REVIEW ARTICLE IMMUNOLOGIC AND GENETIC FACTORS INFLUENCING REPRODUCTION

IMMUNOLOGIC AND GENETIC FACTORS INFLUENCING REPRODUCTION Maternal Response to Pregnancy Studies in Hmlilllans Studies i,, Animals

465 465 470

Reactivity of Maternal and Fetal Lymphocytes 'T'he' Ontogen\ of the Immunec Response Niaternal l ymphocytes tes Fetal I ymphoes

Regtilation by Passively 'T'ransferred Antibodlies

Transplacental Sensitization

478 478 481 481 483

486

\M utual Senisitization of Miother atn( Offsprinig 486 '1 ransport Niechanisms 492 Protectise and Pathogenic Effects of Transplacentally Passed IMacromolecules al(I CellIs 493

The Placenta as an Anatomic Barrier

Immunoregulatory Substances Pregnancy Serumn a- Fetoprotein

Pregnancy-Associated

¼-oins

(52-(,loI)1oblns

f1-Clilo,lins

fetal Lymniphiocytes Placental Proteins A ntibodies

497

502 502 503 505 505 506 506 506 507

Suppressor Cells

507

Hormonal Suppression of the Immune Response (Corticosktroids Estrogetis P'rogesteronte Androgens

510 510 513 515 5 17 519 520 520 520 521 523 523

A Idosterone Protein Hormones lI omirian Chorionic Goonadotropin IIioman Placental Lactogen (Human Chorionic Somatomammotropin)

Prostaglaandinis Catecholarnines Others

Genetic Influences on Growth and Reproduction Size and Reproductive DIefects 'I'he T/t Complex The F9 Antigeni Fetal Wastage

524 525 528 529

Conclusions Addendum

529 532

524

Immunologic and Genetic Factors Influencing Reproduction A Review Thomas J. Gill III, MD, and Charles F. Repetti, PhD

Viviparous reproduction continues to present both theoretic and experimental dilemmas in immunology and genetics, and their practical consequences affect a number of areas in clinical medicine. The literature in this field is large, complex, and often contradictory. The diverse observations in humans and the variety of experimental systems in animals have not yet produced a systematic body of knowledge about the nature of the immune response to the fetoplacental unit and its effect on the maintenance of pregnancy, the immunologic capabilities of the maternal and fetal lymphocytes, the immunologic reactions that result from the traffic of molecules and cells across the placenta, and the genetic factors influencing the immunologic interface between the mother and fetus. This review will attempt to examine the present state of knowledge in these and cognate areas to provide a systematic basis for evaluating the state of the field and to provide some insight into future directions. A schematic representation of the various factors to be discussed is presented in Text-figure 1. Maternal Response to Pregnancy The maternal response to pregnancy involves both humoral and cellular components. The significance of this response in terms of reproductive capacity and the effect of the immune response on the fetus has been the subject of a great deal of discussion and experimentation, and various aspects of the problem have been reviewed recently.48'51'171'173'367 Studies in Humans

The antibody response to pregnancy involves antibodies which are leukoagglutinating,502'688 lymphocytotoxic,231'489 and reactive with antigens in the cytoplasm of the syncytial trophoblast.293'407 These antibodies are directed against HLA, non-HLA, and placental antigens. In one study, 46 From the Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania. Supported by Grants HD 09880 and HD 08662 from the National Institute of Child HIealth and Human Development. Address reprint requests to Thomas J. Gill III, MD, Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261. 465 0002-9440/79/0510-0463$01 .00 © American Association of Pathologists

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IMMUNOREGULATORY SUBSTANCES /

FETUS

/

X

MOTHER

SUPPRESSOR CELLS

LYMPHOCYTES: REACTIVITY

4-- HORMONAL REGULATION

GENETIC CONTROL

//BLOCKING

X ANTIBODY

ANTIBODY

X

4

ANTIBODY: IgG, IgA, IgE

REACTIVITY GENETIC CONTROL

PLACENTAL BARRIER

TEXT-FIGURE I-Schematic representation of the immtunologic and genetic factors infltuencing the rnaternal-fetal interface. The major factors are a) the reactivity of the maternal and fetal lymphocytes. the reaction of the mother agairnst the fetuis and the fetus against the mother, and the genetic control of these reactions, h) the anatonic antd( ftinctionial nature of the placental harrier and the factors controllitug the fluix of cells and molecules across the placenta, c) the hormonal changes during pregnancy, and (c) the various inmmunoregulatory sub)stances pro(dtuce(d (luring pregnancv and their variationis throtughouit the

course

of gestation.

of 100 serums from pregnant women who lacked antibodies cytotoxic to peripheral blood lymphocytes had cytotoxic antibodies directed at nonHLA antigens on cultured human lymphoblastoid cells; these antibodies were

postulated to react with the human equivalent of the Ia antigens. 186

The antibodies bound to the placenta are mainly IgG, IgA and IgE, and they apparently fix complement, since the C3 and C4 components of complement

are

bound to placental trophoblast.66 162,185 In addition to

placental binding of immunoglobulins, the vascular endothelium of the fetal trophoblast can bind aggregated IgG, and this may prevent immune complexes from reaching the fetus.317 The first major class of antibodies found in pregnant women are those directed against HLA antigens. The IgG antibodies directed against HLA antigens block the cytotoxic effect of maternal lymphocytes on trophoblast,651 inhibit the mixed lymphocyte reaction,530 and inhibit the produc-

