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Autoimmune Targeted Disruption of the Pituitary-Ovarian Axis Causes Premature Ovarian Failure¹

Cengiz Z. Altuntas^*,, Justin M. Johnson^* and Vincent K. Tuohy^2,*,

^* Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and Department of Biology, Cleveland State University, Cleveland, OH 44115

Premature ovarian failure (POF) is characterized by amenorrhea and high serum levels of follicle-stimulating hormone (FSH). POF causes female infertility and represents a substantial women’s health risk affecting 1% of women by age 40. Although ovarian autoimmunity has been associated with POF, the identity of ovarian Ags recognized is unknown. In this study, we show that autoimmune-targeted disruption of the pituitary-ovarian axis leads to POF. Immunization of SWXJ female mice with the p215–234 peptide derived from mouse inhibin- activates CD4⁺ T cells and induces experimental autoimmune oophoritis with a unique biphasic phenotype characterized by an early stage of enhanced fertility followed by a delayed stage of POF. Affected mice show high serum levels of inhibin--neutralizing Abs that prevent inhibin-mediated down-regulation of activin-induced pituitary FSH release. The loss of activin/FSH down-regulation leads to prolonged metestrus-diestrus, superovulation, increased numbers of mature follicles, increased offspring, accelerated depletion of primordial follicles, and ultimately premature infertility. Thus, inhibin--targeted experimental autoimmune oophoritis is initiated by CD4⁺ Th1 T cells that stimulate B cells to produce inhibin--neutralizing Abs directly capable of mediating POF and transferring disease into naive recipients. Our inhibin- autoimmune model of POF shows how premature infertility may develop in the context of elevated FSH levels thereby closely mimicking the hallmark features of human POF.

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The JI 2006 177: 1373-1374. [Full Text]  

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