Neuroendocrine dysfunction in Sjogren's syndrome.

Interactions among the immune, nervous and endocrine systems, which are mediated by hormones, neuropeptides, neurotransmitters, cytokines and their receptors, appear to play an important role in modulating host susceptibility and resistance to inflammatory disease. The neuroendocrine system has two main components: the central and the peripheral. The central compartment is located in the locus ceruleus, the brainstem centers of the autonomic system and the paraventricular nucleus; the peripheral mainly consists of the sympathetic/adrenomedullary system, the hypothalamic-pituitary-adrenal axis (HPA), the hypothalamic-pituitary-gonadal (HPG) axis, and the neuroendocrine tissue located in several organs throughout the body. Hormones and neuropeptides may influence the activities of lymphoid organs and cells via endocrine and local autocrine/paracrine pathways or alter the function of different cell types in target organs. Recent studies highlighted alterations of the neuroendocrine system in systemic autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and Sjogren's syndrome (SS). SS, a prototype autoimmune disorder, has a wide clinical spectrum, extending from organ involvement (autoimmune exocrinopathy) to systemic disease and B cell lymphoma. In SS, several functions of the neuroendocrine system are impaired. First, the HPA axis appears to be disturbed, since significantly lower basal ACTH and cortisol levels were found in patients with SS and were associated with a blunted pituitary and adrenal response to ovine corticotropin-releasing factor compared to normal controls. Second, HPG axis is also involved, since lack of estrogens is associated with human disease and the development of autoimmune exocrinopathy in several experimental models. Finally, exocrine glands are enriched with neuroendocrine-related molecules, adjacent to local autoimmune lesions. Certain clinical manifestations of the disease, including the sicca manifestations, easy fatigue, fibromyalgia and psychological disturbances can be very well explained by mechanisms directly related to disturbances of the neuroendocrine axis. On the other hand, the molecular and biochemical effects of the inflammatory molecules or cell-to-cell interaction, observed during the local or systemic autoimmune injury with cells and mediators of the neuroendocrine system, are largely unexplored.