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tion of migration inhibitory factor.539 The antibodies inhibiting the mixed lymphocyte reaction are effective in blocking stimulation between maternal lymphocytes and either paternal lymphocytes or lymphocytes from an unrelated donor.530 In 16 of 45 cases, the maternal serums were inhibitory and the antibody blocked both the stimulator (paternal or unrelated) and the responder (maternal) lymphocytes in a one-way mixed lymphocyte reaction. These antibodies also blocked the response to tuberculin and to streptokinase in 7 of 9 cases, and the degree of inhibition varied with the particular cell combination used, but they did not decrease the response to PHA. The antibodies could be removed by absorption with platelets or leukocytes. The results of these experiments were interpreted to indicate that the blocking factors in the maternal serums were mainly antibodies against HLA antigens (but there might also be some antibodies against other cell surface determinants) and that they were effective against both stimulator and responder lymphocytes of the appropriate type. Maternal serums can block the production of migration inhibitory factor (MIF) when maternal cells react against fetal cells.539 The serums were effective in 5 of 10 cases, and all of the effective serums were from women who had been pregnant three or more times. There was no evidence that the offspring were sensitized to maternal lymphocytes. Maternal serums also block specifically the MIF response to the appropriate paternal lymphocytes, and the blocking factor was isolated in the IgG fraction.506 In all of these cases, there were HLA differences between the mother and the father. These results suggest that the blocking specificity was due to an IgG anti-HLA antibody. Studies on habitual aborters 538 showed that these blocking factors were decreased, and the authors suggested that this might be the cause of the habitual abortion. The production of cytotoxic antibodies to HLA antigens decreased during the last trimester of pregnancy,69 and the incidence of anti-HLA antibodies increased with the number of pregnancies.167 In a study of 851 full-term pregnancies, cytotoxic antibodies were present at delivery in 25 of 272 (9.2%) of first pregnancies, 53 of 367 (14.4%) of second pregnancies, and 56 of 212 (26.4%) of third pregnancies.167 In all these pregnancies, the titer of the anti-HLA-A antibodies was approximately the same as that of the anti-HLA-B antibodies, and ABO compatibility did not influence the incidence or titer of the anti-HLA antibodies. These antibodies could also be eluted from the placenta in the cases in which the fetus had the appropriate HLA antigens; in these cases there was no antibody circulating in the fetus. When the fetus lacked the HLA antigens, the antibodies were found in the fetal circulation but not in the placenta. A subsequent study 667 confirmed these results.

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The specificities of the anti-HLA antibodies were explored in detail in the serum of a woman who had had six pregnancies.211 Her serum inhibited both responder and stimulator cells, and the antibodies inhibited the HLA specificities which her husband had and which she lacked. The inhibition could be removed by absorption of the anti-HLA antibodies. This study led to the conclusions that the inhibition was due to the antiHLA antibodies or to antibodies against antigens in tight linkage disequilibrium with the HLA antigens (possibly associated with the MLR) and that inhibition was effective against the appropriate stimulator or responder cells. The anti-HLA antibodies formed in the mother apparently cross the placenta and react with the fetal lymphocytes to mask the paternal HLA determinants on these cells.169 Quantitative studies on the HLA determinants showed that the amount of such determinants of maternal origin was approximately the same as that on maternal cells, whereas those of paternal origin were decreased 30 to 90% compared with the paternal cells. The masking of the paternal HLA antigen was due to a blocking factor in maternal serum, presumably the antibody against the paternal HLA antigens. The role of antibodies against HLA determinants in the induction of fetal disease has been the subject of several studies. Jenkins et al 311 found a reduced incidence of antibodies to paternal HLA antigens in females with severe toxemia in a study which involved 140 toxemic patients and 144 normal controls. Harris and Lordon 257 reported that an increased lymphocytotoxic antibody response was associated with increased complications in the offspring: there were congenital complications in 39.3% of the neonates of 28 mothers who had lymphocytotoxic antibodies, whereas there were complications in only 19% of the offspring of 101 mothers without antibodies. Terasaki et al 652 studied 574 pregnant females and found that 54.7% had circulating antibody to paternal HLA antigens. There was an increased incidence of congenital abnormalities in the offspring of these women compared with women who did not have antibodies: 10.2% (33 of 322) in antibody-positive women compared with 3.2% (8 of 252) in antibody-negative women. Finally, Carandina et al 117 found that anti-HLA antibodies may play a role in some cases of neonatal

jaundice. The second major class of antibodies that have been identified in pregnant women are those directed against placental antigens. Using the macrophage migration inhibition technique to study the development of maternal cell-mediated immunity to placental antigens, Youtananukorn and Matangkasombut732 showed that the lymphocytes of 41 of 41 postpartum women reacted to a pool of placental antigens from five placentas.

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The lymphocytes from each woman also reacted with antigens specifically extracted from her placenta. Of 17 serums from nonpregnant women, none reacted against the pooled placental antigens of any of the individual placental antigens. The autologous plasma of a pregnant woman blocked the reaction of her lymphocytes with antigens extracted from her placenta, but it did not block the reaction of her lymphocytes to PPD.733 In the course of the first pregnancy, the development of maternal cellmediated immunity to placental antigens could not be demonstrated during the first trimester.734 In the fourth month, 7 of 8 women reacted against placental antigens, and by the fifth month 8 of 8 women were reactive; the degree of reactivity increased during the rest of the pregnancy. A third type of antibody has been found in the serums of pregnant women: it is directed against B-cell alloantigens which are analogous to the Ia antigens in the mouse and in the rat.717 The pregnancy serums were collected at delivery and reacted exclusively with B lymphocytes and monocytes by immunofluorescence and by cytotoxicity. In addition to an antibody response to pregnancy, there is a clearly defined cell-mediated immune response to pregnancy as determined by the cytotoxicity of maternal cells for cultured fetal cells,650'661 the mixed lymphocyte reaction,94"192'277 and the leukocyte migration test 641 between the mother and her offspring. The first detectable reaction occurs shortly after the 14th week of gestation, and then the cell-mediated immune reactivity increases during gestation when judged by cytotoxicity of maternal lymphocytes for trophoblastic cells 650 and by cytotoxicity for semiallogeneic fetal lung cells.66' In the latter study, 0 of 6 (0%) maternal cells were reactive at 8 to 14 weeks, 7 of 12 (58%) were reactive at 15 to 17 weeks, and 7 of 8 (88%) were reactive at 19 to 23 weeks. In addition, the maternal serum contained a factor which could block the cellular reactions. There are conflicting reports about the relative proportions of T and B cells during pregnancy. Strelkauskas et al 634 found an inversion of the T: B cell ratio due to an increase in T cells and a decrease in B cells beginning approximately 3 weeks after conception and returning to normal by 21 weeks. Scott and Feldbush,570 however, failed to confirm these findings, since there was essentially no change in the T: B cell ratio during pregnancy. A more systematic study using a large patient population and a variety of immunochemical techniques to clearly identify T and B cells is needed to resolve this controversy. The mixed lymphocyte response during pregnancy may be influenced by genetic factors in addition to the presence of inhibitory substances in the maternal serum. The two-way mixed lymphocyte reaction between a

