Endogenous oocyte antigens are required for rapid induction and progression of autoimmune ovarian disease following day-3 thymectomy

Female (C57BL/6xA/J)F-1 mice undergoing thymectomy on day 3 after birth (d3 tx) developed autoimmune ovarian disease (AOD) and autoimmune disease of th e lacrimal gland. As both were prevented by normal adult CD25(+) T cells, r egulatory T cell depletion is responsible for d3tx diseases. ACID began as oophoritis at 3 wk. By 4 wk, AOD progressed to ovarian atrophy with autoant ibody response against multiple oocyte Ag of early ontogeny. The requiremen t for immunogenic endogenous ovarian Ag was investigated in d3tx female mic e, d3tx male mice, and d3tx neonatally ovariectomized (OX) females. At 8 wk , all mice had comparable lacrimalitis but only those with endogenous ovari es developed AOD in ovarian grafts. The duration of Ag exposure required to initiate ACID was evaluated in d3tx mice OX at 2, 3, or 4 wk and engrafted with an ovary at 4, 5, or 6 wk, respectively. The mice OX at 2 wk did not have oophoritis whereas similar to 80% of mice OX at 3 or 4 wk had maximal AOD, thus Ag stimulus for 2.5 wk following d3tx is sufficient. AOD progress ion requires additional endogenous Ag stimulation from the ovarian graft. I n mice OX at 3 wk, ovaries engrafted at 5 wk had more severe oophoritis tha n ovaries engrafted at 6 or 12 wk; moreover, only mice engrafted at 5 wk de veloped ovarian atrophy and oocyte autoantibodies. Similar results were obt ained in mice OX at 4 wk. Thus endogenous tissue Ag are critical in autoimm une disease induction and progression that occur spontaneously upon regulat ory T cell depletion.