Autoimmune Ovarian Disease in Day 3-Thymectomized Mice: The Neonatal Time Window, Antigen Specificity of Disease Suppression, and Genetic Control

Abstract

Discovery of the CD4 + CD25 + T cells has stemmed from investigation of the AOD in the d3tx mice. Besides CD4 + CD25 + T cell depletion, d3tx disease induction requires effector T cell activation prompted by lymphopenia. This is supported by other neonatal AOD models in which T cell-mediated injury has been found to be triggered by immune complex or Ag immunization. In addition, there is growing evidence that support a state of neonatal propensity to autoimmunity, which depends on concomitant endogenous antigenic stimulation, concomitant nematode infection, resistance to CD4 + CD25 + T cell regulation, and participation of the neonatal innate system. The suppression of d3tx disease by polyclonal CD4 + CD25 + T cells appears to be dependent on endogenous Ag and the persistence of regulatory T cells. Thus, suppression of AOD occurs in the ovarian LN, and AOD emerges upon ablation of the input regulatory T cells; and in AIP, the hormone-induced expression of prostate Ag in the CD4 + CD25 + T cell donors rapidly enhances the capacity to suppress disease over Ag negative donors. Finally, genetic analysis of AOD and its component phenotypes has uncovered seven Aod loci. As the general themes that emerged, significant epistatic interactions among the loci play a role in controlling disease susceptibility, the majority of the Aod loci are linked to susceptibility loci of other autoimmune diseases, and the genetic intervals encompass candidate genes that are differentially expressed between CD4 + CD25 + T cells and other T cells. The candidate genes include Pdcd1, TNFR superfamily genes, H2, Il2, Tgfb, Nalp5 or Mater, an oocyte autoAg that reacts with autoantibody in sera of d3tx mice.

The Unique Neonatal NK Cells: A Critical Component Required for Neonatal Autoimmune Disease Induction by Maternal Autoantibody

“…The pZP3 (330–342) contains a pathogenic T cell epitope and a native B cell epitope 335–342 (42), and antibodies to this pZP3 B cell epitope inhibit sperm binding to the zona pellucida (41, 43). Adult mice immunized with pZP3 in CFA develop a pathogenic CD4 + T cell response and a non-pathogenic antibody response.…”

Failure of CD25+ T Cells from Lupus-Prone Mice to Suppress Lupus Glomerulonephritis and Sialoadenitis

“…The resultant state of regulatory and effector T cell imbalance is also exaggerated by homeostatic T cell expansion in the profoundly lymphopenic d3tx mice (17,18). Regardless of the precise mechanism of disease induction, all d3tx-induced, organ-specific autoimmune diseases in nonlupus mice are readily prevented by early infusion of CD4 ϩ CD25 ϩ T cells from normal syngeneic adults (19,20). In this study we have investigated the capacity of CD25 ϩ regulatory T cells from lupus-prone NZM2328 mice to suppress autoimmune disease and autoantibody response in d3tx NZM2328 lupus mice.…”

Hypoplastic left heart syndrome: Rheumatic heart disease of the fetus?

“…While a cell-mediated mechanism would not work with the hypothesized transplacental mechanism, a humoral mechanism (antibody or otherwise) transfered across the placenta could secondarily set up a localized cellmediated process in the fetal heart. Recent studies have supported such a pathogenic mechanism in an animal model of neonatal premature ovarian failure caused by maternal antibodies [99][100][101][102].…”