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mother and her offspring was decreased compared with the reaction between the mother and an unrelated third party, and the reactivity of parental lymphocytes with those of older children was also decreased compared with the response of the parental cells to an unrelated person.192 Studies with the one-way mixed lymphocyte culture gave conflicting results. Finn et al192 did not find any effect on the reaction between the cells of a mother and her offspring and concluded that the depressed reaction seen in a two-way culture required the viability of the cells from both parent and offspring. In contrast, Bonnard and Lemos 94 showed that the magnitude of the one-way mixed lymphocyte reaction decreased in following order: mother against offspring > father against offspring > unrelated person against the offspring = reaction between two unrelated people. They also showed that the maternal lymphocytes became cytotoxic after the one-way mixed lymphocyte reaction with newborn lymphocytes and did so to approximately the same extent as lymphocytes from an unrelated adult. The evidence clearly points to a genetic effect in the reactivity between the cells of parent and offspring, but the quantitative details of this reaction are still unclear. There are two other interesting genetic aspects to maternal-fetal disparities: First, a correlation between HLA and the incidence of abortions has been reported.350 In a study of 79 couples with repeated abortions or with hydatidiform moles, a significantly higher frequency of common HLA antigens was found in both members compared with controls. lThe possibility was raised that a higher incidence of abortions may occur when the fetus is homozygous for certain HLA antigens. Second, there is apparently a relationship between the ABO blood groups and trophoblastic neoplasia.32 In a review of 260 cases, the risk of choriocarcinoma developing after any form of pregnancy was related to the ABO groups of both the woman and her husband. Women of Group A married to males of Group 0 seem to be at the highest risk, whereas the risk in Group A women married to Group A males was the lowest. The spontaneous regression of the trophoblast after the evacuation of hydatidiform moles occurred most frequently in women mated to males of their own ABO genotype. Group AB patients tended to have rapidly progressive choriocarcinomas, and the tumors did not respond well to chemotherapy. Thus, genetic factors may strongly affect the development of choriocarcinoma and its response to therapy. Studies in Animals

The presence of both a humoral and cellular immune response in pregnancy has been shown in animals; most studies have been performed

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in mice and rats. The antibodies are predominantly hemagglutinating,278325 leukoagglutinating,430 and cytotoxic."19 The cell-mediated immune response to paternal H-2 antigens has been demonstrated by skin grafting and by a graft-versus-host response 403,600 and by cluster formation of maternal lymphocytes with paternal red blood cells.33 The graftversus-host reaction can occur across both H-2 and non-H-2 barriers.33 Lymphocytes sensitized during pregnancy are also cytotoxic to embryonic antigens 251 and to tumor cells 269,270; the latter reaction can be blocked by autologous serum. Immune complexes have also been demonstrated in the renal glomeruli during pregnancy: their amounts increase with successive pregnancies and do not decrease after the termination of the pregnancy.675 These complexes were not found in pseudopregnant females. Although most of the studies showed an immune response directed at the antigens of the major histocompatibility complex, other antigens are probably also involved in eliciting the immune response to pregnancy. They are probably specific embryonic antigens, since both the cell-mediated immune response 269 and the accumulation of immune complexes 675 were found during syngeneic pregnancies. A number of immunization procedures can prevent or terminate pregnancy. Abortion can be induced by antitrophoblast antiserum in rats.53 Immunization against syngeneic sarcoma or syngeneic embryos significantly decreased the number of successful pregnancies and the litter size after the first matings in mice, but it apparently did not have a significant effect on the second pregnancy.375 Both antiplatelet 207 and antithymocyte serums, but not antilymphocyte serum,246 can markedly reduce or completely ablate pregnancy in mice and rats. Finally, immunologic rejection has been postulated as a potential mechanism in spontaneous abortion.341 Thus, the evidence indicates that an immune response against certain components of the placenta or the embryo or against components of the immune and clotting systems can markedly decrease the success of pregnancy. The physiologic consequences of the immune response to pregnancy have been the subject of much experimentation and debate. In addition to the humoral and cellular responses discussed above, the immune response to pregnancy has also been defined morphologically by the enlargement of the lymph nodes draining the uterus; by the proliferation of blast cells, particularly among the thymus-derived populations 50,55,70,71,74,75, 111,271,403,501,566,609; and by the large numbers of plasma cells in the medullary cords.402 415'587 Similar evidence was obtained from ova transfer experiments which showed that the weights of the fetoplacental units in DA and (DA X F344)F1 hybrids developed in the uteri of (F344 X DA)F1 hybrid

