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Immunol Rev. 2001 Aug;182:135-48.

Regulatory T-cell, endogenous antigen and neonatal environment in the prevention and induction of autoimmune disease.

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Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.


Recent studies on autoimmune ovarian disease (AOD) induced by thymectomy on d3 (d3tx), and AOD induced by immunization with the ovary-specific zona pellucida 3 peptide (pZP3), have yielded the following results. First, female tolerance to pZP3 depends on the persistence of endogenous antigen (Ag). Second, following regulatory T-cell depletion, endogenous Ag in prepubertal d3tx mice triggers AOD and drives disease progression. Third, endogenous ZP3 from ovaries without AOD stimulates a diversified IgG autoantibody (autoAb) response that rapidly follows pZP3 T epitope immunization. Fourth, induction of AOD and autoimmune memory in neonatal female mice by pZP3 in incomplete Freund's adjuvant depends on endogenous Ag stimulation within the neonatal week. Fifth, in a rodent pinworm-positive environment, neonatal but not adult female mice injected with pZP3 in water develop Th2-mediated AOD and Th2 memory. Sixth, neonatal T cells transfer AOD to syngeneic athymic recipients, whereas adult T cells are non-pathogenic and in fact suppress AOD conferred by neonatal T cells. Therefore: 1) the continuous presence of physiologically-expressed autoAg is critical for both tolerance maintenance and autoimmune disease pathogenesis; the outcome is determined by the integrity of regulatory T cells; and 2) the neonatal mice, deficient in the regulatory T-cell function, are more responsive than adults to Ag and environmental stimuli that promote autoimmune disease and memory.

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