Autoimmune ovarian inflammation triggered by proinflammatory (Th1) T cells is compatible with normal ovarian function in mice.
The detection of noninfectious ovarian inflammation (oophoritis) and serum ovarian autoantibodies in a patient with premature ovarian failure is indicative of an autoimmune etiology. The mechanisms of autoimmune ovarian injury leading to loss of function are currently unknown. In this study we investigated the impact of oophoritis on ovarian function based on two murine autoimmune ovarian disease (AOD) models. AOD can be induced by thymectomy at Day 3 after birth (d3tx). D3tx mice develop ovarian inflammation and atrophy with loss of oocytes. In these mice, ovarian atrophy and not oophoritis correlated with abnormal estrous cyclicity. The second AOD model is induced by active immunization of adult mice with a murine ZP3 peptide (pZP3) in adjuvant. After active immunization, the zona pellucida antibody titer, not oophoritis, correlated with reduced fertility. To investigate the effect of oophoritis in the absence of antibody response or ovarian atrophy, pZP3-specific T cells were passively transferred into naive syngeneic mice. This recruited cytokine-producing cells into the ovaries so that elevated cytokine production and its effect on ovarian function could be examined. Recipients of pZP3-specific T cells developed severe granulomatous oophoritis, and the diseased ovaries had elevated ovarian mRNA levels of interferon-gamma, interleukin-1beta, and tumor necrosis factor alpha. Despite these changes, fertility rates and gonadotropin-induced follicular development remained essentially normal. Therefore, normal ovarian function is compatible with severe ovarian inflammation mediated by autoreactive T cells.
Bagavant
H
H
Department of Pathology, University of Virginia, Charlottesville, Virginia 22908, USA. hb5u@virginia.edu
Adams
S
S
Terranova
P
P
Chang
A
A
Kraemer
F W
FW
Lou
Y
Y
Kasai
K
K
Luo
A M
AM
Tung
K S
KS
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000276:immunology* / Q000503:physiopathology; D016207:Cytokines / Q000096:biosynthesis; D004527:Egg Proteins / Q000276:immunology; D004971:Estrus; D005260:Female; D007247:Infertility, Female / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009869:Oophoritis / Q000276:immunology* / Q000503:physiopathology; D010053:Ovary / Q000276:immunology* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface; D018417:Th1 Cells / Q000276:immunology*; D013934:Thymectomy; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015044:Zona Pellucida / Q000276:immunology; D000072216:Zona Pellucida Glycoproteins
D001323:Autoantibodies; D016207:Cytokines; D004527:Egg Proteins; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D000072216:Zona Pellucida Glycoproteins; C000606521:Zp3 protein, mouse; D007371:Interferon-gamma