Modulation of inflammation and adaptive immunity by a progesterone receptor Female sex steroids like progesterone (Pg) are powerful modulators of the immune system. High Pg states, such as pregnancy, are associated with remission of common autoimmune diseases like rheumatoid arthritis, and suppression of T helper type 1 (Th1) responses - effects recapitulated in animal models after Pg treatment. Increased Th1-related cytokines are associated with pre-term birth, a major cause of morbidity and mortality;Pg supplementation is used successfully to prevent it. Pregnancy and Pg treatment in animals leads to altered immunoglobulin levels and antibody responses to immunization. Women using injectable Pg contraception are at significantly increased risk of HIV infection;and this form of birth control is used by an estimated 50 million women, increasingly in Sub-Sahara Africa where HIV is epidemic. Nevertheless, the cellular and molecular targets of Pg immunomodulation in vivo are largely unknown. Immune cells express at least 2 Pg receptor types: intracellular Pg receptors (iPRs) and recently discovered membrane PRs (mPRs). Natural and synthetic progestins bind with variable affinities to these 2 receptors. iPRs are well characterized in reproductive tissues, but their immune functions in vivo remain unexplored. Here, we propose to clarify cellular and molecular targets of Pg immunomodulation in vivo by assessing how loss of iPRs in CD4+ T cells, B cell or dendritic cells impacts inflammation and adaptive immune responses before and after Pg treatment. Comparing vehicle- vs. Pg-treatments within iPR+ mice will allow us to define Pg's effects in our system;comparing iPR+ vs. iPR- groups will allow us to determine which effects require iPRs, and in which cell types, and under what hormonal conditions they are operational. These experiments will clarify cellular and molecular mechanisms of Pg immunomodulation and reveal a framework for understanding important clinical phenomena impacting global health, women's health, maternal-fetal medicine and autoimmunity.
Progesterone, a critical female reproductive steroid hormone, modulates immune system functions during pregnancy and during use of progesterone-containing birth control. The changes in the immune system, while necessary for the maintenance of normal pregnancy, also suppress certain aspects of maternal immune defenses. How progesterone modulates immune functions in vivo is poorly understood. In order to address this fundamental lack of knowledge we have developed a series of genetically-modified mouse strains lacking progesterone receptors only in certain immune cell types. These unique tools will allow us to determine mechanisms of progesterone immunomodulation in vivo.
|Lood, Christian; Hughes, Grant C (2017) Neutrophil extracellular traps as a potential source of autoantigen in cocaine-associated autoimmunity. Rheumatology (Oxford) 56:638-643|
|Wong, Alan H; Agrawal, Nalini; Hughes, Grant C (2015) Altered IgG autoantibody levels and CD4(+) T cell subsets in lupus-prone Nba2 mice lacking the nuclear progesterone receptor. Autoimmunity 48:389-401|
|Hughes, Grant C; Choubey, Divaker (2014) Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat Rev Rheumatol 10:740-51|