Autoimmune targeted disruption of the pituitary-ovarian axis causes premature ovarian failure.
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-alpha 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-alpha-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-alpha-targeted experimental autoimmune oophoritis is initiated by CD4(+) Th1 T cells that stimulate B cells to produce inhibin-alpha-neutralizing Abs directly capable of mediating POF and transferring disease into naive recipients. Our inhibin-alpha 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.
Altuntas
Cengiz Z
CZ
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Johnson
Justin M
JM
Tuohy
Vincent K
VK
D028341:Activins / Q000097:blood; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood / Q000502:physiology; D001327:Autoimmune Diseases / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D001402:B-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D030762:Estrous Cycle / Q000276:immunology; D005260:Female; D005298:Fertility / Q000276:immunology; D005640:Follicle Stimulating Hormone / Q000097:blood; D007106:Immune Sera / Q000008:administration & dosage; D007116:Immunization, Passive; D007265:Inhibins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009869:Oophoritis / Q000276:immunology; D006080:Ovarian Follicle / Q000473:pathology; D010053:Ovary / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D010902:Pituitary Gland / Q000276:immunology*; D016649:Primary Ovarian Insufficiency / Q000097:blood / Q000276:immunology* / Q000503:physiopathology
D001323:Autoantibodies; D007106:Immune Sera; D010446:Peptide Fragments; C094377:inhibin-alpha subunit; D028341:Activins; D007265:Inhibins; D005640:Follicle Stimulating Hormone