Pregnancy-associated immune suppression: risks and mechanisms

Microbial Pathogenesis 1987 ; 3 : 393-397

Mini-review Pregnancy-associated immune suppression : risks and mechanisms Eugene D . Weinberg* Medical Sciences Program, School of Medicine, and Department of Biology, College of Arts and Sciences, Indiana University, Bloomington . Indiana, U .S .A . Pregnant mammals are at increased risk of acquiring infectious diseases for which cell mediated immunity (CMI) is important in defense (Table I) . Apparently, maternal CMI is down-regulated to avoid immunological rejection of the fetus . The amount of depression increases with the duration of the pregnancy . Shortly after parturition, or other loss of the fetus, CMI returns to normal .' Among the various agents that might participate in pregnancy-associated depression of CMI are one or more steroid hormones and/or plasma proteins . Plasma concentrations of progesterone and estradiol increase markedly during gestation (Table 2) . Especially noteworthy is the quantity of 250-450 mg of progesterone that is formed daily by human placental tissue during the third trimester ." At term the placenta contains about 7 um of this hormone, which is 22-fold greater than the amount in maternal plasma ." Between 3 and 60 µnn progesterone can block uptake of thymidine into the lymphocyte nucleoside pool ."" Thus this hormone might induce immunosuppression more strongly in the placenta than in other tissues . Some evidence is available in support of this concept . For example, listerial growth was 100-fold greater in the '7,1e placenta than in the liver or spleen of pregnant mice and 10000-fold greater than in the liver or spleen of non-pregnant controls ." In pregnant malarial patients, placental infection is more frequent than is peripheral parasitemia . 19 Nevertheless, even in diseases in which the agents presumably do not grow in the placenta, such as leprosy, growth of the pathogen is markedly enhanced during pregnancy over that in the same patients prior to and following their pregnancy . 20 The ability of progesterone to suppress host defenses was demonstrated clearly in a study of murine herpesvirus-2 in which the hormone was injected s .c . daily in nongravid females (Table 3) . Virulence of the pathogen was similar in the hormoneinjected set to that of pregnant controls and was much enhanced over that in the nonpregnant set that received no hormone . 21 In in vitro tests, estrogens are as active as progesterones in suppression of CM1 . 22,23 Furthermore, one laboratory found that estrogens but not progesterone inhibited interleukin-2 synthesis, lymphocyte activation, and CMI defense against Listeria monocytogenes . 24 However, in maternal plasma and placenta, respectively, the quantity of estrogen is only 20% and 0 .8% that of progesterone . The quantity of cortisol in human plasma in pregnancy is 2-3-fold greater than in the non-gravid state ; the adrenal gland rather than the placenta is the major source ." 'Address reprint requests to : E . D . Weinberg, Ph .D ., Jordan Hall 142, Indiana University, Bloomington IN 47405, U .S .A . 0882-4010/87/060393+05 $03 .00/0

© 1987 Academic Press Ltd

E . D . Weinberg

39 4

Table 1 Infectious diseases for which (a) cell mediated immunity is important in s defense and (b) increased risk in pregnancy has been reported ."' Diseases caused by : DNA viruses Procaryotes

RNA viruses Acquired immunedeficiency 2 Encephalomyocarditis Hepatitis A Influenza A Junin fever Poliomyelitis

0

Burkitt's lymphoma Cytomegalovirus disease Hepatitis B Herpes simplex Papillomatous warts Varicella pneumonia 3 Variola

Eucaryotes

Chlamydial infections' Leprosy Listeriosis Pasteurellosis' Plague Systemic campylobacteriosis" Tuberculosis Typhoid fever

Amoebic dysentery Coccidioidomycosis Cysticercosis Histoplasmosis' Malaria Strongyloidosis Toxoplasmosis Trypanasomiasis

References for diseases that lack a citation number are given in ref . 1 .

Table 2 Increased concentration in plasma in human pregnancy of selected steroids and proteinslo 13 Concentration in non-pregnant (preovulatory phase) plasma'

Compound Progesterone" Estrad iol" Cortisol-unbound 10 Cortisol-total 10 Chorionic gonadotropin" N-terminal-/3-lipotrophin'" x-fetoprotein'' x 2 -pregnancy-associated macroglobulin 13

Fold increase in plasma in trimester I II III

1 1 11 303 18 IU 0 .009 PM 100

110 4 1 1,5 11 1 1

170 28 2 2 3 .5 1 7 .5

100

4

18

320 66 3 3 2 2 36 29

'Concentrations are given as Nanomolar unless otherwise indicated . Data derived from portions of Table 1 of ref . 10, Figures 1 and 2 of ref 11, Figure 1 of ref . 12, and Table 1 and Figure 1 of ref . 13 .

