Why Did Your Mother Reject You? Immunogenetic Determinants of the Response to Environmental Selective Pressure Expressed at the Uterine Level

Abstract

PROBLEM: Maternal “rejection” of the implanted conceptus is considered to account for a significant proportion of miscarriages (abortions) in both humans and animals. Our understanding of mechanisms has been limited, and hence, explanations for nonrejection have remained largely speculative. Losses, when they occur, could represent either random accidental failure of protective 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 pregnancy 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 the implanted embryo, appears to represent a major loss‐causing mechanism—a form of ischemic autoamputation. Proinflammatory T‐helper (Th) 1‐type cytokines trigger this process via upregulation of a novel prothrombinase, fg***12. Th2/3 cytokines, such as interleukin (IL)‐4, IL‐10, and transforming growth factor (TGF)‐β2, may antagonize the processes involved. Cytokine balance is determined by the genetics of the mother, which regulate her response to stress; endotoxin (LPS); and paternal antigens, selectively expressed on the trophoblast of the embryo, via imprinting. Based on studies in abortion‐prone mice, where immunity to paternal alloantigens prevents loss, three distinct gene products in the embryo are proposed to determine the cytokine response of maternal lymphomyeloid cells in the uterus.