The literature contains increasing evidence that the hypothalamic hormone, GnRH, possesses direct immunomostimulatory properties. Lymphocytes are known to produce GnRH mRNA and the GnRH peptide. Thus, GnRH resembles a cytokine. Our central hypothesis is that GnRH may play a role in increasing the incidence or severity of certain types of autoimmunity. We have tested this hypothesis in a murine model of lupus. We found that GnRH antagonists ameliorated murine lupus, whereas GnRH agonists exacerbated disease. Results were similar in male and female mice, whether they were intact or castrated, demonstrating that the effects of GnRH are independent of gonadal steroids. In an effort to test whether GnRH is a necessary cofactor in the development of autoimmune disease, we propose to create a congenic mouse model by breeding the truncated GnRH gene of the HPG/BM mouse onto autoimmune-prone backgrounds. We propose a pilot study to test whether autoimmune-prone mice differ from normal background strains in the lymphoid expression of GnRH and/or its receptor. Little is known about which lymphocyte subsets produce and respond to GnRH. We propose to perform lymphocyte purification procedures followed by quantitative RT-PCR to determine which lymphocyte subsets produce GnRH and its receptor. Functional studies of B and T lymphocytes will be performed. We will also use the GnRH deficient HPG/Bm mouse model and bone marrow reconstitution experiments to determine the relative contribution of lymphoid system and the central nervous system to total circulating GnRH levels. We speculate that at least some of the immune actions of gonadal steroids might be mediated through feedback on GnRH/GnRH receptor. One of the major goals of this proposal is to disentangle the immunological effects of gonadal steroids from their feedback effects on GnRH. The HPG/Bm mouse model will be invaluable in these studies. We have recently demonstrated that GnRH receptor expression is dynamically modulated in the thymus and spleen during the estrous cycle in the normal female mouse, as it is in the pituitary. We speculate that the GnRH and/or its receptor is modulated in the peripheral lymphoid system by the same factors, namely gonadal steroids, inhibin, and GnRH itself, all of which regulate GnRH related gene expression in the CNS. These studies are important because they may provide new and important information with respect to gender differences in immunity and autoimmunity, and may offer hope for new, more specific treatments for certain autoimmune diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Reproductive Endocrinology Study Section (REN)
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Gretz, Elizabeth
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University of Missouri Kansas City
Schools of Medicine
Kansas City
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Ansari, Mansoor A; Dhar, Minati; Spieker, Sreelatha et al. (2004) Modulation of diabetes with gonadotropin-releasing hormone antagonists in the nonobese mouse model of autoimmune diabetes. Endocrinology 145:337-42
Jacobson, Jill D; Ansari, Mansoor A (2004) Immunomodulatory actions of gonadal steroids may be mediated by gonadotropin-releasing hormone. Endocrinology 145:330-6
Morton, Terri L; Ansari, Mansoor A; Jacobson, Jill D (2003) Gender differences and hormonal modulation of G proteins Galpha(q/11) expression in lymphoid organs. Neuroendocrinology 78:147-53
Jacobson, J D (2001) Gonadotropin-releasing hormone: potential role in autoimmunity. Int Immunopharmacol 1:1077-83
Walker, S E; Jacobson, J D (2000) Roles of prolactin and gonadotropin-releasing hormone in rheumatic diseases. Rheum Dis Clin North Am 26:713-36
Jacobson, J D (2000) Gonadotropin-releasing hormone and G proteins: potential roles in autoimmunity. Ann N Y Acad Sci 917:809-18
Jacobson, J D; Ansari, M A; Mansfield, M E et al. (1999) Gonadotropin-releasing hormone increases CD4 T-lymphocyte numbers in an animal model of immunodeficiency. J Allergy Clin Immunol 104:653-8
Jacobson, J D; Ansari, M A; Kinealy, M et al. (1999) Gender-specific exacerbation of murine lupus by gonadotropin-releasing hormone: potential role of G alpha(q/11). Endocrinology 140:3429-37