Non-inherited maternal antigens, pregnancy, and allotolerance

Non-inherited maternal antigens (NIMA) are those protein products derived from polymorphic genes that the mothers express but not the offspring. During normal human pregnancy, a bidirectional regulation occurs in such a way that the maternal immune system tolerates the inherited paternal antigens (IPA) expressed by the fetus and the developing fetal immune system tolerates NIMA. The process by which the described bidirectional regulation is developed is related to microchimerism, due to the bidirectional traffic of cells allowed by the decidua-trophoblast interface. An extensive body of knowledge from the transplantation and pregnancy physiology fields suggests a role for microchimerism and NIMA exposure in the development of NIMA-specific alloresponse regulation, which may include transforming growth factor β (TGF-β) as well as interleukin (IL)-10 and IL-35, producing peripheral T regulatory lymphocytes. The induction of this NIMA-specific allotolerance is called the "NIMA effect." Some experimental data suggest the existence of a "split tolerance" phenomenon associated with NIMA effect, in which regulation of NIMA-specific indirect pathway is induced without tolerogenic impact on the direct pathway. In this review, the most relevant literature about the immunological phenomena underlying the NIMA effect is discussed, including the most recent proposals about the role played by antigen-acquisition and the semi-direct pathway of allorecognition.