Endogenous Oocyte Antigens Are Required for Rapid Induction and Progression of Autoimmune Ovarian Disease Following Day-3 Thymectomy

Abstract

Female (C57BL/6×A/J)F1 mice undergoing thymectomy on day 3 after birth (d3tx) developed autoimmune ovarian disease (AOD) and autoimmune disease of the lacrimal gland. As both were prevented by normal adult CD25+ T cells, regulatory T cell depletion is responsible for d3tx diseases. AOD began as oophoritis at 3 wk. By 4 wk, AOD progressed to ovarian atrophy with autoantibody response against multiple oocyte Ag of early ontogeny. The requirement for immunogenic endogenous ovarian Ag was investigated in d3tx female mice, d3tx male mice, and d3tx neonatally ovariectomized (OX) females. At 8 wk, all mice had comparable lacrimalitis but only those with endogenous ovaries developed AOD in ovarian grafts. The duration of Ag exposure required to initiate AOD 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 ∼80% of mice OX at 3 or 4 wk had maximal AOD, thus Ag stimulus for 2.5 wk following d3tx is sufficient. AOD progression requires additional endogenous Ag stimulation from the ovarian graft. In mice OX at 3 wk, ovaries engrafted at 5 wk had more severe oophoritis than ovaries engrafted at 6 or 12 wk; moreover, only mice engrafted at 5 wk developed ovarian atrophy and oocyte autoantibodies. Similar results were obtained in mice OX at 4 wk. Thus endogenous tissue Ag are critical in autoimmune disease induction and progression that occur spontaneously upon regulatory T cell depletion.

Maternal Autoantibody Triggers De Novo T Cell-Mediated Neonatal Autoimmune Disease

“…Third, nAOD occurs only in pups that are exposed to the autoantibody in the first 5 days of life. This corresponds precisely with the neonatal time window when B6AF 1 mice are prone to T cell-dependent AOD following pZP3 injection (30) or thymectomy (26,29,(31)(32)(33)(34)(35). Finally, the most severe nAOD occurred in inbred mice that express the IA(␣ k ␤ b ) haplotype, a dominant MHC for pZP3-specific T cell response (36) (Y. Setiady and K. S. Tung, unpublished observation).…”

“…The histology and cellular infiltrates of nAOD closely resembled those of the AOD in adult recipients of pZP3-specific T cells (25) and the 3-day-old recipients of T cells transferred from day 3 thymectomized donors (26,27). These immunopathologic findings along with the latency period noted between immune complex deposition and ovarian pathology prompted an investigation on neonatal T cell requirement in nAOD pathogenesis.…”

Cutting Edge: Autoimmune Disease in Day 3 Thymectomized Mice Is Actively Controlled by Endogenous Disease-Specific Regulatory T Cells

“…Fox1 nu heterozygotes were identified using a single-strand conformation polymorphism of the denatured sequence amplified by the 5Ј-CAGACCCAGAGC AGATCCAG-3Ј and 5Ј-AGGAGTGTCCATCAAGTGCC-3Ј primers. Thymectomy was performed by suction under hypothermia (15). Mice with an incomplete thymectomy were excluded.…”

“…The timing of Ab treatment coincided with the duration of pathogenic T cell priming by endogenous ovarian Ags (15). D3tx mice treated with anti-CD25 Ab had a dramatic increase in mean AOD severity (p ϭ 0.011) (Fig.…”

“…At the onset of AOD (3-4 wk) (15), an average of 13% (n ϭ 11) of the ovarian CD4 ϩ T cells were Foxp3 ϩ , with some exceeding 35% (data not shown).…”