Androgen stimulation of lacrimal gland function in mouse models of Sjögren's syndrome

Abstract

Sjögren's syndrome, an autoimmune disease that occurs primarily in women, causes extensive inflammation and significant dysfunction in the lacrimal gland, and is one of the leading causes of dry eye syndromes throughout the world. Recently, our research has shown that androgen treatment causes a significant suppression of the immunopathological lesions in lacrimal tissues of female mouse models (MRL/Mp-lpr/lpr [MRL/lpr] and NZB/NZW F1 [F1]) of Sjögren's syndrome. To extend these findings, the objective of the present study was to determine whether this androgen-induced anti-inflammatory action may be paralleled by an increase in the functional activity of lacrimal glands in these autoimmune mice. Towards this end, we measured the tear levels of immunoglobulin A (IgA), which originates from lacrimal tissue and whose concentration is known to be diminished in mucosal sites in Sjögren's syndrome. For comparative purposes, we also evaluated whether the administration of other steroid hormones or immunosuppressive agents might duplicate possible androgen effects on the secretory function of lacrimal tissue. Female MRL/lpr and F1, as well as non-autoimmune BALB/c, mice were treated with vehicle, steroids or immunosuppressive compounds for 17 to 54 days after the onset of disease. Lacrimal glands, tears and sera were collected immediately before (pretreatment), or after, therapy and processed for the analysis of either tear IgA (enzyme-linked immunosorbent assay; ELISA) and protein content or the magnitude of lymphocyte infiltration (computer-assisted image analysis). Our findings demonstrated that testosterone treatment stimulated a significant increase in the concentration and total amount of tear IgA, as well as tear protein, compared to levels in pretreatment or placebo controls. This hormone action was reproduced by exposure to a diverse array of "anabolic" and "androgenic" androgen analogues, but not by treatment with estradiol, danazol, cyclosporine A, dexamethasone or cyclophosphamide. In contrast, only dexamethasone increased serum IgA concentrations. Of particular interest is the fact that the androgen control of IgA output by the lacrimal gland appeared to be independent of this steroid's suppression of lymphocyte infiltration in lacrimal tissue. Overall, these results show that androgen therapy enhances the functional activity of the lacrimal gland in mouse models of Sjögren's syndrome.