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females were similar.55 An increase in the size of the paraaortic lymph nodes during allogeneic pregnancies has been observed in rats 71,241,414,452,566 rabbits,414 mice,414 hamsters,50'71 and humans,71 whereas it was not seen in the presence of syngeneic fetuses. Since allogeneic pregnancies result in larger litters and larger mean weight of the offspring,50'52'76'309'343 the suggestion has been made that activation of the immune system of the mother brings about beneficial conditions for implantation and intrauterine development of the fetuses. The corollary of this proposition is that abrogation of the mother's capacity to mount an immune response by the removal of the lymph nodes involved should lead to loss of the advantage that allogeneic fetuses have over syngeneic fetuses. Tofoski and Gill 664 showed that a cell-mediated immune response, as measured by the production of migration inhibitory factor (MIF), occurred during allogeneic pregnancies but not during syngeneic ones. The results support the proposition that the lymph nodes draining the uterus participate in providing a selective advantage to histoincompatible fetuses in terms of the number of concepti implanted and sustained to term: removal of the regional lymph nodes is followed by a decreased cellmediated immune response (decreased MIF production), by a significant decrease in litter size, and by uneven fetal development, as shown by an increase in the variance of the weights of individual offspring. The mean weights of the offspring were not affected, and they were different from those previously reported by Beer et al 52 because they were measured after birth rather than at 18 days of gestation. The genetic control of the MIF response to pregnancy in the rat appears to lie in the A region of the MHC, since mating combinations that differed only at the A region resulted in MIF production, whereas those that differed only in the B region did not. 220a In contrast, all other immune response linked to the MHC that have been studied in detail are controlled by the B region.216 This finding suggests that the genetic control of the immune response to pregnancy may differ significantly from the control of those responses that are primarily host defense functions and that the maternal-fetal immunologic interface may elicit a unique type of response to the fetal antigens. Based on the evidence presented above, the proposal has been advanced that the genetic disparity between the fetus and the mother affords the fetus a selective advantage over genetically compatible fetuses in terms of the number of concepti that implant and survive to term and the weight of the offspring produced.52'343 There is a contradictory school of thought,96133"190'279-283'410'411 however, which states that all of the advan-

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tages of the hybrid fetus are due to heterosis and not to an activation of the immune response. The length of gestation has been reported to vary inversely with litter size.69'413 McLaren and Michie 413 concluded that the effect of litter size on gestational length reflected the total mass of fetal tissue, and ova transfer experiments in rats 537 led to the same conclusion. This effect was not seen in other experiments,664 however, which indicated that the immune response to the fetus plays the crucial role in the number of fetuses implanted and in their individual weights. The production of MIF parallels the course of gestation, reaching a maximum at parturition and then rapidly decreasing.664 Removal of the spleen did not affect the ability of the mother to respond to her genetically alien fetuses, but removal of the paraaortic and renal lymph nodes markedly did. These data provide functional evidence for a continued cell-mediated immune response during pregnancy. Whatever role this response plays in pregnancy, it is not necessary for the induction or maintenance of pregnancy, because no significant amount of MIF is produced during homozygous pregnancies. Since MIF production following the removal of the regional lymph nodes did not completely disappear, the alien fetus must be stimulating lymph nodes other than those in the immediate vicinity of the uterus. This hypothesis is compatible with the intricate system of lymphatic drainage which has a variety of by-pass systems. 660,664 Although pregnancy can occur in the absence of an immune response, ie, in the derivation of inbred strains, this situation is a biologically special case and probably represents a maximal stress on the reproductive mechanism. There are several reasons for this: First, in the initial selection of rats or mice for inbreeding from wild populations, a large number of mating pairs are unable to adapt to breeding in the laboratory; these animals are removed from the study.537 Thereafter, it is common to select animals on the basis of their reproductive performance,240'537 and this procedure introduces a continuing selective process. Second, the development and maintenance of inbred strains is frequently difficult or impossible because of reduction in litter size and in viability of the offspring due to adverse genetic or environmental effects on the various components of the reproductive cycle. In some strains of inbred rats 145 and mice,354'394'405'406 the reduction in litter size is due to postimplantation losses. Another potent reducer of litter size and source of inherited partial sterility is chromosomal aberration.678702 Third, in the course of inbreeding, many of the females develop polycystic ovaries or a uterine environment unconducive to implantation either by normal fertilization or by ova transplantation.2531'

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Fourth, the mother can have difficulty with lactation and not be able to nurse beyond the first few days after delivery.253a,219a Finally, there are also defects in the male, such as loss of libido, which contribute to the difficulties of inbreeding.219a Similar findings have been reported in attempts to inbreed rabbits. 99,128,252,253a,662 The process of implantation follows the interaction of the fertilized ovum and the endometrium; it includes ovular maturation, endometrial receptivity, and tubal transport. Experiments with the transfer of ova have shown that asynchrony in the process of implantation affords the concepti initial developmental advantages that can be maintained throughout pregnancy. For example, in mice at Day 18 of gestation, concepti which arose from ova that were 1 day overdeveloped weighed approximately 23% more than those of normally aged ova.477 However, the advantage obtained from the overdeveloped ovum may be offset by a compensatory shortening of the length of pregnancy.401 Gates et al 209 reported that by the time ova in the same litter of inbred strains of mice reached the uterus, there was a spread in development of approximately 24 hours among them. Hybrid ova have a much narrower developmental spread than do the ova of inbred strains; therefore, the variances in the weights of individual offspring are smaller.209 The immune response to the paternal histocompatibility antigens of the fetus, particularly in the regional lymph nodes, may affect the time at which the ova implant or the state of the endometrium when they implant. Thus, this aspect of the selective advantage ascribed to heterosis may have an important immunologic component. A number of investigators have tried to explore the role of the immune response to pregnancy by using the immunized female as a model for heterozygous pregnancies and the tolerant female as a model for homozygous pregnancies. The evidence that immunization can affect reproductive capacity in this setting is conflicting. James 308,309 showed in mice that there was increased growth in the fetuses of immunized mothers and that the mothers delivered earlier. Other studies in the mouse, however, showed that immunization either had no effect or was detrimental since it decreased the litter size, placental weight, or fetal weight. 104"133'281'283 Beer and Billingham 50 found that isologous tail grafts, vaginal skin grafts, and viable epidermal cells could implant in the uteri of rats provided that a state of estrogen excess was established at transplantation. In the absence of estrogen, most of the grafts failed to implant. Shaikh 579 also found that isografts were accepted when transplanted into the uterus 4 to 5 days after mating; this time coincides with the endogenous surge of estrogen in the blood. Once established, the grafts survived indefinitely without further estrogen treatment. If a continual estrous is established, the skin epi-

