Possible mechanism of success of an allotransplantation in nature: mammalian pregnancy.

A new hypothesis is presented to explain the mechanism of non-rejection of a natural allograft: the mammalian fetus during early development. Using the rabbit as a model, it is proposed here that uteroglobin (UG., MW. 15,800) synthesized in the uterus during early pregnancy, crosslinks with beta 2-microglobulin (part of the H-2 and HL-A antigens) on the embryonic cell surface. This crosslinking is achieved by the enzyme transglutaminase (coagulation factor XIIIa), which has a 4--5 fold increased activity in the uterus during early pregnancy. The conversion of pre-uteroglobin (Pre-UG) to uteroglobin (UG) and pro-transglutaminase (factor XIII) to active transglutaminase (factor XIIIa) is achieved by the concurrent increased activity of proteases present in the uterus at this time. UG is a dimeric protein with two alpha-helices running in parallel and connected by two disulfide bonds. We propose that UG molecules crosslink with beta 2-microglobulin in the presence of transglutaminase (factor XIIIa). A crosslinked beta 2-microglobulin-uteroglobin complex is formed which masks the H-2 or HL-A antigen of the implanting embryo. Thus, the maternal lymphocytes do not recognize the fetal cells as foreign. This mechanism may also explain the non-immunogenicity of ejaculated sperm in the uterus, as well as the non-immunogenicity of fetal cells found in the maternal circulation during pregnancy. At later stages of pregnancy, other proteins and/or hormones as well, may play a role in non-rejection of the fetus. However, the beta 2-microglobulin-uteroglobin complex masking the transplantation antigens of the embryo may be the major mechanism for immunological protection and non-rejection of the implanting embryo.