Mechanisms responsible for the female predominance of autoimmune diseases remain obscure, but an important modulatory role for gonadal steroid hormones is likely. We have found previously that the thymus is an important target of androgen action within the immune system, with attendant impact on peripheral T cell immunity. The proposed studies aim to investigate how androgens alter development of the other major compartment of the immune system, B cells. We propose to investigate the mechanisms underlying androgen-mediated effects of developing B cells. The three specific aims of these studies are as follows: 1. The functional significance of bone marrow target cells for androgen action will be determined. The approach will utilize in vivo model of androgen resistance, the testicular feminization (Tfm) mouse in bone marrow transplantation experiments with normal C57 mice, resulting in targeted expression of functional androgen receptors in either stromal or lymphoid cells. Effects of androgen deprivation and replacement on developing B cell subpopulations will be assessed. 2. The physiologic processes mediated by androgens in the bone marrow will be examined through studies of effects on cell cycling and apoptosis. These studies will be done ex vivo using bone marrow cells from animals which have undergone androgen manipulation and in vitro in cultures of developing B cells. 3. The role of two potential mediators of androgen actions on developing B cells, transforming growth factor-beta and interieukin-7 (IL-7), will be defined using in vitro models of B cell development. These studies will elucidate how androgens directly alter development of B cells in the bone morrow, and have potentially important implications of the role of androgens in mechanisms underlying the female predominance of autoimmune diseases.