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dermis can migrate from the graft and invade the uterine epithelium. Thus, the endocrinologic parameters for the establishment of a skin graft in the uterus are similar to those for the implantation of blastocysts. Beer and Billingham 5 and Beer et al 54 demonstrated in the rat that the uterus is immunologically autonomous and that immunologic memory cells can develop and persist in the uterus after initial exposure to antigen. Intrauterine sensitization with allogeneic skin grafts or cells led to a secondary response, a "recall flair," following local challenge with cells of the same antigenic specificity. The reaction did not occur if the cell challenge was given in extrauterine sites. They also reported that more embryos developed in the uterine horn sensitized against paternal antigens than in the unsensitized horn. The studies investigating the effect of tolerance on pregnancy are equally conflicting. Some experiments in the mouse showed that tolerance led to decreased fetal growth and placental weight,308'309 whereas others showed that the development of runt disease made it difficult to make these kinds of measurements accurately.133 Studies in the mouse and the rat showed that the induction of tolerance generally decreased the immune response in the paraaortic lymph nodes.50'53 Breyere,'03 however, obtained conflicting results depending on, for example, the parity of the animal and previous sensitization. Thus, the studies on immunized and tolerant animals did not lead to an unequivocal conclusion concerning the effect of the immune response on pregnancy. One of the hypotheses purported to explain the maintenance of histoincompatibility is that the polymorphism may confer a selective advantage on the progeny.134'296'343'704 This idea is predicated on the assumption that the immune response elicited in an allogeneic pregnancy is beneficial for reproductive capacity. The evidence from studies of allogeneic and syngeneic pregnancies supports this conclusion, although the studies on immunization and induction of tolerance in the pregnant female are inconclusive. Michie and Anderson 424 found that after 72 generation of brother X sister matings in the A2 strain of Wistar rats, approximately half the skin grafts transplanted between members of the strain were rejected in approximately 2 weeks. Attempts to breed brother X sister pairs that had successfully accepted skin grafts from each other were not successful. In successive generations, the frequency of two-way graft acceptance remained approximately 50%. The authors postulated a powerful genetic stabilizing mechanism capable of holding the genotypic proportions in the population constant in the face of intensive selection. The mechanism apparently involved, among other things, maintenance of heterozygosis at histocompatibility loci, which may have been due to natural selection

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against homozygous individuals. This putative genetic locus was subsequently called "Ag-E." "I These studies were not pursued or repeated; hence, the basis of this effect still remains problematic. Hull 297 studied the effect of fetal compatibility with the mother on the genotypic proportions of fetuses born. He studied a cross between the C3H and Hg strains of mice, both of which had been brother X sister mated for at least 35 generations. The C3H mice carried the non-agouti allele a, and the Hg mice carried the black and tan allele af. A diallele cross was performed using females of the a/a, a/al, and af/af genotypes mated with each of the three kinds of males. The backcross matings produced offspring whose genotypic ratio deviated significantly from the expected 1: 1; the F2 hybrids produced offspring whose proportions differed significantly from the 1:2: 1 ratio. This deviation was due to the lack of offspring of the same genotype as the mother and not to decreased fitness of a particular genotype; therefore, a deleterious effect due to the specific interaction between the mother and her offspring was suspected. Despite variations in the ratios of homozygotes to heterozygotes, the litter sizes in all of these crosses were the same; there was no evidence of differences in fertility among females of the three genotypes as a possible cause of changes in gene frequency. No mention was made in these studies of abnormalities in the male to female ratio. A theoretic treatment of these data 298 was developed to explain the existence and stability of this polymorphism on the basis of incompatibility between the mother and a certain class of her offspring. It was tested by examining five closed populations of laboratory mice for the effect of syngeneic incompatibility on the gene frequency at the a locus. 300 The at allele was being replaced by the wild (+) allele at the a locus, as would be expected. Hull 299 investigated the effects of maternal-fetal incompatibility in another system using the H-3 histocompatibility locus, which is 10 crossover units from the a locus. In this study, C57BL females (H-3a) were crossed with heterozygous congenic males (H-3a/H-3b), and BlO. LP (H3b) females were crossed with the same males. The animals were identified by their coat color, and it was assumed that the H-3 histocompatibility markers were appropriately reflected by scoring the coat color. In both cases the proportion of homozygous offspring decreased and that of heterozygous offspring concomitantly increased; the proportion of heterozygotes increased with successive pregnancies. The male to female ratio and the litter sizes were not significantly affected. In the H-3b cross, the proportion of heterozygotes was greater among the males than among females. In neither of the two types of crosses studied by Hull was there

