiotypic networks arising to establish peripheral tolerance. The resulting incremental increases in lymphocytic infiltration are suggested to represent essentially cryptic autoimmune processes which may impair lacrimal secretory function and regeneration. Failure to establish peripheral tolerance is predicted to permit unrestrained CD(4) cell proliferation and an environment favoring B cell activation. Recruitment of B lymphocytes, perhaps in events influenced by re-activated viruses, is predicted to lead to Sjogren's autoimmunity as recognized by stringent diagnostic criteria. Finally, the possibility is discussed that androgen supplementation or hormone replacement therapy might prevent simple PLD and avoid the initiation of autoimmune processes.

Hormonal Support of Lacrimal Function, Primary Lacrimal Deficiency, Autoimmunity, and Peripheral Tolerance in the Lacrimal Gland

Several causes of lacrimal insufficiency have been recognized, including Sjögren's syndrome and other immune-related processes as well as a disparate group of non-immune related disorders. However, the mechanisms underlying primary lacrimal deficiency (PLD), the most common cause of dry eye, have remained obscure. After summarizing mechanisms of lacrimal secretion and stimulus-secretion coupling, the authors review the thesis that optimal lacrimal gland function depends on a hormonal milieu in which androgens play a crucial role. According to this thesis, simple acquired PLD results when bioavailable androgen levels decrease below critical values. However, it is noted that PLD also may be complicated by local autoimmune processes, and hypothetical pathways leading to such processes are discussed. Cell death following withdrawal of hormonal support may lead to processing and presentation of parenchymal cell antigens. Normal intracellular membrane traffic patterns may cause acinar cells to secrete autoantigens into the interstitium. When acinar cells have been induced to express major histocompatibility complex Class II molecules, their intracellular membrane traffic may allow them to process and present autoantigens, essentially mimicking the functions of professional antigen presenting cells. The possibility is discussed that perturbations of the spectra of released and presented autoantigens upset the equilibria of idiotypic networks arising to establish peripheral tolerance. The resulting incremental increases in lymphocytic infiltration are suggested to represent essentially cryptic autoimmune processes which may impair lacrimal secretory function and regeneration. Failure to establish peripheral tolerance is predicted to permit unrestrained CD(4) cell proliferation and an environment favoring B cell activation. Recruitment of B lymphocytes, perhaps in events influenced by re-activated viruses, is predicted to lead to Sjögren's autoimmunity as recognized by stringent diagnostic criteria. Finally, the possibility is discussed that androgen supplementation or hormone replacement therapy might prevent simple PLD and avoid the initiation of autoimmune processes.

Dry Eye in Waldenstr??m??s Macroglobulinemia

Waldenström's macroglobulinemia is an uncommon cause of dry eye. We describe a case of dry eye associated with Waldenström's macroglobulinemia that responded poorly to substitutive topical treatment but improved spectacularly in response to systemic chemotherapy. As far as we know, no similar case has been reported.