Why aren’t Embryos Immunologically Rejected by their Mothers?

BIOLOGY OF REPRODUCTION Why 38, Aren’t CAROL 17-29 (1988) Embryos Immunologically M. WARNER,2 MELODY Department Rejected S. BROWNELL, of Biochemistry Iowa State Ames, Since that mammals, time, and organisms an for (reviewed in Klein, defined lower 1986). The set of genes that encodes the information found on the surface of cells of each proteins are highly polymorphic, and in the that species has individual’s products a particular tissue of the MHC type or MHC of a variety of biological functions, interactions in the immune response, rejection, and reproductive success. The best-studied diagram of the MHC current is view that of of the the shown in Figure 1. Extensive work on sequencing the genes of the H-2 complex, 1980, has shown that the H-2 complex least 50 genes (Steinmetz, 1987). The code for three different types of proteins, both of which 28,000. encoded is a MHC and control cell-cell and graft mouse. proteins are the some is termed both chromosomes in proteins Gorer Class cloning and initiated in encodes at MHC genes designated codominant that the chain. The heavy chain is encoded in the H-2 complex, but the light chain, 132 -microglobulin, is encoded on mouse chromosome 2. In most species, the Class I Medawar’s are clustered at the telomeric but in the mouse, two Class located to the centromeric end I genes have end of the transgene complex. by the for the immune 1953). ‘This work was supported Reprint requests. by NIH Grant HD These proteins of components 21-hydroxylase, the the are of MHC MHC chromo- genes from genotype constitute the In general, H-2 of MHC MHC complex interest recognized. came in graft rejection and The about rejection. and graft that both rejecwere complex. Hypotheses In 1953, Medawar proposed that the mammalian embryo, like tumors and grafts, should be susceptible to immunological rejection by the mother, since paternal as well as maternal MHC genes are expressed of the MHC, been MHC Medawar’s H-2 of rejection was a significant more than ten years before Medawar realized that tumor tion were similar processes genes heterodimers of his discovery was of Gorer’s discovery by the of expression. discovery of the in tumor but it was of Peter the on a single and Class I, Class II, and Class III. Class I molecules are membrane-bound glycoproteins, all of which have a similar structure, a 35-45,000 molecular weight heavy chain and a 12,000 molecular weight light mediated genes constitute the importance popularization II III proteins. Expressed genes each individual. and its role breakthrough, because are Class are membranemajor types approximately 32,000, weight approximately and consist the enzyme a haplotype, of show knew are of the Class II proteins the MHC. The third type tumor necrosis factor. The collection of all MHC the individual. phenotype A MHC Both chains by genes of are not membrane-bound of serum complement, The the mouse II proteins, proteins Class I proteins There are two MHC phenotype. including tumor of MHC an a-chain, molecular weight and a 13-chain, molecular defining for type which like glycoproteins. Class for proteins individual. The each individual are crucial second proteins, bound for most vertebrate set of proteins genes Biophysics 50011 The been of A. EWOLDSEN University Iowa Peter Gorer discovered the complex (MHC) of the (Gorer, 1936a,b; 1937). MHC has a variety MARK Mothers?’ fetus. Medawar hypothesized immunologic tolerance system for allogeneic fetal His first hypothesis was three possibilities of the maternal antigens (Medawar, that the fetus was anatomically separated from the mother; in the second, he proposed that the fetus was antigenically immature and therefore could not stimulate the 13748. 17 over 50 years ago, histocompatibility the H-2 complex and and INTRODUCTION Just major mouse, by Their 18 WARNER The Mouse Chromosome 17 Major H)stocompotlbj)lty ceotromerjc . end telomerlc K cjo_ofrQt7Jppro0hco 9r 2 of Gen I S II III 7 8 nod I IL 1-5 1-10 least #{149} 50 genes! 2600 1. The FIG. complex. mouse The major diagram kb maternal immune suggested relatively that inert Over the years, been challenged, emerge et al., about 1984; each and only that one which in the 1987). This hypotheses, aspect of the during or third hypothesis, he immune system was hypotheses have have begun to relationship Lewis et (Jacoby al., 1986; paper will focus and will concentrate maternal/fetal the (MHC) (1987). of Medawar’s new insights the maternal/fetal Beer et al., 1985; occurs complex Steinmetz maternal pregnancy. Rodger and Drake, Medawar’s first two on on system; the during cM) hisrocompatibility is based period Early Embryo mammalian Development development is characterized a preimplantation period tion and the time the uterus. In the of implantation of the mouse, the preimplantation encompasses about of 21 embryonic the five between days the time of a total days. The preimplantation system has been studied mouse.The relatively inbred, reasons inexpensive, congenic, are that the and available recombinant-inbred, by of fertiliza- time mammalian extensively of Figure 2. superovulated mouse embryos Expression Mouse of Class I has been Goldberg, 1976; Krco 1977; et 1977; Cozad and Webb al., and Warner, 1981, 1982; Sawicki et al., 1981; Warner and Spannaus, 1984; Goldbard et al., 1984; Warner et al., 1985a,b; 1987a). Not only are MHC Class I antigens detectable on preimplantation mouse embryos, but they are actively synthesized by the embryos not simply cytophilically adsorbed cell surface (Goldbard et al., 1985). no positive preimplantation reports themselves and to the embryonic There have been of MHC Class II antigens embryonic cell surface. The finding of Class I antigens on surface puts into doubt the validity hypothesis, namely that on the the embryonic of Medawar’s embryos are anti- genically immature. Not only are Class I MHC antigens found on embryos, but there is mounting evidence that MHC antigens may play an important role in the reproductive process. Recent evidence suggests that of an allogeneic pregnancy may be beneficial for the survival of the fetus (Toder and Beer, 1985; Lewis et a!., 1986; Rodger and Drake, 1987). In humans, it is still controversial whether recurrent spontaneous abortion is associated with in 1 cell is small, in random-bred, and mutant is shown Of particular interest to our laboratory has been the question of the antigenic maturity of preimplantation mouse embryos, especially with respect to MHC 0 post-hCG 17 41 4 cell 53 8 cell 65 in on Embryos Hours 2cell morula MHC-Antigen Preimplantation of demonstration mouse embryos (...truncated)