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any evidence of incompatibility between a heterozygous mother and her offspring: the ratio of homozygous to heterozygous offspring, male to female ratio, and litter sizes were all normal. Palm 492,494 studied a similar situation in rats. She found an excess of heterozygous offspring in six mating combinations in which the mother was an inbred strain and the father was an Fl hybrid. There were no differences in the number of heterozygous and homozygous offspring in the same six mating combinations when the Fl hybrid was the mother and the inbred animal was the father. The most extensively studied strain combinations were BN X (BN X DA)F1 and DA X (BN X DA)F1 (maternal strain first and paternal strain second). There was a deficiency in the number of males in these mating combinations; hence, there was distortion of the male to female ratio. The excess of heterozygous offspring was most prominent among male progeny, and the number of heterozygotes and homozygotes was the same in the female progeny. These effects seemed to be especially marked among the offspring of DA mothers, but the results from several studies varied in their quantitative aspects. In reciprocal matings in which the Fl hybrid was the mother and the inbred strain was the father, the offspring had normal sex ratios, and the number of heterozygotes and homozygotes was the same in both males and females. When the mortality of the offspring in these two mating combinations was examined, the percentage of survival to 30 days was found to be markedly affected in both combinations. In the BN X (BN X DA)F1 combination, 80% of the offspring survived, whereas 35% of the reciprocal mating combination survived. In the DA x (BN X DA)F1 combination, 34% of the offspring survived, and in the reciprocal combination 42% survived. The mortality was higher and occurred earlier in each successive pregnancy. Death among the offspring of Fl mothers was acute (8 to 14 days); death among the offspring of inbred mothers was more gradual (several weeks) and followed general debilitation and runting reminiscent of a graft-versus-host reaction. The mortality was higher among the runts, death occurred mostly in homozygotes, and males predominated in the group that died. All animals surviving to 60 days, whether they were normal or runts, lived a normal lifespan thereafter. Palm postulated that the mechanism leading to the excess of Ag-B heterozygotes was due to postnatal loss of homozygotes secondary to wasting (graft-versus-host disease). At times of "general high mortality" in the colony, all runts died and the differences in survival were most dramatic. At times of "general low mortality" in the colony, many of the runts survived and the differences in mortality rate were discerned only by

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careful examination of the animals in the postnatal and postweaning period. The mechanism by which this effect occurred was postulated to be the transfer of cells from the mother to the fetus during gestation, and the data raised the possibility that non-Ag-B antigens were involved in causing the disease, If this were the case, the Ag-B incompatibility would then protect the heterozygotes against a non-Ag-B incompatible reaction much in the same way that an ABO incompatibility protects against the induction of Rh disease in humans. Thus, studies in the mouse 296,298-300 and in the rat 492,494 showed that incompatibility between mother and offspring led to an alteration in the survival of the offspring. At this stage, it appears as if the mechanism operative in the mouse may be somewhat different from that in the rat, but the effect of genetic incompatibilities on postnatal survival seems clear. The H-Y antigen elicits an immune response in the female, which may play a role in reproduction. In the mouse, it may have a stimulating effect on placental growth and be important in the determination of sex ratio, even in inbred strains.208 It is present on virtually all tissues and first appears in the 11-day-old mouse embryo. The expressivity of H-Y is strongly influenced by the genetic background and by male sex hormones. The H-Y antigen is involved in sex determination and in male gonadal differentiation, which, evidently, is a specific function of the plasma membrane antigen.480'699 Treatment of sperm with anti-H-Y antibody in experimental animals can affect the sex ratio by decreasing the proportion of males born.63 Reactivity of Maternal and Fetal Lymphocytes The Ontogeny of the Immune Response

The ability of the host to synthesize the humoral and cellular components of the immune response develops sequentially, and there is interaction between the immune system of the host and the mother due to the passage of the immunoglobulins across the placenta. 01,131"143174223 359,426,622 The ability to deal with specific antigens develops sequentially in many species, as discussed below. The major events of immunologic development, eg, immunoglobulin production, transplant rejection, and delayed hypersensitivity, appear to develop in a synchronous fashion among a wide variety of species. By normalizing the time of development of these various functions to the gestational period of the species, Solomon has evolved an age equivalence theory which suggests that all of these events occur at the same relative time among a wide variety of spe-

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FACTORS INFLUENCING REPRODUCTION

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cies.607608 The sequence of development of the immunocompetence in several species is summarized in Table 1. The mouse develops the ability to produce antibody at approximately the 17th day of gestation.592 The time of appearance of the cells which can react with different antigens varies, and the number of such antigen reactive cells is different for various antigens; both of these parameters differ in different species (Table 2). Studies with inbred mice showed that T-cell function is present in utero and gradually increases with age.450 Similar studies showed that the stem cells for B lymphocytes are probably identical to, or closely related to, the splenic colony-forming unit or hemopoietic stem cell. This stem cell appears not to be specifically restricted, and it lacks immunoglobulin surface markers. As these cells mature, they acquire surface markers (Ig).115'116'210'427'439'582 The number of cells reactive to a given antigen varies among inbred strains, eg, there are approximately 4-fold more antigen reactive precursors in CBA mice than in BALB/c mice (Table 2). Nonetheless, the proportion of antigen-reactive cells is the same in each individual of a given strain. In contrast, the proportion of cells binding a given antigen varies among individuals in the random-bred Swiss L mice. The ratio of antigen-binding cells for any two antigens is the same in all mice, however. Thus, there appear to be two independent genetic systems which regulate the production of antiTable 1-Sequential Development of Immunocompetence in Several Species Lamb*

Bacteriophage OX1 74 Ferritin Q fever vaccine Allogeneic grafts Snail hemocyanin SV-40 virus Bacteriophage T4 DNP Arsanilate Ovalbumin Bluetongue virus LCM virus -birthDiptheria toxoid Salmonella typhosa 0 antigen BCG *

Mouse (BALB/c)t

Opossum$

BacteriophagePX174

Bacteriophage F2

Bacteriophage F2 DNP§

Bacteriophage T4 DNP-BSA Fluorescein-BSA Lysozyme

Fluorescein§

BacteriophagekX174 Bacteriophage T4 Ribonuclease

Ribonuclease Myoglobin

See Reference 592.

t The AKR strain is the same except for myoglobulin. See Reference 583. $ See Reference 541. § Carriers were bovine serum albumin (BSA), hemocyanin, and bovineY-globulin.