Table 3 Virulence of herpesvirus-2 in non-pregnant mice with and without exogenous progesterone and in pregnant mice .'' 4

Days post-infection' 8 10

6

12

14

10

10

0 12 66 26 26 88 Plasma progesterone (}inn)

88 88

mortality Non-pregnant Non-pregnant progesterone" Pregnant`

Non-pregnant Non-pregnant progesterone`' Pregnant`

0

0

0 0

0 0

0

0

0 .006

<0 .003

0 .003

0 .006

0.009

ND

0 .292 0 .079

0 .263 0 .225

0 .266 0 .048

0 .336 0 .032

ND ND

ND ND

'5x 10" TCID 50 HSV-2 inoculated intravaginally in 6-8 wk mice . '2 mg progesterone injected s .c . daily starting 6 days prior to infection mice were 6 days pregnant at time of infection (end of trimester I) . Data compiled from Figs 1 and 3 of ref . 21 . ND - not determined .



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Generally, neither unbound (0 .034 µnn) nor total (0 .924 µnn) cortisol in third trimester human plasma are sufficient to suppress in vitro or in vivo models of CMI . 22,24 However, in one in vitro study, the 50% dose of cortisol that suppressed CMI was 0 .2 ,um ; neither 2 µnn estrogen nor 30µM progesterone were active . 25 The plasma concentrations of two of the four proteins in Table 2 increase markedly as the pregnancy continues . Alpha-fetoprotein (AFP), produced in fetal liver, is a normal component of amniotic fluid and fetal serum . It passes through the placenta into maternal serum in increasing quantities in the latter two trimesters . 12 In in vitro tests, 3µM AFP induced generation of suppressor cel ls26,27 and inhibited macrophage expression of surface la antigens . 28 Alpha 2 -pregnancy-associated macroglobulin (a 2 PAG) is synthesized by maternal B lymphocytes and monocytes .29,3' During the last trimester of gestation, the plasma concentrations of AFP and a 2 -PAG are similar to the quantities needed to suppress CMI in vitro . However, neither protein has been shown to lower resistance of hosts to any of the diseases in Table 1 . A novel 85 kDa glycoprotein that suppresses in vitro transformation of human T lymphocytes at the remarkably low ED50 level of 80 picomolar has been isolated from urine of women in the latter half of gestation . 31 The protein, termed uromodulin, has no effect on B lymphocyte function . It will be of considerable interest to determine if uromodulin might suppress resistance in animal models to diseases listed in Table 1 . In a different study, a 100 kDa factor obtained from non-T decidua-associated suppressor cells was found to block the activity of interleukin-2 and to inhibit the generation of cytotoxic effector cells . 32 Inasmuch as ability to form alpha/beta interferon (IFN-a//3) is not a component of CMI, this important defense capability should remain unimpaired during pregnancy . In two studies, this indeed was true . 33,34 In a third study, however, an unusual form of acid-labile IFN-a//3 was synthesized during the third trimester by pregnant mice that had been injected with listerial cell wall antigen ." In contrast to IFN-a//3, interferon gamma is a T cell lymphokine ; thus its synthesis would be predicted to be suppressed during the latter stages of pregnancy . This prediction has been confirmed ." T lymphocytes obtained from pregnant hosts are as capable of normal response to mitogens as are T cells derived either from non-pregnant females or from males . 35 .36 To function normally in an in vitro system, the cells obtained during pregnancy must, of course, be washed free of potential suppressors of CMI mentioned above . Additionally, resuspension of the cells must be made in heterologous pooled nonpregnant plasma rather than in autologous plasma . Not surprisingly, the recent medical literature on possible methods of prevention of maternal and fetal infections due to conditions listed in Table 1 is concerned mainly with those diseases for which vaccines are not yet available and/or for which chemotherapy is not entirely safe or effective . For example, gravid women are recommended to forego travel to malarial areas during the second half of gestation . For all pregnant women who must visit or reside in a malarial region, continuous chemoprophylaxis is advised provided that the protozoan strains are susceptible to drugs that can be used safely during gestation .' 1,3' To reduce transmission of cytomegalovirus (CMV) to the 15-50% of pregnant women who are not immune, only CMV-seronegative blood should be used in transfusions of seronegative mothers, of their fetuses, and of their infants . 38 ' 39 Also recommended are scrupulous hand-washing by health and child care personnel after each contact with urine and respiratory tract or other potentially infectious secretions, and careful disposal of articles contaminated with these secretions .40 42 Antibody mediated immunity (AMI) remains intact during gestation . Thus improved prevention of infectious diseases due to pregnancy-associated CMI depression will,



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in many cases, include development and use of vaccines that stimulate AMI toward the potential pathogens .

