Specific Effects of Estrogen on Autoimmunity
In women, the cumulative physiological degeneration associated with normal aging is augmented by a dramatic and systemic estrogen deprivation. Estrogens generally favor immune processes involving CD4+ Th2 cells and B cells, thereby promoting B-cell-mediated autoimmune diseases. Physiologic levels of estrogen, however, also stimulate the expansion of CD4+ CD25+ Tregs, which help maintain tolerance to self-antigens and therefore ameliorate autoimmune disease, as well as the expression of the Foxp3 gene, a marker for Treg function. Follicular Th cells by contrast, appear to drive autoantibody production in the germinal center and are associated with the development of systemic autoimmunity.
Androgens, on the other hand, encourage processes involving CD4+ Th1 cells and CD8+ cells, acting to suppress or ameliorate B-cell-mediated autoimmune diseases. The influence of these hormones on the immune system, therefore, produce more autoimmune pathology in women in autoimmune disease mediated by Th2 dominant processes, and more in men when Th1 processes are involved (Table 3).
Hormonal manipulations can alter immune reactivity and modulate disease expression. Estrogens provoke involution of the thymus; treatment of castrated animals with exogenous sex hormones causes massive atrophy of the thymus. Thymus regeneration occurs following ovariectomy, and thymus involution occurs during pregnancy, which reverts after lactation ceases.
Estrogen-induced involution of the thymus is associated with a reduction in numbers of immature T lymphocytes. Estrogen affects T-cell subset composition, as well as T-cell function and activation. Oral estrogen-replacement therapy has been shown to restore T-cell function.
Estrogen drastically reduces not only the size of the thymus, but also the bone marrow cavity as well, the sites where most deletion of autoreactive cells occur. B cells developing at alternative sites (liver and spleen), where less stringent selection occurs, may escape normal controls.
Estrogens, in fact, stimulate lymphopoiesis outside of the bone marrow. Mice treated with exogenous estrogen develop impressive hemopoietic centers in the liver and spleens filled with antibody-producing cells.
Estrogen depletion in women, characteristic of postmenopausal women, has been specifically associated with reductions in B and T cells and Th-derived cytokines as well as an impaired immune response to viral infections. In vitro, estrogen stimulates Th1 cytokine production by T cells.
Estrogens diminish the number of monocytes, through apoptosis, as well as through a modulation of the cell cycle which delays mitosis. Autoreactive B-cell apoptosis, particularly, is inhibited. Estrogen, however, simultaneously induces a rapid maturation of B lymphocytes and stimulates Th lymphocytes to secrete type 2 cytokines that promote antibody production.[33,35]
Expert Rev of Obstet Gynecol. 2012;7(6):557-571. © 2012 Expert Reviews Ltd.