480

GILL AND REPETTI

a1D C. 5 D 5

American Journal of Pathology

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12-16 5-33% in cord blood 14% + (3.5% + in adult) 9.7% + 9.5 7.9% + 9.5 2% + 11.5 Thymocytes have SRBC recep12 (thymus) tors and thymus-specific 14-15 (peripheral antigens when first detected lymphoid tissue) 10-1 2 (thymus) 13-14 (spleen, PBL) 7.5 (liver cell) 12.5 (thymus) 12 (spleen) 18 (thymus) 18.2/106 in fetus 6/10' in child 0.5/105 in adult Cord blood < adult Cord blood > adult

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lymphocytes is increased, decreased, or the same compared with that of adult cells. There may be a dose dependence in the response to PHA such that the stimulation of fetal lymphocytes compared with that of adult lymphocytes may depend on the dose of PHA.122 Following nonspecific mitogen stimulation, there appears to be an earlier onset of DNA synthesis in fetal lymphocytes than in adult lymphocytes.731 A variety of studies in humans and in mice indicate that fetal lymphocytes produce a soluble substance that inhibits both the PHA response and the mixed lymphocyte reactivity of adult lymphocytes. This substance

Vol. 95, No. 2 May 1979

FACTORS INFLUENCING REPRODUCTION

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appears to act on T cells during the induction of the immune response, since it can block T-dependent primary immune responses but not Tindependent responses.392 Fetal lymphocytes express determinants which stimulate the mixed lymphocyte reaction in adult cells, and they respond better in alloantigenic mixed lymphocyte reactions than in xenogeneic reactions. Fetal lymphocytes are capable of causing cell-mediated lympholysis (CML). They can react to a variety of antigens, depending on their stage of embryologic development, but their reactions are generally reduced compared with those of adult cells. Thus, the studies on fetal lymphocytes indicate two clear findings: they can inhibit the MLR and PHA responses of adult cells, probably by elaborating a soluble inhibitory substance, and they can react to a variety of antigenic stimuli but at a reduced level. Regulation by Passively Transferred Antibodies

Macromolecules, including IgG immunoglobulin, pass from mother to fetus; the magnitude of this passage differs with the different types of placentas (Table 6). There are three general mechanisms regulating the transport of molecules across the placenta, which show varying degrees of selectivity. 223263'558'721'722 First, transport can be accomplished by a firstorder process which is related to the molecular weight of the protein. Table 4-Effect of Pregnancy on the Immunologic Responsiveness of Maternal Lymphocytes

Immunologic stimulant

Effect of pregnancy*

Species

PHA

Human

Decrease No effectt

MLR§

Mouse Human

Decreaset

PFCII

Mouse Mouse

Other Skin graft PPD reactivity

Decrease No effect Decrease Decrease Increase

85,659,666 81,123,348, 371,516,735 547 508,521,659 81, 124, 126, 141,368, 371 180,250 552 180,301,336

Longer survival Decrease Decrease No effect

14 811,601 649 114

Human

Cytotoxicity to HLA T-cell rosetting *

References

Cells in neutral, eg, normal adult AB plasma

t One study'23 showed changes in kinetics of PHA stimulation, but not in the magnitude of

the response. t In midgestation only § Alloantigenic stimulus 1 To sheep red blood cells 1¶ During second half of pregnancy only

American Journal of Pathology

GILL AND REPETTI

484

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Vol. 95, No. 2 May 1979

FACTORS INFLUENCING REPRODUCTION

485

Table 6-The Passage of Antibodies in Animals With Different Types of Placentas* Transmission of maternal antibodies Prenatal Animal

Type of placenta Amount

Horse, pig, cow

Epitheliochorial

Sheep

Syndesmochorial

Dog, cat Mouse, rat Rabbit, guinea pig Human, monkey

Endotheliochorial Hemochorial Hemochorial Hemochorial

*

0 0 + + +++ +++

Route

Postnatal (via the milk) Amount Route +++ +++

Unknown Yolk sac Yolk sac Placenta

++ ++

Gut Gut Gut Gut

Duration (days) 1-1.5 1 1-2 16-20

0 0

Adapted from Reference 101

Diffusion may be involved in this type of transport, but other mechanisms could also give the same results. Examples of proteins which are transported across the placenta via this mechanism are as follows: a,-acid glycoprotein, albumin, transferrin, fibrinogen, and IgM. Second, active transport can regulate selective permeability via specific receptors on the placenta. The major protein transported by this mechanism is IgG. In addition to regulating the total IgG concentration, this mechanism appears to influence selectively the concentration of specific antibodies. For example, the fall in total immunoglobulin transported from the mother is not necessarily the same as the fall in the specific antibodies, eg, diphtheria antitoxin,112 and the titers of specific antibodies in the fetus are not necessarily the same as those in the mother.149 Pathogenic antibodies are also transported, since the fetus may transiently display a maternal disease in which an immunoglobulin or other macromolecule is the pathogenic agent.667,6f68 Third, the placenta appears to be an impermeable barrier to some molecules, eg, HCG and human insulin, during the early period of gestation. Studies on transplacental transport have left many questions unanswered. For example, why do some large macromolecules such as fibrinogen and IgG easily pass the placenta while small molecules, eg, HCG, do not? The difference in permeability to IgG immunoglobulin and to specific antibodies is difficult to explain on the basis of any known mechanism. There is also the unresolved question of directional transport: the permeability of the placenta to a protein need not be the same in both directions, eg, IgG at term appears to travel in greater quantities from the mother to the fetus than in the other direction. The transplacental passage of antibodies from the mother is involved in the passive regulation of antibody synthesis by the fetus. First, the trans-

