The changing maternal "self" hypothesis: a mechanism for maternal tolerance of the fetus.
Recent advances in placental biology and immunology lead us to propose a novel hypothesis for maternal tolerance of the semi-allogeneic fetus and amelioration of rheumatoid arthritis (RA) during pregnancy. The initial event in this hypothesis is extrusion of placental apoptotic syncytiotrophoblast debris recently identified to contain intracellular fetal HLA Class II molecules, into maternal blood. The second event is uptake of apoptotic syncytiotrophoblast by immature maternal dendritic cells and presentation of fetal HLA class II peptides. In addition to presenting foreign antigens, HLA molecules also present HLA self-peptides. In the setting of the non-inflammatory environment of pregnancy, this process is expected to induce peripheral tolerance of fetal antigens through T cell death, anergy or induction of regulatory T cells in the lymph nodes. This hypothesis suggests a mechanism by which the simultaneous presentation of fetal and self (RA-associated) HLA peptides by tolerogenic dendritic cells during pregnancy may explain the observed amelioration of RA as a secondary benefit of fetal tolerance. After delivery, apoptotic syncytiotrophoblast debris disappears from maternal blood, autoimmunity returns and RA recurs. Thus, during pregnancy maternal immunologic "self" includes fetal HLA Class II as a result of apoptotic syncytiotrophoblast uptake by maternal tolerogenic dendritic cells.
Adams
K M
KM
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Human Immunogenetics Program, 1100 Fairview Ave. N., D2-100, P.O. Box 19024, Seattle, WA 98109-1024, USA. adamsk@u.washington.edu <adamsk@u.washington.edu>
Yan
Z
Z
Stevens
A M
AM
Nelson
J L
JL
D001172:Arthritis, Rheumatoid / Q000517:prevention & control; D005260:Female; D005333:Fetus / Q000276:immunology*; D006681:HLA-D Antigens / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D008431:Maternal-Fetal Exchange / Q000276:immunology*; D011247:Pregnancy / Q000276:immunology / Q000502:physiology*; D011248:Pregnancy Complications / Q000517:prevention & control
D006681:HLA-D Antigens