Why did your mother reject you? Immunogenetic determinants of the responseto environmental selective pressure expressed at the uterine level

PROBLEM: Maternal "rejection" of the implanted conceptus is considered to a ccount for a significant proportion of miscarriages (abortions) in both hum ans and animals. Our understanding of mechanisms has been limited, and henc e, explanations for nonrejection have remained largely speculative. Losses, when they occur, could represent either random accidental failure of prote ctive mechanisms or a more purposeful discrimination. METHOD OF STUDY: An analysis of the most recent data. RESULTS AND CONCLUSIONS: The embryo is most akin to a parasite, and pregnan cy is most akin to a host-parasite interaction. If one excludes chromosome abnormalities in the embryo as a cause of death, activation of coagulation mechanisms, leading to vasculitis affecting the maternal blood supply to th e implanted embryo, appears to represent a major loss-causing mechanism-a f orm of ischemic autoamputation. Proinflammatory T-helper (Th) 1-type cytoki nes trigger this process via upregulation of a novel prothrombinase, fg12. Th2/3 cytokines, such as interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-beta 2; may antagonize the processes involved. Cytokine balan ce is determined by the genetics of the mother, which regulate her response to stress; endotoxin (LPS); and paternal antigens, selectively expressed o n the trophoblast of the embryo, via imprinting. Based on studies in aborti on-prone mice, where immunity to paternal alloantigens prevents loss, three distinct gene products in the embryo are proposed to determine the cytokin e response of maternal lymphomyeloid cells in the uterus.