486

GILL AND REPETTI

American Journal of Pathology

placental passage of the maternal antibody in many species depresses the antibody response of the fetus to immunization well into the neonatal period; this suppression is antigen-specific.101'608,'680 The mechanism by which the maternal antibody passively suppresses the immune response may involve the B cells. Antibody to TNP-SRBC suppresses the response to SRBC but not to the TNP 465; hence, T-cell function appears to be intact, suggesting that the defect is in the B cell. Allotype suppression induced in a maternal-fetal situation can be broken in vitro by B-cell mitogens.93 Second, allotype suppression is an important example of regulation by antibody.5168 307'400'690'705 For example, rabbits with the a2a2 allotype that were reared in the uteri of a'a' mothers exhibited suppressed svnthesis of a2a2 immunoglobulins due to an immune response by the mother against the a2a2 allotype of her artificially implanted offspring. Third, suppression by passive antireceptor (anti-idiotype) antibodies may be an important way of regulating the immune response.2,79,349,512,633,710 The antireceptor antibody, made against the receptor site on another antibody, can regulate concentration of this antibody possibly by reacting with it and removing it from the circulation. The possibility of this being an important regulatory mechanism in a maternalfetal situation has not been explored. Fourth, the presence of antibody can also increase the immune response. Enhancement of fetal immune responses by passively acquired maternal antibodies has been reported in mice 553 and in humans,379 and the passive administration of antigens and their antibodies has been reported to increase the antibody response in chickens,404 mice,654707 and guinea pigs.514 The enhancement of the antibody response to one set of antigenic determinants may follow the reaction of the passively administered antibody with another set of determinants on the antigen in which the complex acts as an adjuvant to increase the response to the unreacted antigenic determinant.404 Thus, antibodies which reach the fetus from the mother either suppress or enhance the fetal antibody response specifically. The mechanism by which these effects occur is not clearly understood, so it is not possible to predict a priori what immunization of the mother against any particular antigen will do to her offspring's immune response to that antigen. Transplacental Sensitization Mutual Sensitization of Mother and Offspring

A variety of studies have been done in humans and in animals to determine whether the sensitizations possessed by the mother are trans-

Vol. 95, No. 2 May 1979

FACTORS INFLUENCING REPRODUCTION

487

mitted to the fetus.'47'214 The studies in humans are summarized in Table 7: most of them have only small numbers and do not have the appropriate control populations. In addition, using the stimulation index as the assay method for lymphocyte transformation, especially when the positive responses are only slightly above the control level, is hazardous, because the fluctuations in the responses of control lymphocytes from normal populations can significantly alter the stimulation ratio.164'238'488 Even at that, most of these studies do not show a correlation between positive reactivity in the offspring and positive reactivity in the mother. In the one study in which a large population was investigated,314 only 5 offspring of 1102 tuberculin-positive mothers were tuberculin-positive, and this reactivity disappeared in 4 of the 5 within several months after delivery. The significance of this finding, particularly since there was no control population, is difficult to evaluate. Many studies on the environmental exposure to antigens, in which the fetus may be exposed to naturally occurring antigens via the mother, showed variable results, generally because of the small numbers reported (Table 7). In one study in which 70 patients were examined,290 the average immune responsiveness to dental plaque of offspring from mothers with and without periodontal disease was measured. Although an analysis of the mean incidence of responsiveness indicated a difference at the P < 0.05 level, there were 38 concordant results, in which both offspring and mother were positive or negative, and 32 discordant results. A clear picture would have been obtained by analyzing the data for each maternal-fetal pair using the paired t test. In addition, most of the lymphocyte stimulation ratios were marginal: 3 to 5, where > 3 was significant. In a large clinical study, Gill and his colleagues 222,256 investigated a population of 107 maternal-fetal pairs and analyzed the data by cross-classification techniques. They found no significant correlation between maternal and fetal sensitivity as determined by lymphocyte stimulation by antigens (candida, mumps, varicella, SKSD, and tetanus). Hence, the exposure of women to antigens under natural circumstances has no effect on the responsiveness of their offspring to these antigens. In the studies on active immunization, the one study in which a pregnant woman was immunized showed that there was a positive response to the antigen in her offspring. In cases in which the pregnant mother was actively infected, a relatively high proportion of the offspring was sensitized to the appropriate antigens. The populations involved in these studies, however, were small, and appropriate control populations were lacking (Table 7). Thus, although these data are suggestive of an active transfer of sensitization from mother to offspring, they are not conclusive.

488

GILL AND REPETTI

American Journal of Pathology

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498

GILL AND REPETTI

American Journal of Pathology

Table 9-Tissues Separating the Fetal and Maternal Blood Maternal tissue

Classification

Fetal tissue

ConConGross Endo- nec- Epinec- Endo- morphology of the the- tive the- Tropho- tive thelium tissue lium blast tissue lium placenta

Typical examples

+ +

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cow

-

Adapted from Reference 12

role that they play in tissue matching for renal transplantation.486'487 Placental and fetal tissues express various antigens at different stages of pregnancy (Table 10), and immune responses to several of these antigens have been detected in the mother. (See Transplacental Sensitization.) In addition, a variety of proteins have been isolated from the placenta and studied chemically,91"83 but their role as antigens during pregnancy has not been explored. Experimental evidence indicates that the placenta is poorly antigenic 31,294,312,344,571651 in natural and experimental situations. Although placental preparations can elicit hypersensitivity to paternal histocompatibility antigens and placental grafts are subject to rejection, the cell types involved in these phenomena are not known. Membranes have been prepared from human placentas, and their major components are proteins and glycoproteins.18'332 The importance of the trophoblast as a barrier is shown by experiments in which treatment of the pregnant animals with hyaluronidase induced tolerance to skin homografts in their offspring, presumably by altering the permeability of the placenta and allowing the developing fetus to become tolerant to the maternal antigens.468'469 Placental cells also have the ability to transform into hematopoietic cells.'80 A great deal of discussion has centered on the putative lack of antigenicity of the trophoblastic proteins; three sets of arguments are used to substantiate this position. First, an argument is based on the notion that purified carbohydrates are poor antigens. This line of argumentation finds some support in studies showing that glycoprotein hormones such as human chorionic gonadotropin (HCG) are produced by trophoblastic cells, can adsorb to their surfaces, and can protect them from eliciting an

FACTORS INFLUENCING REPRODUCTION

Vol. 95, No. 2 May 1979

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Immunologic and genetic factors influencing reproduction. A review.

REVIEW ARTICLE IMMUNOLOGIC AND GENETIC FACTORS INFLUENCING REPRODUCTION IMMUNOLOGIC AND GENETIC FACTORS INFLUENCING REPRODUCTION Maternal Response t...
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