title: Maternal autoantibody triggers de novo T cell-mediated neonatal autoimmune disease.
abstract: Although human maternal autoantibodies may transfer transient manifestation of autoimmune disease to their progeny, some neonatal autoimmune diseases can progress, leading to the loss of tissue structure and function. In this study we document that murine maternal autoantibody transmitted to progeny can trigger de novo neonatal pathogenic autoreactive T cell response and T cell-mediated organ-specific autoimmune disease. Autoantibody to a zona pellucida 3 (ZP3) epitope was found to induce autoimmune ovarian disease (AOD) and premature ovarian failure in neonatal, but not adult, mice. Neonatal AOD did not occur in T cell-deficient pups, and the ovarian pathology was transferable by CD4(+) T cells from diseased donors. Interestingly, neonatal AOD occurred only in pups exposed to ZP3 autoantibody from neonatal days 1-5, but not from day 7 or day 9. The disease susceptibility neonatal time window was not related to a propensity of neonatal ovaries to autoimmune inflammation, and it was not affected by infusion of functional adult CD4(+)CD25(+) T cells. However, resistance to neonatal AOD in 9-day-old mice was abrogated by CD4(+)CD25(+) T cell depletion. Finally, neonatal AOD was blocked by Ab to IgG-FcR, and interestingly, the disease was not elicited by autoantibody to a second, independent native ZP3 B cell epitope. Therefore, a new mechanism of neonatal autoimmunity is presented in which epitope-specific autoantibody stimulates de novo autoimmune pathogenic CD4(+) T cell response.
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Yulius Y
authors.initials: YY
authors.lastname: Setiady
authors.forename: Eileen T
authors.initials: ET
authors.lastname: Samy
authors.forename: Kenneth S K
authors.initials: KS
authors.lastname: Tung
mesh_terms: D000284:Administration, Oral; D019264:Adoptive Transfer; D000375:Aging / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn / Q000276:immunology*; D001323:Autoantibodies / Q000008:administration & dosage / Q000502:physiology*; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D018450:Disease Progression; D004198:Disease Susceptibility / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004527:Egg Proteins / Q000276:immunology; D018985:Epitopes, B-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D007113:Immunity, Innate; D007150:Immunohistochemistry; D016130:Immunophenotyping; D008212:Lymphocyte Depletion; D008297:Male; D008431:Maternal-Fetal Exchange / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008892:Milk / Q000276:immunology; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000276:immunology; D010049:Ovarian Diseases / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D010446:Peptide Fragments / Q000276:immunology; D011247:Pregnancy; D011956:Receptors, Cell Surface; D017452:Receptors, IgG / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D015044:Zona Pellucida / Q000276:immunology*; D000072216:Zona Pellucida Glycoproteins
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D004527:Egg Proteins; D018985:Epitopes, B-Lymphocyte; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D015375:Receptors, Interleukin-2; C000606517:ZP3 protein, human; D000072216:Zona Pellucida Glycoproteins; C000606521:Zp3 protein, mouse