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

Abstract

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 CD₄ 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.