Valuable bibliographic assistance was provided by Deborah Lynn Stanley .

References 1 . Weinberg ED . Pregnancy associated depression of cell mediated immunity . Rev Infect Dis 1984, 6 . 814-31 . 2 . Brabin BJ . Epidemiology of infection in pregnancy . Rev Infect Dis 1985 ; 7 : 579-603 . 3 . Pickard RE . Varicella pneumonia in pregnancy . Am J Obstet Gynecol 1968 ; 101 : 504-8 . 4 . Kunimoto D, Brunham RC . Human immune response and Chlamydia trachomatis infection . Rev Infect Dis 1985 ; 7 : 665-73 . 5 . Heggie AD, Wyrick PB, Chase PA, Sorenson RU . Cell-mediated immune responses to Chlamydia trachomatis in mothers and infants . Proc Soc Exp Biol Med 1986; 181 : 586-95 . 6 . Johnson FWA, Matheson BA, Williams H, Laing AG, Jandial V, Davidson-Lamb R, Halliday GJ, Hobson D, Wong SY, Hadley KM, Moffat MAJ, Postlewaite R . Abortion due to infection with Chlamydia psittaci in a sheep farmer's wife . Br Med J 1985, 290 : 592-4 . 7 . Rasaiah B, Otera JG, Russell IJ, Butler-Jones DA, Prescott JF, West MM, Maxwell BE, Beaver J . Pasteurella multocida septicemia during pregnancy . Can Med Assoc J 1986 ; 135 : 1369 71 . 8 . Simor AE, Karmali MA, Jadvaji T, Roscoe M . Abortion and perinatal sepsis associated with campylobacter infection . Rev Infect Dis 1986 ; 8 : 397-402 . 9 . McGregor JA, Kleinschmidt-DeMasters BK, Ogle J . Meningoencephalitis caused by Histoplasma capsulatum complicating pregnancy . Am J Obstet Gynecol 1986 ; 154 : 925-31 . 10 . Abou-Samra AB, Pugeat M, Dechaud H, Nachury L, Bouchareb B, Fevre-Montange M, Tourniaire J . Increased plasma concentration of N-terminal ft-lipotrophin and unbound cortisol during pregnancy . Clin Endocrinol 1984 ; 20 : 221--8 . 11 . Page EW, Villee CA, Villee DB . Human Reproduction, 3rd edn . Philadelphia : WB Saunders, 1981, 231 52 . 12 . Ward AM . The clinical relevance of alpha-fetoprotein in maternal serum in pregnancy . Prot Biol Fluids 1976 ; 24 : 307-15 . 13 . Stimson WH . Variations in the serum concentration of a human pregnancy-associated a-macroglobulin during pregnancy and after delivery . J Reprod Fert 1975, 43 : 579-82 . 14 . Khan-Dawood FS, Dawood MY . Estrogen and progesterone receptor and hormone levels in human myometrium and placenta in term pregnancy . Am J Obstet Gynecol 1984, 150 : 501 --5 . 15 . Mori T, Kobayashi H, Suzuki A, Nishimura T, Mori T Inhibitory effect of progesterone and 20 zhydroxypregn-4-en-3-one on the phytohemagglutinin -induced transformation of human lymphocytes . Am J Obstet Gynecol 1977 ; 127 : 151 -7 . 16 . Clemens LE, Siiteri PK, Stites DP . Mechanism of immunosuppression of progesterone on maternal lymphocyte activation during pregnancy . J Immunol 1979 ; 122 : 1978-85 . 17 . Nakane A, Minigawa T, Yasuda I . Induction of alpha/beta interferon and gamma interferon in mice infected with Listeria monocytogenes during pregnancy . Infect Immun 1985 ; 50 : 877-80 . 18 . Redline RW, Lu CY . Role of local immunosuppression in murine fetoplacental listeriosis . J Clin Invest 1987, 79 :1234-41 . 19 . Diro M, Beydoun SN . Malaria in pregnancy . South Med J 1982, 75 : 959-63 . 20 . Duncan ME, Pearson JMH, Ridley DS, Melsom R, Bjune G . Pregnancy and leprosy : the consequences of alterations of cell-mediated and humoral immunity during pregnancy and lactation . Int J Lepr 1982, 50 :425-35 . 21 . Baker DA, Plotkin SA . Enhancement of vaginal infection in mice by herpes simplex virus type II with progesterone . Proc Soc Exp Biol Med 1978 ; 158 : 131 5 . 22 . Wyle FA, Kent JR . Immunosuppression by sex steroid hormones . Clin Exp Immunol 1977, 27 : 407 15 . 23 . Grossman CJ . Regulation of the immune system by sex steroids . Endocrine Rev 1985 ; 5 : 435 -55 . 24 . Pung OJ, Tucker AM, Vore SJ, Luster MI . Influence of estrogen on host resistance : increased susceptibility of mice to Listeria monocytogenes correlates with depressed production of interleukin-2 . Infect Immun 1985 ; 50 : 91-6 . 25 . Skinnider LF, Laxdal V . The effect of progesterone, oestrogens and hydrocortisone on the mitogenic response of lymphocytes to phytohaemagglutinin in pregnant and non-pregnant women . Br J Obstet Gynaecol 1981 ; 88 :1110-4 . 26 . Murgita RA, Goidl EA, Kontiainen S, Wigzell H . -r-Fetoprotein induces suppressor T cells in vitro Nature 1977 ; 267 : 257-9 . 27 . Toder V, Blank M, Nebel L . Immunoregulatory mechanisms in pregnancy . 1 . Evidence for the -j fetoprotein generation of suppressor cells in vitro . Transplantation 1982 ; 33 : 41 -4 . 28 . Lu CY, Changelian PS, Unanue ER . a-Fetoprotein inhibits macrophage expression of la antigen . J Immunol 1984 ; 132 : 1722-5 .



