Murine postthymectomy autoimmune oophoritis develops in association with a persistent neonatal-like Th2 response.
Autoimmune oophoritis develops in some patients despite evidence of impaired cellular immunity. Here, using the murine postthymectomy model of autoimmune oophoritis, we investigate the hypothesis that neonatal thymectomy induces autoimmune oophoritis by disrupting the normal postnatal balance of T helper cell regulation. Stimulated CD4+ splenic lymphocytes from adult mice sham-operated as neonates produced the expected T helper type 1 (Th1) predominant response normally seen in adult mice (low levels of interleukin-4 and high levels of interferon gamma). In contrast, cells from adult mice thymectomized as neonates produced an inappropriate neonatal-like Th2-predominant response (high levels of interleukin-4 and low levels of interferon-gamma). Manipulations that restored the postnatal shift to an adult Th1-dominant pattern ameliorated the autoimmune oophoritis. Thus, neonatal thymectomy abrogates the postnatal shift to a Th1-dominant pattern, and the resulting persistent neonatal-like Th2-dominant response is tightly associated with the development of postthymectomy autoimmune oophoritis. These results (i) suggest that the postnatal shift to the normal adult Th1/Th2 balance is established by a thymus-dependent process and (ii) raise the possibility that specific genetic defects, as yet to be determined, might mimic the effect of neonatal thymectomy in this model, impair the development of normal Th1/Th2 balance, and be a cause autoimmunity. These results hold implications for the pathogenesis and possibly for the therapy of autoimmune polyglandular failure in humans.
Maity
R
R
Developmental Endocrinology Branch, NICHD, NIH, Bethesda, Maryland 20892, USA.
Caspi
R R
RR
Nair
S
S
Rizzo
L V
LV
Nelson
L M
LM
D019264:Adoptive Transfer; D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001327:Autoimmune Diseases / Q000209:etiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D005260:Female; D018664:Interleukin-12 / Q000627:therapeutic use; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009869:Oophoritis / Q000209:etiology* / Q000276:immunology* / Q000517:prevention & control; D011183:Postoperative Complications; D011247:Pregnancy; D013154:Spleen / Q000166:cytology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D013934:Thymectomy
D018664:Interleukin-12; D015847:Interleukin-4