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29 . Gill TJ III . Immunity and pregnancy . CRC Crit Rev Immunol 1985; 5 : 201-27 . 30 . Horne CHW, Thomson AW, Hunter CBJ, van Heyningen V, Deane DL, Steel CM . Association between pregnancy-associated a2 -glycoprotein (a 2 -PAG) and mixed leukocyte reaction determinants on the leukocyte surface . Experientia 1979 ; 35 : 411-4 . 31 . Muchmore AV, Decker JM . Uromodulin : a unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women . Science 1985; 229 : 479-81 . 32 . Clark DA, Chaput A, Walker C, Rosenthal KL . Active suppression of host-vs-graft reaction in pregnant mice . J Immuno! 1985 ; 134 :1659-62 . 33 . Farber PA, Glasgow LA . Factors modifying host resistance to virus infection . II . Enhanced susceptibility of mice to encephalomyocarditis virus infection during pregnancy . Am J Pathol 1968; 53 : 463-81 . 34 . Evans AT, Carandang G, Quilligan EJ, Cesario TC . Interferon responses in maternal and fetal mice . Am J Obstet Gynecol 1985 ; 152 : 99-102 . 35 . Stites DP, Pavia CS, Clemens LE, Kuhn RW, Siiteri PK . Immunologic regulation in pregnancy . Arth Rheum 1979 ; 22 : 1300-7 . 36 . Hawes CS, Kemp AS, Jones WR, Need JA . A longitudinal study of cell-mediated immunity . J Reprod Immunol 1981 ; 3 :165-73 . 37 . Bruce-Chwatt U . Malaria and pregnancy . Br Med J 1983 ; 286 : 1457-8 . 38 . Yeager A . Transmission of cytomegalovirus to mothers by infected infants : another reason to prevent transfusion-acquired infections . Ped Infect Dis 1983 ; 2 : 295-7 . 39 . Adler SP . Neonatal cytomegalovirus infections due to blood . CRC Crit Rev Clin Lab Sci 1986 ; 23 : 114 . 40 . Stagno S, Whitley RJ . Herpesvirus infections of pregnancy . Part I : Cytomegalovirus and Epstein-Barr virus infections . N Engl J Med 1985 ; 313 : 1270-4 . 41 . Hatherly Ll . Prevalence of cytomegalovirus antibodies in obstetric nurses . Med J Austral 1985 ; 142 : 186-9 . 42 . Young AB, Reid D, Grist NR . Is cytomegalovirus a serious hazard to female hospital staff? The Lancet 1983 ; is 975-6 .